What ARE Turmeric and Curcumin?
Turmeric is a medicinal plant belonging to the Curcuma botanical group, which is part of the ginger family of herbs, the Zingiberaceae. The most interesting component of this plant is represented by Curcuma longa's roots; the rhizomes are boiled, dried in the sun, and crushed in order to produce a yellow-orange powder. The biologically active compound within this powder is curcumin, one of the most studied phytochemicals in science, from one of the most beneficial plants in history. Turmeric powder contains approximately 3% curcumin, which we extract to 95% purity for medical research and nutritional supplementation.

 

What are the health properties of Curcumin?
 
"Curcumin has been approved as a food additive by the World Health Organization and the US Food and Drug Administration and has been listed as a third-generation cancer chemoprevention drug by the National Cancer Institute of the United States due to its safety, non-toxicity, and lack of adverse effects." - Curcumin Targeting Non-Coding RNAs in Colorectal Cancer: Therapeutic and Biomarker Implications, Biomolecules | 2022

"Curcumin may not fit medical chemists’ definition of the perfect drug, but many in vitro, in vivo and clinical trials have irrefutably confirmed its medicinal potential. Curcumin, as a natural product with low price, has received increasing attention in recent years. Many studies have indicated that it has multiple biological activities." - Frontiers in Pharmacology | 2022

"For centuries, turmeric containing curcumin and Piper nigrum containing piperine have been used as food additives and folk medicine, including Traditional Chinese Medicine. Curcumin and piperine have been shown to interact synergistically in various preclinical pharmacological studies. Many recent studies reported synergistic effects of curcumin and piperine combination in various pharmacological models, including lung cancer, aging, and hepatocellular carcinoma. Pharmacodynamically, the combination of curcumin and piperine could simultaneously inhibit multiple sites of action in the pain pathway. The ability of curcumin and piperine to modulate diverse pathways of pain could lead to robust inhibition of pain transmission when those are coadministered." - CM Journal | 2022

"Curcumin has been selected as a third-generation cancer chemopreventive agent by the National Cancer Institute" - Effects and Mechanisms of Curcumin for the Prevention and Management of Cancers: An Updated Review | 2022

"Curcumin, the key bioactive phytochemical present in turmeric (Curcuma longa L.), is the most studied natural compound in cancer. Preclinical studies (in vitro and in vitro) and clinical trials have demonstrated curcumin's effectiveness as an anti-inflammatory agent. The existing evidence supports that curcumin inhibits the proliferation of many types of cancer cells related to the effect on different types of cancers, such as chronic myeloid leukemia, multiple myeloma, prostate, colorectal and pancreatic cancer as well as cancer therapy-related complications, including oral mucositis and radiation dermatitis." - The golden spice curcumin in cancer: A perspective on finalized clinical trials during the last 10 years, Journal of Cancer Research and Therapeutics | 2022

"Curcumin, the active ingredient of Curcuma longa L., is the most studied compound described as a potential anticancer agent due to its multi-targeted signaling/molecular pathways." - Frontiers in Pharmacology | 2022

"The development of new drugs from natural products is still challenging, and the most extensively studied plant material is turmeric, Curcuma longa, which is the chief source of curcumin. Based on the findings, it can be said that curcumin, a natural substance, has good therapeutic qualities when it is isolated." - Applied Biochemistry and Biotechnology | 2022

"Curcumin, a multi-targeted compound, has traditionally been used as a dietary spice and a medicinal herb in Asian countries for a variety of pathologies due to its anti-inflammatory properties, and antioxidant properties. Moreover, curcumin possesses antibacterial, antiviral, antifungal, anti-arthritic, hepatoprotective, anti-thrombotic, cardio-protective, hypoglycemic, anti-allergic, wound-healing, and chemo-preventive and anticancer properties. Curcumin’s anti-inflammatory and antioxidant effects, among others, form the basis of curcumin’s critical neuroprotective effects in a variety of neurological diseases affecting both the central and peripheral nervous systems. Several molecular targets of curcumin have been identified based on extensive evidence from in vitro and in vivo studies." - Neuroprotective Activities of Curcumin in Parkinson’s Disease: A Review of the Literature | 2021

"During the last decade, pharmacokinetics, pharmacodynamics and pharmacological properties of curcumin, a yellow-orange polyphenolic compound, have been extensively studied. Significant antitumor, antioxidant, antiviral, lipid-lowering, chemopreventive, hepatoprotective and neuroprotective properties of curcumin have been confirmed. Recent studies have also confirmed the pharmacological activity of curcumin as anti-inflammatory and immunomodulatory agent. Due to its pronounced anti-inflammatory activity, curcumin is considered to be a potential mediator of accelerating the healing process." - Curcumin: Natural Antimicrobial and Anti Inflammatory Agent, Journal of Pharmaceutical Research International | 2021

"We found 12,595 papers on curcumin (1924–2018) and 4738 (1983–2018) on curcumin and cancer; that means 37% of the published papers on curcumin has cancer as the major targeted disease. The therapeutic benefits of curcumin have been demonstrated in multiple chronic diseases: inflammation, arthritis, metabolic syndrome, liver disease, obesity, neurodegenerative diseases and, above all, in several cancers." - Nutrients Journal

"Curcumin (a diferuloylmethane) was found to be the most widely studied compound as evinced by more than 9000 citations in the literature, with antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, antidiabetic, antiarthritic, antiatherosclerotic, antidepressant, antiaging, antimicrobial, wound healing and memory-enhancing activities. Moreover, it exerts chemopreventive, chemosensitization and radiosensitization effects as well. In traditional Indian medicine, this spice has been also used to treat different ailments such as gynecological problems, gastric problems, hepatic disorders, infectious diseases, blood disorders, acne, psoriasis, dermatitis, rash and other chronic ailments. Diverse in vivo studies have also indicated its potential against pro-inflammatory diseases, cancers, neurodegenerative diseases, depression, diabetes, obesity and atherosclerosis. Besides its safety and tolerability, cost-effectiveness is an added advantage of this compound. To date, over 100 different clinical trials have been completed with curcumin, which clearly show its safety, tolerability and its effectiveness against various chronic diseases in humans." - British Journal of Pharmacology

"7,000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases." - Food and Chemical Toxicology Journal

"6.000 articles published within the past two decades have discussed the molecular basis for the antioxidant, anti-inflammatory, antibacterial, antiviral, antifungal, and anticancer activities assigned to this nutraceutical. Over sixty five clinical trials conducted on this molecules, have shed light on the role of curcumin in various chronic conditions, including autoimmune, cardiovascular, neurological, and psychological diseases, as well as diabetes and cancer." - Biotechnology Advances Journal

"Curcumin has been used as pharmacological traditional medicinal agent in Ayurvedic medicine for 6000 years. The current review article presents effective role of curcumin against cancer, diabetes, oxidative stress, cardiovascular, obesity, and aging. Curcumin is a promising and significant natural bioactive compound which has been shown to possess numerous pharmacological activities including anticancer, antidiabetic, cardiovascular protective, antiobesity, antimicrobial, wound healing, and nephroprotective activities. The molecule has also potential to protect from reproductive and respiratory disorders in association with its strong antioxidant potential. In near future, curcumin is expected to be proven as a novel drug to treat and cure several human disorders such as carcinogenesis, inflammatory disorders, and oxidative stress-induced pathogenesis." - Trends in Food Science & Technology

 
Where to purchase Curcumin?
Since 2000, TURMERIC-CURCUMIN.COM has been the largest supplier of Curcumin 95% extract supplements at wholesale prices to the general public, research institutions, physicians, and university medical centers. Quality control tests, laboratory analysis certification, and rigorous cGMP manufacturing standards all ensure freshness, potency, and purity of contents. Orders are shipped FedEx or USPS Priority Air for fast and secure delivery. Contact support@turmeric-curcumin.com for bulk ordering, private labeling, contract manufacturing or any other questions. Multiple bottle orders will receive increasing quantity discounts listed below. Case purchases (12 bottles) will also receive free US shipping.


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200 capsules per bottle.

Each bottle contains 200 capsules, and every 12-bottle case contains over 2.6 lbs (1.2 kg) of curcumin 95% turmeric root extract. The suggested serving size is one (1) to four (4) capsules with each meal.

500 mG OF Curcumin 95% turmeric extract per capsule.

Our label clearly indicates the contents (curcumin extracted from turmeric root), purity (95% standardized), amount per capsule (500mg) and number of capsules per bottle (200). The geographical source  of our curcumin extract is turmeric grown in India, never China. Within India, we are extensively networked with selected farms in the Eastern Ghats highlands, known for turmeric with the highest natural curcumin content in the world, at 8.8% and West Jaintia Hills, Meghalaya, where Lakadong turmeric is one of the world's finest with a curcumin content of about 7.5%.  From this high quality turmeric (Curcuma longa) root, we extract curcumin to a minimum 95% concentration. Within this extraction is the full spectrum of curcuminoids - curcumin, demethoxycurcumin, and bisdemethoxycurcumin - in their natural composition ratio of 76:19:5 for maximum potency. This is the same extract used in clinical trials and medical studies, free of added chemicals, treatments, unknown "formulas", "complexes" or "proprietary blends" which do not even disclose how much of each ingredient the product contains. Our supplement contains just two active ingredients; 500mg Curcumin 95% and 5mg of Piperine. You will receive a 100% natural, additive-free product. There are no synthetics, no starch, no sugars or sweeteners, no artificial colors or flavors, no sodium, no soy, no yeast, no wheat, no corn, no rice or other grains, no gluten, no dairy, no preservatives, no gums, no dyes, and no GMO.

 

how are  "curcumin" products deceptively marketed and advertised?

When selecting a curcumin extract product, it is important to know the difference between curcumin and turmeric. Turmeric root contains only 3% curcumin on average. Consumers may be misled by deceptive marketing to believe there more curcumin per capsule and per bottle  than there actually is. Unfortunately, these deceptions are not uncommon in the supplement industry today:

HeartWise Inc., doing business as NatureWise, was hit with a class action lawsuit for falsely advertising that its dietary supplements contain “2250 mg Per Day” of curcumin, when each pill actually only contains 750 mg. Plaintiff Martha Valentine says the dietary supplement actually requires three capsules to provide the advertised 2250 mg dosage. She maintains that she was led to believe each of the 180 capsules in the container contains 2250mg of the curcumin supplement after reading and relying on the product’s label that represented “2250 mg Per Day” of curcumin and “180 vegetarian capsules.” She says that at the time of her purchase, she did not know the product required her to take three capsules to reach the full dosage of 2250 mg of curcumin, and if she had known the truth regarding NatureWise’s misrepresentations and omissions, she would not have purchased the product. She maintains that this representation led her to believe that each of the capsules contained 2250 mg of the curcumin supplement. However, upon closer inspection of the bottle, NatureWise reveals that three capsules must be consumed to provide the 2250 mg per day serving. NatureWise’s misleading representations and omissions lead consumers to pay a premium for the supplements because they falsely believe that they are receiving three times as much curcumin as they actually receive in each bottle. “NatureWise intentionally fails to adequately disclose to consumers that more than one capsule is required to obtain the labeled dosage amount. Defendant knew and intended that consumers would purchase, and pay a premium for, a supplement labeled as having a 2250 mg of curcumin per day, leading consumers to believe that by taking 1 capsule per day they would be able to get all the benefits of consuming a large dosage of curcumin." - Valentine et al v. HeartWise Inc. d/b/a NatureWise and HeartWise Wonder Inc., Case No. 20-cv-4302, N.D. Cal.

"Doctor's Curcumin" on the front of the label, but the details confirm that each capsule is 100% turmeric spice.

"Turmeric Curcumin 500mg Enhanced Formula" only contains 200mg Curcumin extract, and the remainder is 300mg turmeric.

"1000mg Super Complex Curcumin (25%)" is actually just 250mg of Curcumin extract and the remaining 750mg is turmeric.

"Turmeric Curcumin Proprietary Blend 1000mg" but contains only 50mg Curcumin 95% extract per capsule, or 3,000mg per bottle (60 capsules x 50mg) and yet is priced higher than our bottle, which contains a total of 100,000mg of Curcumin 95% extract.

"Premium Turmeric Curcumin Complex Plus 1500" contains 150mg of Curcumin and 600mg of turmeric spice per serving, and the serving size is two capsules, meaning only 75mg of Curcumin 95% extract per capsule.

Actual labels from "Curcumin" bottles:

  

does piperine improve absorption, enhance bioavailability, and work synergistically with Curcumin?

 
"Coadministration of piperine and curcumin enhances the oral bioavailability of curcumin, and thereby, its therapeutic efficacy. It has been proved that piperine can increase the delivery of curcumin to systemic circulation due to its ability to improve the pharmacokinetic profiles of curcumin. Piperine was reported to increase the bioavailability of oral curcumin: 154% and 2000% increase in curcumin concentration in the plasma was observed in rats and humans, respectively. The increased concentration of curcumin in the bloodstream is due to the ability of piperine to decrease the rate of metabolism of curcumin in the intestine and liver. In the intestine, piperine regulates membrane lipid dynamics and inhibits the intestinal metabolism of curcumin, leading to enhanced curcumin retention in the intestine. Furthermore, piperine reduces the rate of curcumin metabolism in the liver. In addition, curcumin and piperine interacted synergistically, reducing proinflammatory mediators. The combination also demonstrated better compatibility profiles with neuronal cells. Curcumin and piperine significantly ameliorate inflammation. Curcumin and piperine synergistically attenuate inflammatory response in-vitro. The curcumin-piperine combination at the highest dose exhibited significantly lesser expression of pro-inflammatory cytokines compared to the individual treatment at respective concentrations. Curcumin-piperine combination showed better compatibility with neuronal cells compared to individual treatments. The combination of curcumin and piperine synergistically interacts in suppressing pain. Curcumin and piperine interacted synergistically, suppressing inflammatory mediators with favorable compatibility with neuronal cells. The combination of curcumin and piperine elicited a greater antinociceptive effect compared to that of either curcumin or piperine alone." - CM Journal | 2022

"Curcumin-piperine supplementation led to fewer thromboembolic episodes following recovery from COVID-19 infections." - Effectiveness of Curcumin on Outcomes of Hospitalized COVID-19 Patients: A Systematic Review of Clinical Trials, Nutrients | 2022

"The combination of curcumin and piperine had synergistic additive effects. Furthermore, the combination of piperine and curcumin can enhance the bioavailability of curcumin in human and animal models.The absorption, distribution, metabolism, excretion, and toxicity of a therapeutic could be achieved by combining with bioenhancers like piperine." - Evidence-Based Complementary and Alternative Medicine | 2022

"Piperine can increase the uptake of curcumin. The most important findings of this study were the administration of curcumin associated with piperine can inhibit the elevation of plasmatic levels of some cytokines. This result shows the capacity of curcumin to modulate an inflammatory response acutely induced by exercise. The anti-inflammatory action of curcumin associated with piperine prevented the expression of inflammatory cytokines. Supplementation of 500 mg curcumin with piperine for seven days was able to inhibit the inflammatory response after an experimental protocol of running on a treadmill until voluntary fatigue." - The Curcumin Supplementation with Piperine Can Influence the Acute Elevation of Exercise-Induced Cytokines: Double-Blind Crossover Study, Biology | 2022

"Studies have shown that using higher oral doses of curcumin results in appropriate levels of curcumin necessary for clinical activity. Coadministration with piperine, an extract of black pepper or with lecithin can enhance solubility, and the former can increase plasma bioavailability by up to 2000%." - A Review On Curcuma Longa Effect On Human Health, Journal of Emerging Technologies and Innovative Research | 2022

"Piperine behaves as a bio-enhancer and inhibits drug-metabolizing enzymes to aid curcumin absorption and bioavailability. It has numerous pharmacological effects and some health benefits, particularly against chronic diseases (decrease in insulin resistance, anti-inflammatory properties, amelioration of hepatic steatosis. Shoba et al. reported that curcumin bioavailability improved by 2000% at 45 min after concomitant orally administrated piperine." - Molecules | 2022

"A study examined the effects of curcumin combined with piperine (from black pepper extract used to improve the bioavailability of curcumin) as an add-on to the ongoing antipsychotic treatment. At the end of 16 weeks, both groups showed significant improvements in total scores and general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS). Both the doses were tolerated well without much adverse effects." - Role of Curcumin in the Management of Schizophrenia: A Narrative Review | 2022

"Improvement in weakness was more in the curcumin-piperine group than with placebo group. Conclusion: The present study results showed that curcumin-piperine cosupplementation in outpatients with COVID-19 could significantly reduce weakness." - The efficacy of curcumin-piperine co-supplementation on clinical symptoms, duration, severity, and inflammatory factors in COVID-19 outpatients: a randomized double-blind, placebo-controlled trial, Trials | 2022

"Piperine, an alkaloid responsible for the pungency of black pepper, dramatically increases the serum levels of curcumin in rats and humans." - Protective Effects of Curcumin in Cardiovascular Diseases - Impact on Oxidative Stress and Mitochondria, Cells | 2022

"Piperine together with curcumin could improve its bioavailability and make its anti-epileptic action even more effective." - New Promising Therapeutic Avenues of Curcumin in Brain Diseases, Molecules | 2022

"Piperine (found in black pepper) increases your body's ability to hold onto curcumin by up to 2,000%. Piperine slows down the metabolization of turmeric's active compound, leaving it available for your body to absorb. If you're going the supplement route, it's best to choose options that also contain piperine to improve the potential effects." - The Untold Truth Of Turmeric, Mashed | 2022

"Curcumin + piperine treatment was associated with a significant reduction in the mean serum levels of immunoglobulin E (IgE). Curcumin plus piperine might have positive effect on serum immunoglobulin E (IgE) levels." - Effects of curcumin-piperine supplementation on systemic immunity in young women | 2022

"There is evidence that the combination of piperine in black pepper with curcumin in turmeric increases the bioavailability of curcumin by 2000% and inhibits the intestinal and hepatic glucuronidation of curcumin." - Curcumin-Rich Curry Consumption and Neurocognitive Function from 4.5-Year Follow-Up of Community-Dwelling Older Adults, Nutrients | 2022

"Bioavailability enhancer curcumin-piperine considerably increased the curcumin blood levels." - Role of Curcumin in Retinal Diseases, Clinical and Experimental Ophthalmology | 2022

"One pilot study concluded that an oral dosage of 500 mg of curcumin with piperine could restore lipid peroxidation in patients suffering from tropical pancreatitis." - A Comprehensive Review on the Therapeutic Potential of Curcuma longa in Relation to its Major Active Constituent Curcumin, Frontiers in Pharmacology | 2022

"Piperine, a bio-enhancer improves the absorption of curcumin. Of note, piperine (10 mg/day) was used to increase the bioavailability of curcumin." - An Update on the Exploratory Use of Curcumin in Neuropsychiatric Disorders, Antioxidants | 2022

"Concomitant administration of piperine with curcumin significantly reduced elimination and half-life clearance of curcumin. Perkins and colleagues reported that humans require a daily dose of 1.6 g curcumin to achieve the desired results." - Neuroprotective Activities of Curcumin in Parkinson’s Disease: A Review of the Literature | 2021

"Piperine, a bio-enhancer, considerably improves the absorption of curcumin." - Oral Curcumin With Piperine as Adjuvant Therapy for the Treatment of COVID-19: A Randomized Clinical Trial, Frontiers in Pharmacology | 2021

"Piperine is a natural alkaloid that is found in black pepper (Piper nigrum), which is capable of increasing the bioavailability of curcumin by inhibition of biotransformation—especially glucuronidation - in the liver and small intestine. As Hewlings and Kalman emphasized in their work, piperine has been associated with an increase in the bioavailability of curcumin by 2000%." - Curcumin and Its Potential Impact on Microbiota, Nutrients | 2021

"The protective action of curcumin and piperine consumption is associated with weight loss, anti-inflammatory potential, and control of prostate epithelial cell homeostasis." - Protective effect of the association of curcumin with piperine on prostatic lesions: New perspectives on BPA-induced carcinogenesis, Food and Chemical Toxicology | 2021

"Combined with piperine, curcumin can synergistically improve anti-inflammatory and antioxidant activity. Combinations of curcumin with piperine have been successfully used for the bio-enhancement of curcumin." - Anti-Inflammatory Effects of Curcumin in the Inflammatory Diseases | 2021

"Piperine, a pungent alkaloid recovered from black pepper, enhances bioavailability of curcuminoids Improved gastrointestinal absorption and bioavailability of curcumin has been observed using other plant bioactive components such as piperine. Short-term supplementation with a curcuminoid-piperine combination also improves oxidative stress and inflammatory status in metabolic syndrome patients." - Turmeric and its bioactive constituents trigger cell signaling mechanisms that protect against diabetes and cardiovascular diseases, Molecular and Cellular Biochemistry | 2021

"In the case of curcumin, there has been a great interest in piperine owing to its ability to decrease curcumin hepatic and intestinal glucuronidation with consequent augmentation of curcumin bioavailability. This pharmacological effect was demonstrated by comparing serum curcumin concentration when given alone versus administration together with piperine. In this last case, curcumin blood levels presented a significant increase." - Anti‑inflammatory role of curcumin in retinal disorders, Experimental and Therapeutic Medicine | 2021

"The bioavailability of curcumin can be increased by 2000% when using piperine as an adjuvant." - Turmeric Root and Its Bioactive Ingredient Curcumin Effectively Neutralize SARS-CoV-2 In Vitro, Viruses | 2021

"Curcumin supplements are commonly produced in capsule form with piperine, or black pepper extract, which increases curcumin absorption and bioavailability. This combination is therefore proffered as the ideal formulation." -  Turmeric as a Possible Treatment for COVID-19-Induced Anosmia and Ageusia, Cureus | 2021

"A way to improve bioavailability would be through piperine, as demonstrated by Delecroix et al. who included 6g of curcumin + 60mg of piperine/day. Piperine is a thermonutrient that exerts its thermogenic action on the epithelial cells of the small intestine, increasing the rate of nutrient absorption and therefore increasing its bioavailability." - Modulation of Exercise-Induced Muscle Damage, Inflammation, and Oxidative Markers by Curcumin Supplementation in a Physically Active Population, Nutrients | 2020

"The naturally occurring molecules curcumin and piperine suppressed the growth of and inhibited the migration and invasion of the leukemia cells, indicative of their anticancer potential. Curcumin is a polyphenolic pigment generally obtained from Curcuma longa while piperine is an alkaloid generally isolated from Piper nigrum. Both of these naturally occurring compounds have been shown to exhibit enormous anticancer potential and have been utilized in the traditional healthcare systems in the management of abnormal human conditions. They have also been shown to exhibit potent bioactivities which also include their anticancer properties. Curcumin has been shown to suppress the growth of pancreatic cancer. It has also been shown to cause inhibition of proliferation of prostate cancer cells via induction of apoptosis. Similarly, piperine has been shown to inhibit the growth of colon cancer cells and trigger apoptosis in lung cancer cells." - Antiproliferative potential of piperine and curcumin in drug-resistant human leukemia cancer cells, Journal of the Balkan Union of Oncology | 2020

"Piperine, the major active component of black pepper, represents the most utilized natural agent used to improve curcumin bioavailability, by blocking curcumin metabolism in order to increase its absorption.." - Interaction between Gut Microbiota and Curcumin: A New Key of Understanding for the Health Effects of Curcumin, Nutrients | 2020

Archived studies on curcumin and piperine
 

HAS THE SAFETY OF CURCUMIN 95% BEEN ESTABLISHED?

The safety, tolerability, and nontoxicity of curcumin at high doses has been well established by human clinical trials. The US FDA classifies Turmeric as GRAS (Generally Recognized As Safe).  Curcumin, even in large quantities, does not produce any known side effects in humans. Preclinical and clinical studies indicate that curcumin is well tolerated and the overwhelming safety profile of curcumin is evident. Before using any herbs or dietary supplements in amounts greater than usually found in foods, consult a health care provider.

"Curcumin is considered a safe compound and authorized as a GRAS compound (generally recognized as safe) by US FDA (United States Food and Drug Administration). It is well tolerated at a higher dose of 12g in humans. Cells treated with the curcumin-piperine combination at their EC90 concentration showed no toxicity to neuronal cells. Reduction in locomotive behaviors was not observed with the curcumin-piperine combination, indicating no potential CNS side effects of curcumin-piperine combination at its highest therapeutic doses. We found no effects of the combination on the spontaneous locomotor activity at their high doses. The results indicate no potential central nervous system (CNS) side effects of the curcumin and piperine combination." - CM Journal | 2022

"According to the US Food and Drug Administration, curcumin is classed as safe for both human consumption and pharmacological purposes without any known side effects." - Life | 2022

"Studies have shown that systemic exposure to curcumin-containing products at doses of up to 8,000 mg/day was safe and tolerable and did not cause serious adverse events." - Curcumin (Curcuma, Turmeric) and Cancer, PDQ Integrative, Alternative, and Complementary Therapies Editorial Board | 2022

"According to relevant clinical trials on safety and toxicity, the acceptable dose of curcumin for maximum efficacy is 4 – 8 grams per day. It has been reported that humans can tolerate treatment with curcumin at a dose up to 12 grams per day." - Frontiers in Pharmacology | 2022

"The US Food and Drug Administration has marked curcumin as a "By and large Recognized As Safe" item. The United Nations and World Health Organization Expert Committee on Food Additives and European Food Safety Authority suggested the everyday admission of 0-3 mg/kg body weight of curcumin. Furthermore, curcumin supplementation in a few clinical preliminaries exhibited wellbeing profiles at dosages in the range of 4000 and 8000 mg/ day." - Journal of Antimicrobial Agents, Prevention of Female Reproductive Disorders with the Help of Curcumin | 2022

"Curcumin is not toxic to humans up to 8,000 mg/day. A Phase I clinical trial of curcumin is well tolerated, when administered in patients with high risk conditions or pre-malignant lesions of the bladder, skin, cervix, stomach, or oral mucosa as a single daily oral dose ranging from 500,to 8000 mg/day for 3 months. "- Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions | Anticancer Research

"Curcumin has a long established safety record. For example, according to JECFA (The Joint United Nations and World Health Organization Expert Committee on Food Additives) and EFSA (European Food Safety Authority) reports, the Allowable Daily Intake (ADI) value of curcumin is 0–3 mg/kg body weight. Several trials on healthy subjects have supported the safety and efficacy of curcumin." - Curcumin, an active component of turmeric (Curcuma longa), and its effects on health |  Critical Reviews in Food Science and Nutrition

"Most studies have classified curcumin as a non-toxic and safe material with a safe dose for human clinical trials greater than 120 mg/m2" - Pharmacological properties and underlying mechanisms of curcumin and prospects in medicinal potential | Biomedicine & Pharmacotherapy

"Curcuminoids have been approved by the US Food and Drug Administration (FDA) as “Generally Recognized As Safe” (GRAS), and good tolerability and safety profiles have been shown by clinical trials, even at doses between 4000 and 8000 mg/day and of doses up to 12,000 mg/day of 95% concentration of three curcuminoids: curcumin, bisdemethoxycurcumin, and demethoxycurcumin." - Curcumin: A Review of Its’ Effects on Human Health

"A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be safe." - The Journal of Alternative and Complementary Medicine

"Patients received 8 grams curcumin by mouth daily, no toxicities were observed. Phase II trial demonstrates that 8 g/day curcumin for 2 months is well tolerated and exhibits biological effects in patients with advanced pancreatic cancer. " - Phase II trial of curcumin in patients with advanced pancreatic cancer | Clinical Cancer Research

"Oral curcumin 6 g/day for 4–7 weeks during radiotherapy reduced the severity of radiation dermatitis without any toxicity in breast cancer patients." - Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients | Radiation Research

"Studies on human did not show toxic effects, and curcumin was safe at the dose of 6 g/day orally for 4-7 weeks. Curcumin is known as a generally recognized as safe substance. Turmeric and curcumin are nontoxic for human especially in oral administration. Based on the numerous experimental and clinical evidences, curcumin is well tolerated in humans without significant side effects." - Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances | Phytotherapy Research

"3.6 g/day oral curcumin for 6 months was well tolerated and safe in leucoplakia patients demonstrating significant clinical response." - A Randomized Double-Blind Placebo-Controlled Phase IIB Trial of Curcumin in Oral Leukoplakia | Cancer Prevention Research

"Phase I trials reported that curcumin extract in doses between 440 and 2200 mg/day for up to 4 months was well tolerated and is devoid of dose limiting toxicity in patients with advanced colorectal cancer, substantiating the safety of curcumin." - Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer | Clinical Cancer Research

"Therapy using 8000 mg oral curcumin daily was safe and feasible in patients with pancreatic cancer." - A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer | Cancer Chemotherapy and Pharmacology

"Curcumin at a dose of 2 g/day for 6 months as oral maintenance therapy proved to be safe in patients with ulcerative colitis." - Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial | Clinical Gastroenterology and Hepatology

"A six month randomized, placebo controlled, double blind pilot trial of 4 g/day curcumin in Alzheimer’s patients was found to be tolerated well." - Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease | Journal of Clinical Psychopharmacology

"3 mg per kg curcumin is generally regarded as a safe accepted daily intake in healthy humans." - Curcumin, an active component of turmeric (Curcuma longa), and its effects on health | Critical Reviews in Food Science and Nutrition

"Six months curcumin administration at a dose of 1.5 g/ day orally to type 2 diabetes mellitus patients was well tolerated." - Evaluation of the effect of curcumin capsules on glyburide therapy in patients with type-2 diabetes mellitus | Phytotherapy Research

"Regular oral intake of 1 g/day of curcumin for 3 months in osteoarthritic patients shows no sign of toxicity." - The efficacy of Curcuma longa extract as an adjuvant therapy in primary knee osteoarthritis: a randomized control trial | Journal of the Medical Association of Thailand

"A good safety profile of curcumin was observed in patients with cardiovascular risk factors and patients affected by high risk conditions or pre-malignant lesions of internal organs taking a dose of curcumin ranging from 500 to 8000 mg/day for 3 months. This safety has been observed also in patients with advanced colorectal cancer, in breast cancer patients undergoing radiotherapy while taking up to 6000 mg/day of curcumin, and advanced pancreatic cancer patients taking 8000 mg/day of curcumin for 2 months." - Potential of Curcumin in Skin Disorders | Nutrients

 
Why NATURAL curcumin 95% extract from turmeric root rhizome without nanoparticles or other processed synthetics?
"This study evaluated the toxic events of curcumin nanoparticles with alterable surface polarity in alveolar macrophages. In conclusion, the cytotoxicity of curcumin nanoparticles on alveolar macrophages is surface-charge dependent, which in turn is associated to the uptake pathway and localization of curcumin nanoparticles in cells." - Toxicity of curcumin nanoparticles towards alveolar macrophage, Food and Chemical Toxicology | 2022

"The harmfulness of nanoparticles is impacted by their condition of conglomeration and mechanical properties, which are reliant upon their creation and decontaminating strategies. Worries about the poisonousness of nanoparticle-based conveyance strategies incorporate neuroinflammation, excitotoxicity, and unfavorably susceptible responses." - Alternative & Integrative Medicine | 2022

"Curcumin nanomicelle suppressed spermatogenesis, increased immunoreactivity of 8-oxodG, stimulated the Hsp70–2a and Hsp90 expressions, and resulted in severe DNA and mRNA damages. Moreover, the curcumin nano-micelle received animals exhibited remarkable reductions in the spermatozoa count, motility and DNA integrity. In conclusion, chronic and high dose consumption of curcumin nano-micelle results in remarkable oxidative stress." - Curcumin nano-micelle induced testicular toxicity in healthy rats; evidence for oxidative stress, Biomedicine & Pharmacotherapy | 2021

"A number of nanoparticles have negative impacts on male germ and somatic cells which could ultimately affect fertility or the ability to produce healthy offspring." - Toxicity mechanisms of nanoparticles in the male reproductive system | 2021

"Nanoparticles may act as reproductive toxicants depending on several factors, and induce damage to the male reproductive system by affecting the seminiferous tubules and spermatogenesis. This is mainly due to the fact that nanoparticles can easily enter the blood circulatory system and reach the testes by crossing the blood testes barrier. The bioaccumulation of nanoparticles in the testes causes seminiferous tubule histopathology and severely affects the sperm number, motility and morphology. Moreover, nanoparticles also induce disturbances to the Leydig cells, causing decline in the testosterone level with consequent testicular injury and reduced sperm production." - Perspectives of Nanoparticles in Male Infertility: Evidence for Induced Abnormalities in Sperm Production |  2021

"Curcumin nanoparticles suppressed the proliferation of testicular cell lines in vitro. In the present study, we disclosed the acute damage on mouse spermatogenesis and sperm parameters by nano-curcumin. Our results suggested that the reproductive toxicity of nanoformulated curcumin needs to be prudently evaluated before its application." - Acute Damage to the Sperm Quality and Spermatogenesis in Male Mice Exposed to Curcumin-Loaded Nanoparticles, International Journal of Nanomedicine | 2020


"Nanoparticles are able to pass certain biological barriers and exert toxic effects on crucial organs, such as the brain, liver, and kidney. Only recently, attention has been directed toward the reproductive toxicity of nanomaterials. Nanoparticles can pass through the blood–testis barrier, placental barrier, and epithelial barrier, which protect reproductive tissues, and then accumulate in reproductive organs. nanoparticles accumulation damages organs (testis, epididymis, ovary, and uterus) by destroying Sertoli cells, Leydig cells, and germ cells, causing reproductive organ dysfunction that adversely affects sperm quality, quantity, morphology, and motility or reduces the number of mature oocytes and disrupts primary and secondary follicular development. In addition, nanoparticles can disrupt the levels of secreted hormones, causing changes in sexual behavior. However, the current review primarily examines toxicological phenomena. The molecular mechanisms involved in nanoparticles toxicity to the reproductive system are not fully understood, but possible mechanisms include oxidative stress, apoptosis, inflammation, and genotoxicity. Previous studies have shown that nanoparticles can increase inflammation, oxidative stress, and apoptosis and induce ROS, causing damage at the molecular and genetic levels which results in cytotoxicity." - Potential adverse effects of nanoparticles on the reproductive system

"Recent studies have shown that nanoparticles disturb the developing oocyte by invading the protective barrier of theca cells, granulosa cell layers and zona pellucida. Nanoparticles disrupt sex hormone levels through the hypothalamic–pituitary-gonadal axis or by direct stimulation of secretory cells, such as granule cells, follicle cells, thecal cells and the corpus luteum. Some nanoparticles can cross the placenta into the fetus by passive diffusion or endocytosis, which can trigger fetal inflammation, apoptosis, genotoxicity, cytotoxicity, low weight, reproductive deficiency, nervous damage, and immunodeficiency, among others." - Nanoparticles and female reproductive system: how do nanoparticles affect oogenesis and embryonic development

"Females are particularly more vulnerable to nanoparticle toxicity, and toxicity in this population may affect reproductivity and fetal development. Moreover, various types of nanoparticles have negative impacts on male germ cells, fetal development, and the female reproductive system." - Toxicity of Nanoparticles on the Reproductive System in Animal Models: A Review
 

What are the pharmacological actions of Curcumin?

First shown to have anti-bacterial activity in 1949, curcumin has since been shown to have anti-inflammatory, anti-oxidant, pro-apoptotic, chemopreventive, chemotherapeutic, anti-proliferative, wound healing, anti-nociceptive, anti-parasitic, and anti-malarial properties as well.  Numerous clinical and preclinical studies and trials evaluating curcumin's safety and efficacy have revealed its potential against a wide range of human diseases and ailments have been completed. These pathologies include diabetes, obesity, neurologic and psychiatric disorders, and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys, and gastrointestinal and cardiovascular systems. Curcumin has also been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. Growing experimental evidence reveals that curcumin exhibits multitarget biological implications signifying its crucial role in health and disease, with pharmacological effects against numerous diseases like neuronal, cardiovascular, metabolic, kidney, endocrine, skin, respiratory, infectious, gastrointestinal diseases and cancer. The ability of curcumin to modulate the functions of multiple signal transductions are linked with attenuation of acute and chronic diseases. Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn’s disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis.

Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Extensive preclinical studies over the past three decades have indicated curcumin’s therapeutic potential against a wide range of human diseases. In addition, curcumin has been shown to directly interact with numerous signaling molecules. These preclinical studies have formed a solid basis for evaluating curcumin’s efficacy in clinical trials. The clinical trials conducted thus far have indicated the therapeutic potential of curcumin against a wide range of human diseases. Curcumin has a potential to prevent and/or manage various diseases due to its anti-inflammatory, anti-oxidant and anti-apoptotic properties with an excellent safety profile. In contrast, the anti-cancer effects of curcumin are reflected due to induction of growth arrest and apoptosis in various premalignant and malignant cells. Curcumin reduces the risk of osteoporosis via amelioration of mitochondrial membrane function, PKB phosphorylation, microRNA-365 activation, osteoblasts proliferation. It reduced ulcerative colitis by inhibiting neutrophil chemotaxis. The gastroprotective effect is due to inhibition of acid release, amelioration of blood flow, angiogenesis and collagenization of gastric tissue. Curcumin shows hepatoprotective action due to inhibitory activity against NF-jB. Additionally, curcumin reduced liver marker enzymes, cholesterol levels and replication of hepatitis B and C viruses. Curcumin treatment reduces asthma and allergy symptoms mainly due to inhibition of histamine release, attenuation of IgE, inhibition of COX-2 enzyme, suppression of JNK54/56, ERK 42/44 and p38 MAPK, stimulation of Nrf-2/HO-1 pathway, upregulation of Notch1, Notch2 receptors, GATA3 etc. Curcumin blocks certain cytokines and enzymes, inhibits ROS generation, downregulate NF-kB activation, induce extracellular matrix production, upregulate collagen and fibronectin expressions thereby reduce inflammatory diseases. Curcumin treatment reduces fibronectin and collagen IV expressions, suppresses TGF-bsignaling and exhibits antioxidant, anti-inflammatory and anti-apoptotic potential thereby ameliorates kidney functions. Studies have indicated the anticancer effects of curcumin by evaluating its effect on a variety of biological pathways involved in cell cycle regulation, apoptosis, tumorigenesis, mutagenesis and metastasis.

Curcumin mediates its effects by modulation of various molecular targets including transcription factors, enzymes, cell cycle proteins, receptors, cell surface adhesion molecules, neurotransmitters etc. Curcumin exhibits antioxidant, anti-inflammatory and anti-apoptotic potential thereby reduce neurodegenerative, cardiovascular, metabolic, gastrointestinal, respiratory and inflammatory diseases. Clinical and preclinical data have conclusively proved that curcumin modulates neurotransmitter levels and reduces neurodegeneration thereby ameliorate neuronal and behavioral dysfunctions. Curcumin reduces Alzheimer’s pathology by reducing Abplaques and tau phosphorylation. The anti-depressant and anxiolytic mechanism of curcumin includes inhibition of brain MAO activity, modulation of serotonin receptor and amelioration of neurotrophic factors. Curcumin reduces drug addiction and withdrawal symptoms, possibly through modulation of HAT, DNA methyl transferases, CREB, BDNF and CaMKIIalevels. Curcumin administration reduced Huntington’s disease by reducing huntingtin aggregates. In cardiovascular disease, the anti-atherosclerotic mechanism of curcumin includes the inhibition of platelet aggregation and modulation of cholesterol homeostasis. Curcumin effectively reduce hypertension by blocking angiotensin I receptor, reducing circulating angiotensin-converting enzyme and inducing vasodilation. The antiarrhythmic mechanisms of curcumin are due to modulation of Ca 2þ homeostasis and blockade of potassium channels. The anti-fungal mechanisms of curcumin includes the leakage of intracellular component, disruption of plasma membrane, generation of oxidative stress, induction of apoptosis, inhibition hyphae development, upregulation of chitin synthase and PKC etc. Curcumin treatment downregulated genomic transcription and translation, inhibited viral oncoproteins, suppressed the Akt/SREBP-1 pathway, inhibited hemagglutination, proteases, integrase and Tat protein acetylation resulting in antiviral effects. Curcumin administration reduces cerebral infracts size and volume during stroke. During metabolic diseases, curcumin treatment ameliorates b-cell dysfunction, insulin signaling and GLP-1 secretion while reduces glucose intolerance, hyperglycemia, hyperinsulinemia and hyperlipidemia.
 
what studies on Curcumin have been published in medical literature and science journals?

December 2022

Curcumin for COVID-19: real-time analysis of all studies
c19curcumin.com | December  2022
Curcumin reduces risk for COVID-19 with very high confidence for mortality, hospitalization, recovery, and in pooled analysis, high confidence for viral clearance. Statistically significant improvements are seen for mortality, hospitalization, recovery, and viral clearance. 11 studies from 10 independent teams in 6 different countries show statistically significant improvements in isolation (7 for the most serious outcome).

The protective effects of curcumin on depression: Genes, transcription factors, and microRNAs involved
Journal of Affective Disorders | December 2022
Curcumin is one of the natural compounds that have been developed for depression therapy. Curcumin, the main therapeutic component of turmeric (Curcuma longa), has long been recognized for its significant anti-inflammatory and antioxidant properties due to its unique molecular structure (Duc et al., 2021; Nguyen and Kim, 2021; Nguyen et al., 2021c). Curcumin is well-known for its potential as a neuroprotective compound against depression. Curcumin has also been shown to possess physiological effects that are comparable to those of typical antidepressant medications (Ramaholimihaso et al., 2020). Curcumin may have an anti-depressant effect via the relevant genes. We also observed 74 miRNAs associated with depression that are targeted by curcumin, with hsa-miR-146a-5p having the greatest expression and interaction.  Curcumin's physicochemical characteristics and pharmacokinetics are consistent with its antidepressant effects due to its high gastrointestinal absorption, which did not remove it from the CNS, and its ability to penetrate the blood-brain barrier. Curcumin also inhibits CYP1A9 and CYP3A4. Our data mining found that curcumin's antidepressant effects were regulated by 14 different genes. The GeneMANIA prediction plug-in presented interaction types among the identified genes targeted by curcumin's possible benefits to counteract the development of depression. Converging evidence indicates that curcumin has been shown to exert modulating effects on neuroplasticity, insulin resistance, inflammatory pathways, excitotoxicity, neurotransmitter levels, nitrosative and oxidative stress, hypothalamic-pituitary-adrenal disturbances, and the endocannabinoid system, all of which can be implicated in the pathophysiology of depression (Ramaholimihaso et al., 2020).Our findings suggest that curcumin may have a possible anti-depressant impact via the following genes: ADORA2A, ALB, BDNF, FGF2, GLO1, GSK3B, IL6, MIF, NOS1, PTGS2, RELN, SELP, SOD1, and NR3C1.

Mechanism of apoptosis activation by Curcumin rescued mutant p53Y220C in human pancreatic cancer
Molecular Cell Research | December 2022
Based on our studies, it reflects that apoptosis in pancreatic cancer cells is mediated by curcumin-rescued mutant p53Y220C. In this study, we have shown through different biophysical and cell-based studies that curcumin binds and rescues mutp53Y220C to an active wild-type conformation and restores its apoptotic transcription function in BxPC-3-pancreatic cancer cells. In addition, the curcumin-rescued-p53Y220C (CRp53) showed significant hyperphosphorylation at Ser15, Ser20, and acetylation at Lys382 with an 8-fold increase in transcription activity in the BxPC-3 cell lines.

An in silico investigation on the interactions of curcumin and epigallocatechin-3-gallate with NLRP3 Inflammasome complex
Biomedicine & Pharmacotherapy | December 2022
The binding energies of curcumin and inhibitor MCC950 are almost identical.  Curcumin and EGCG, plant-derived compounds, inhibit the NLRP3-mediated IL-1β and IL-18 production.  Curcumin and epigallocatechin-3-gallate (EGCG) suppress the activation of the NLRP3 inflammasome. Our data showed that NLRP3 had a higher binding affinity for curcumin and EGCG than other complex proteins. The therapeutic effect of curcumin and EGCG may be due to the inhibition of inflammasome activation. The molecular and protein-protein interaction data indicated that the therapeutic effects of these two polyphenols are mediated by preventing the development of the NLRP3 complex.

MACC1-Dependent Antitumor Effect of Curcumin in Colorectal Cancer
Nutrients | November 2022
Curcumin is the curcuminoid compound of turmeric (Curcuma longa). Its remedial effect was shown for various diseases, such as Alzheimer’s and gastrointestinal disorders. Recent studies also demonstrated curcumin’s inhibitory impact on cancer progression and distant dissemination of tumors. Curcumin is able to inhibit proliferation and induces apoptosis. Further studies revealed that curcumin treatment enhances G1/S cell cycle arrest. Moreover, curcumin treatment induces autophagy through the suppression of the AKT/mTOR/p70S6K pathway. In addition to these, its effect on angiogenesis, cancer stemness, and NFκB signaling was reported in different tumor entities. Preliminary studies indicated the potential inhibitory effect of curcumin on prostate cancer metastasis by decreasing the expression of CXCL1 and 2. Curcumin reduced the metastasis-associated in colon cancer 1 expression, restricted the metastasis-associated in colon cancer 1-induced proliferation, and was able to reduce the metastasis-associated in colon cancer 1-induced cell motility as one of the crucial steps for the distant dissemination of the tumor. We further showed the metastasis-associated in colon cancer 1-dependent effect of curcumin on clonogenicity and wound healing. This study is, to our knowledge, the first identification of the effect of curcumin on the restriction of cancer motility, proliferation, and colony-forming ability by using metastasis-associated in colon cancer 1 as a target. Taken together, we illustrated the prominent inhibitory effect of curcumin on MACC1 expression and MACC1-induced phenotypes. In addition, we further revealed the MACC1-dependent anti-proliferative and anti-migratory effects of curcumin. Although the experiments have been conducted in the established cell lines, these promising results can expand in the other models so that curcumin can further supplement the treatment of CRC patients, notably those who cannot tolerate statins and have high MACC1 expression. This is the first study showing the effect of curcumin on reducing MACC1 expression in the established cell lines. In this study, we demonstrated the MACC1-dependent inhibitory effect of a wide range of curcumin concentrations on MACC1-induced viability, proliferation, migration, wound healing, and clonogenicity.

Effects of curcumin, a bioactive component of turmeric, on type 2 diabetes mellitus and its complications: an updated review
Food & Function | November 2022
Among the herbal supplements, turmeric (Curcuma longa L.) has been attracting an avalanche of attention owing to its main component, curcumin. This review examines the physiological activities and mechanisms of action of curcumin associated with type 2 diabetes and its complications. The anti-diabetic characteristic of curcumin is mainly attributed to its anti-inflammatory as well as anti-oxidant activities. In addition to these activities, curcumin has been developed as a promising prevention/treatment choice for diabetes complications by modulating various critical signal steps owing to the anti-hyperglycemic and anti-hyperlipidemic activities of curcumin. Studies on diabetic humans and animals have revealed that curcumin may have positive effects on oxidative stress and inflammation and may reduce fasting blood glucose levels, increase insulin sensitivity/secretion and regulate the lipid profile. Thus, it may prevent and treat diabetes by affecting various molecular targets.

Curcumin Represses Colorectal Cancer Cell Proliferation by Triggering Ferroptosis via PI3K/Akt/mTOR Signaling
Nutrition and Cancer  | November 2022
Curcumin is known to suppress the progression of colorectal cancer by inhibiting cancer cell proliferation. In this study, we explored the role of ferroptosis in the antiproliferative properties of curcumin. The effect of curcumin on ferroptosis In Vitro was evaluated in HCT-8 cells. Ferroptosis was first blocked by ferrostatin-1 and the antiproliferative effect of curcumin was evaluated by determining the levels of ferroptotic markers, including glutathione, SLC7A11, GPX4, iron, malondialdehyde, and reactive oxygen species. Curcumin repressed HCT-8 cell proliferation in a dose-dependent manner. Treating HCT-8 cells with curcumin significantly downregulated GSH, SLC7A11, and GPX4, while significantly increasing levels of iron, MDA, and ROS. In addition, curcumin promoted ferroptosis and reduced proliferation of HCT-8 cells by suppressing the PI3K/Akt/mTOR pathway, and these effects were antagonized by Fer-1. The effects of curcumin were antagonized by a PI3K agonist and reinforced by a PI3K inhibitor. Curcumin triggers ferroptosis and suppresses proliferation of colorectal cancer cells by inhibiting the PI3K/Akt/mTOR signaling pathway. These results indicate its potential as a treatment against colorectal cancer.

Neuroprotective Activities of Curcumin in Parkinson’s Disease: A Review of the Literature
International Journal of Molecular Sciences | November 2022
Curcumin is a neuroprotective agent with antioxidant, anti-inflammatory, free radical scavenging, mitochondrial protecting, and iron-chelating properties, which enhance DA levels in the brain.  Curcumin is a polyphenolic compound isolated from the rhizomes of Curcuma longa (turmeric). It has been demonstrated to have potent anti-inflammatory, antioxidant, free radical scavenging, mitochondrial protecting, and iron-chelating effects, and is considered a promising therapeutic and nutraceutical agent for the treatment of Parkinson’s disease. The interaction of curcumin with α7-nACh receptors provides further evidence for a potential neuroprotective role for curcumin in Parkinson’s disease. Additionally, curcumin and derivatives show a high safety profile with minimal reported toxicity as demonstrated both in in vitro and in in vivo studies in Parkinson’s disease models. Therefore, gaining a better understanding of the neuroprotective properties of curcumin could have significant therapeutic implications. The evidence reviewed supports curcumin’s powerful molecular and cellular effects in neurodegenerative disorders as an appealing strategy for improving Parkinson’s disease management and prognosis. Perkins and colleagues reported that humans require a daily dose of 1.6 g curcumin to achieve the desired results. Concomitant administration of piperine with curcumin significantly reduced elimination and half-life clearance of curcumin.

Schizophrenia, Curcumin and Minimizing Side Effects of Antipsychotic Drugs: Possible Mechanisms
Neurochemical Research | November 2022
Curcumin has important therapeutic properties such as antioxidant, anti-mutagenic, anti-inflammatory, and antimicrobial functions and protection of the nervous system. Also, the ability of curcumin to pass the blood-brain barrier raises new hopes for neuroprotection. Curcumin can improve and prevent further probable neurological and behavioral disorders in patients with schizophrenia. Alternative therapy such as curcumin can reduce the severity of symptoms without significant side effects. It decreases the side effects of neuroleptics and retains lipid homeostasis. Curcumin increases the level of brain-derived neurotrophic factor and improves hyperkinetic movement disorders. Curcumin may act as an added counteraction mechanism to retain cell integrity and defense against free radical injury. Thus it appears to have therapeutic potential for improvement of schizophrenia. In this study, we review several properties of curcumin and its ability to improve schizophrenia and minimize the side effects of antipsychotic drugs, and we explore the underlying mechanisms by which curcumin affects schizophrenia and its symptoms.

Glutathione Compared to Curcumin in the Management of Systemic Lupus Erythematosus: A Systematic Review
Cureus | November 2022
Curcumin can be a more promising alternative since it operates on various pathways and is a more easily accessible source. Based on the data available, curcumin shows a broader range of applications. It has actions on many more pathways. Hence, curcumin is a more apt drug for usage soon. Curcumin is a more available, naturally occurring compound. In addition, some studies also indicate the effect of curcumin on glutathione function. Curcumin also has more studies proving its role in the management of SLE, thus making it a safer bet for case management. The ability of curcumin to interact with several immunomodulatory pathways makes it so valuable for managing autoimmune diseases. The activation of oxidative pathways is how curcumin's anti-inflammatory role is activated. Curcumin targets the inhibitor of kappa-B kinase subunit beta (IKKβ) of the NFκB pathway to help reduce inflammation. NFκB downregulation by curcumin minimizes the release of nitric oxide, ILs, and various other inflammatory markers from the T cells. Curcumin also prevents neutrophil chemotaxis, thus reducing inflammatory responses in tissues. Curcumin acts by causing impairment in the formation of pro-inflammatory markers. Curcumin plays a role in adjusting the levels of inflammatory markers from cells. It reduced IL types 4, 6, and 8 and tumor necrosis factor (TNF) alpha. Reducing free radicals in the body helps reduce inflammatory changes in tissues.

Curcumin improves insulin sensitivity in high-fat diet-fed mice through gut microbiota
Nutrition & Metabolism | November 2022
Curcumin is a polyphenolic compound extracted from tropical plant Curcuma longa, and as a phytochemical derived from a medicinal and edible food, it not only has an extremely low level of toxicity but also has been used in traditional medicine to improve metabolic diseases. Moreover, curcumin has been shown to improve metabolic syndrome in basic research, and its potential efficacy in improving diabetes has also been demonstrated in clinical trials. Therefore, curcumin has excellent prospects for clinical application in the prevention and treatment of insulin resistance. In a recent study by our research team, gut microbiota were shown to mediate the enhancement of uncoupling protein 1-dependent thermogenesis by curcumin in high-fat diet-fed mice, while curcumin increased energy consumption by improving high-fat diet-induced gut microbiota dysbiosis and hence ameliorating high-fat diet-induced obesity in mice. Accordingly, we speculated that curcumin may exert its protective effects against insulin resistance via gut microbiota modulation. We believe this knowledge would provide a theoretical basis for the clinical application of curcumin in the prevention and treatment of metabolic syndrome and type 2 diabetes, as well as new ideas for the treatment of metabolic diseases. Curcumin-restructured fecal microbiota produced similar effects to curcumin, while also confirming that curcumin improved insulin sensitivity through gut microbiota modulation in high-fat diet-fed mice. This study demonstrated that curcumin ameliorated high-fat diet-induced GLMDs and increased insulin sensitivity, and verified that the beneficial effects of curcumin required its modulation on gut microbiota. Moreover, we found that curcumin upregulated the expression of the gut-derived hormone FGF15, and this upregulation was also dependent on gut microbiota. Our findings suggested that curcumin at least partly exert its effects on increasing insulin sensitivity via FGF15 upregulation in high-fat diet-fed mice. This study provided a theoretical basis for the clinical application of curcumin in the treatment of metabolic syndrome and type 2 diabetes. In addition, it is hoped that our findings will provide novel ideas on nutritional manipulations of gut microbiota for the treatment of metabolic diseases.

Curcumin and Its Analogs in Non-Small Cell Lung Cancer Treatment: Challenges and Expectations
Biomolecules | November 2022
Curcumin, a natural polyphenolic compound extracted from the root of turmeric, possesses diverse pharmacologic activities, including anti-diabetes, anti-aging, anti-Parkinson’s disease and Alzheimer’s disease, anti-cardiovascular disease, and anti-cancer, etc. Specifically, in tumor treatment, modern medicine has demonstrated that curcumin exerts therapeutic effects on various cancers, including breast cancer, colorectal neoplasm, liver carcinoma, glioblastoma, gastric tumor, and lung carcinoma, etc. We determined via a PubMed database search that researchers first reported assessing curcumin as an anticancer drug in 1985. Ten years later, investigators found that Cur could suppress lung tumor metastasis and extend the life span of mice. Since then, many non-small cell lung cancer (NSCLC) preclinical studies revealed that curcumin could inhibit tumor nodules ; restrain cancer stem cells; control the cell cycle; suppress immigration, invasion, and repair; induce the production of ROS and ER stress; trigger apoptosis; elevate DNA damage and ferroptosis; and promote necrotic cell death, thereby treating and preventing NSCLC. The broad actions through which curcumin can affect non-small cell lung cancer (NSCLC) in vitro and in vivo are summarized. Considerable preclinical evidence has revealed that curcumin and its analogs affect non-small cell lung cancer (NSCLC) via various mechanisms, such as inducing ROS production, increasing ferroptosis, changing mitochondrial potential, and disturbing cellular signaling pathways. Additionally, co-treatment with curcumin and other agents synergistically enhances cytotoxicity in non-small cell lung cancer (NSCLC) cells to suppress tumor cell growth, migration, and invasion. This evidence suggests that curcumin and its analogs offer promise to prevent non-small cell lung cancer (NSCLC) in humans.

Quinacrine and Curcumin in combination decreased the breast cancer angiogenesis by modulating ABCG2 via VEGF A
Journal of Cell Communication and Signaling | November 2022
Curcumin + QC inhibited the proliferation, invasion, migration and expression of representative markers of metastasis and angiogenesis. Curcumin + QC inhibited the ABCG2 expression and thus reduced the angiogenesis. Reduction of vascularization was also observed after treatment of Curcumin + QC.  Curcumin + QC inhibited the process by inhibiting ABCG2 in breast cancer.

Combination of curcumin and piperine synergistically improves pain-like behaviors in mouse models of pain with no potential CNS side effects
CM Journal | November 2022
For centuries, turmeric containing curcumin and Piper nigrum containing piperine have been used as food additives and folk medicine, including Traditional Chinese Medicine. The combination of C. longa curcumin, and P. nigrum piperine, has been used in traditional medicine.  Many recent studies reported synergistic effects of curcumin and piperine combination in various pharmacological models, including lung cancer, aging, and hepatocellular carcinoma.   Curcumin has also been reported as a potential analgesic both in animals and humans and exhibits diverse cellular and molecular targets. Curcumin inhibits pain neurotransmission by modulating immune and neuronal cells at cellular and mechanistic levels. In animal models of pain, curcumin suppresses pro-inflammatory mediators and increases endogenous anti-inflammatory mediators by modulating peripheral and central immune cells. The present study demonstrates strong antinociceptive synergism between curcumin and piperine in mouse models with no potential CNS side effects, suggesting its possible use in clinical trials.  The combination of curcumin and piperine produced synergistic interaction in the formalin, tail-flick, and cold plate tests. The synergistic interaction of curcumin and piperine was further confirmed by the efficacy of the combination in LPS-stimulated RAW 264.7 macrophage cells. Curcumin and piperine interacted synergistically, reducing proinflammatory mediators. The combination also demonstrated better compatibility profiles with neuronal cells.  The combination of curcumin and piperine synergistically ameliorates pain-like behaviors in the mouse formalin model. Curcumin and piperine significantly ameliorate formalin-induced peripheral and central inflammation. Curcumin and piperine synergistically attenuate inflammatory response in-vitro.  The curcumin-piperine combination at the highest dose exhibited significantly lesser expression of pro-inflammatory cytokines compared to the individual treatment at respective concentrations. Curcumin-piperine combination showed better compatibility with neuronal cells compared to individual treatments. The combination of curcumin and piperine synergistically interacts in suppressing pain-like behaviors induced by heat stimuli. The combination of curcumin and piperine synergistically interacts in suppressing pain-like behaviors by cold stimuli. Reduction in locomotive behaviors was not observed with the curcumin-piperine combination, indicating no potential CNS side effects of curcumin-piperine combination at its highest therapeutic doses.  Curcumin and piperine interacted synergistically, suppressing inflammatory mediators with favorable compatibility with neuronal cells. Curcumin and piperine have been shown to interact synergistically in various preclinical pharmacological studies. The combination of curcumin and piperine elicited a greater antinociceptive effect compared to that of either curcumin or piperine alone. The isobolographic analysis was performed to evaluate the type of interaction, wherein strong antinociceptive synergism between curcumin and piperine was found. This interaction produced by the combination of these two compounds could be due to their pharmacodynamic and pharmacokinetic interactions. Pharmacodynamically, the combination of curcumin and piperine could simultaneously inhibit multiple sites of action in the pain pathway. The ability of curcumin and piperine to modulate diverse pathways of pain could lead to robust inhibition of pain transmission when those are coadministered. Hence, the pharmacodynamic interaction between curcumin and piperine could be one of the potential reasons for the observed antinociceptive synergism in this study. In addition, it has also been proved that piperine can increase the delivery of curcumin to systemic circulation due to its ability to improve the pharmacokinetic profiles of curcumin. Piperine was reported to increase the bioavailability of oral curcumin: 154% and 2000% increase in curcumin concentration in the plasma was observed in rats and humans, respectively. The increased concentration of curcumin in the bloodstream is due to the ability of piperine to decrease the rate of metabolism of curcumin in the intestine and liver. In the intestine, piperine regulates membrane lipid dynamics and inhibits the intestinal metabolism of curcumin, leading to enhanced curcumin retention in the intestine. Furthermore, piperine reduces the rate of curcumin metabolism in the liver by hindering aryl hydrocarbon hydroxylation, ethylmorphine-N-demethylation, 7-ethoxycoumarin-O-deethylation, and 3-hydroxy-benzo(a)pyrene glucuronidation and glucuronidation, which subsequently reduce the first-pass metabolism of curcumin. Hence, coadministration of piperine and curcumin enhances the oral bioavailability of curcumin, and thereby, its therapeutic efficacy. This factor may also have influenced the strong antinociceptive synergism observed in this study. Cells treated with the curcumin-piperine combination at their EC90 concentration showed no toxicity to neuronal cells. We found no effects of the individual curcumin and combination on the spontaneous locomotor activity at their high doses, while individual piperine reduced locomotor activity. The results indicate no potential CNS side effects of the curcumin and piperine combination.

Curcumin Sensitizes 4T1 Murine Breast Cancer Cells to Cisplatin
In Vivo | November 2022
Curcumin, which is highly effective at inducing cell death in various types of cancer, is a polyphenolic yellow pigment derived from Curcuma longa. It can selectively chemosensitize tumor cells, thereby protecting normal cells from chemotherapy and radiotherapy. In this study, treatment of mice with curcumin led to a decrease in tumor mass. Treatment with curcumin followed by cisplatin led to complete tumor mass regression in mice compared with the control group. Zhao et al. reported that high levels of PAR4 in the serum and plasma of mice inhibited the growth of metastatic lung tumor nodules derived from Lewis lung carcinoma cells in syngeneic mice. Curcumin is a good inducer of PAR4 expression in breast cancer cells and a secretagogue in non-tumor cells in vivo. In addition, it sensitizes cells to the effect of cisplatin; hence, curcumin, alone or in combination with chemotherapy, might be used as an alternative treatment for breast cancer.

Curcumin Prevents Diabetic Osteoporosis through Promoting Osteogenesis and Angiogenesis Coupling via NF-κB Signaling
Evidence-Based Complementary and Alternative Medicine | November 2022
Curcumin, an effective component extracted from Curcuma longa, exhibits antioxidation, regulation of bone metabolism and hypoglycemic effects. Treatment prevented bone loss and promoted vessel formation in diabetic osteoporosis mice. Based on these results, we concluded that curcumin ameliorated diabetic osteoporosis.. Reports demonstrate that curcumin may ameliorate bone microarchitecture and enhance BMD in APP/PS1 transgenic mice and has shown bone protective effect on postmenopausal osteoporosis animal models and patients. More importantly, recent studies have found the therapeutic value of curcumin on osteoporosis induced by diabetes. The benefits of curcumin on bone formation and regeneration are attributed to its capacity to reduce H2O2-stimulated osteoblast apoptosis, improving osteoblast mitochondrial function, and recovering the high glucose-impaired osteogenic differentiation of osteoblast and BMSCs. To our knowledge, this is the first to confirm that curcumin prevents diabetes-induced bone loss by promoting BMSC-mediated osteogenesis and angiogenesis coupling. In this study, our results showed that curcumin treatment rescued high glucose-inhibited osteogenic differentiation ability of BMSCs in vitro. Furthermore, our in vivo results also revealed that curcumin prevented bone loss in diabetic mice. Our findings reveal the effects of curcumin in promoting the BMSCs-mediated osteogenesis and angiogenesis coupling in high glucose conditions. These impacts are preliminarily considered to be via NF-κB signaling pathway inhibition. Furthermore, curcumin may become a potential drug to prevent and treat diabetic osteoporosis through promoting bone regeneration and vessel formation.

In patients with osteoarthritis, is curcumin, compared to placebo, effective in reducing pain?
Journal of the Oklahoma State Medical Association | November 2022
Yes. Studies have shown that curcumin extract has benefit in treating osteoarthritic pain, compared to placebo. It is reasonable to use curcumin in addition to traditional osteoarthritis treatments, as studies show it has a low side effect profile. Curcumin is a bright yellow powder derived from turmeric, and has been used for centuries in alternative medicine for its anti-inflammatory properties. Subjects took 500 mg of curcimin plus 5 mg piperine extract (to enhance bioavailability) three times daily for 6 weeks.  WOMAC scores for patients taking curcumin averaged 37, while those taking placebo averaged 57. Results from this literature review suggest that curcumin can be considered by physicians as an adjunctive therapy to traditional therapies for osteoarthritis, as it does appear to offer benefit in pain relief compared to placebo. Although more evidence is needed to support curcumin as a replacement for NSAIDs or other mainstay therapies, the results of the studies reviewed are promising. Larger trials to investigate the efficacy of curcumin compared to NSAIDs would be appropriate. However, curcumin appears to be a safe and effective addition to osteoarthritis treatments for patients, and should not be overlooked by physicians.

Curcumin protects retinal neuronal cells against oxidative stress-induced damage by regulating mitochondrial dynamics
Experimental Eye Research | November 2022
Data indicate that curcumin protects against oxidative stress-induced injury in retinal neuronal cells by promoting mitochondrial fusion. Curcumin has anti-inflammatory, antimutagenic and antimicrobial properties, and has been administrated for asthma, diabetes and cancer in traditional medicine for a long history (Nabavi et al., 2015; Qadir et al., 2016; Shahid et al., 2019). Curcumin has been found to regulate the apoptosis, proliferation, transformation and metastasis of cancer cells by inhibiting NF-κB signaling (Aggarwal et al., 2006). Curcumin also exerts its anti-inflammatory function via downregulation of COX-2, PGE-2 and proinflammatory factors including IL-1, 6, 8 and TNF-α or upregulation of peroxisome proliferator-activated receptor-γ (Michalik et al., 2006; Taylor and Leonard, 2011). In addition, several studies indicate that curcumin also shows therapeutic effect on several retinal diseases including primary retinitis, age-related macular degeneration, diabetic retinopathy and glaucoma (Nebbioso et al., 2021). Pretreatment with curcumin effectively attenuated H2O2-induced mitochondrial fission, and inhibited the intracellular ROS generation, mitochondrial membrane potential disruption, PINK1 expression, caspase-3 cleavage and apoptosis in R28 cells. Notably, knockdown of mitochondrial fusion protein Mfn2 dramatically attenuated curcumin's protection against H2O2-induced growth inhibition in R28 cells. In conclusion, our results indicate that mitochondrial fusion plays a vital role in curcumin-mediated protection against oxidative stress-induced retinal neuronal damage, and also suggesting mitochondria as a crucial target for the protection of neurons.

Effects of curcumin-piperine supplementation on systemic immunity in young women with premenstrual syndrome and dysmenorrhea: A randomized clinical trial
European Journal of Obstetrics, Gynecology, Reproductive Biology | November 2022
Curcumin decreased the serum immunoglobulin E (IgE) levels in women with premenstrual syndrome and dysmenorrhea. Curcumin + piperine treatment was associated with a significant reduction in the mean serum levels of  immunoglobulin E (IgE). Curcumin plus piperine might have positive effect on serum immunoglobulin E (IgE) levels with no significant changes on serum IL-10 and IL-12 in healthy young women with PMS and PD. Studies with higher doses and longer durations of treatment with curcumin are required to confirm these findings.

Alzheimer’s disease large-scale gene expression portrait identifies exercise and curcumin as top theoretical treatments
Scientific Reports | October 2022
For the Alzheimer’s disease portrait, the top three scoring treatments for reversing Alzheimer’s disease expression with little effect on exacerbating Alzheimer’s disease expression were for exercise. Overall, the ranking of treatments was similar for male and female portrait, although in males, curcumin was the second highest ranked treatment.

Isolation and In silico Study of Curcumin from Curcuma longa and Its Anti-Diabetic Activity
Applied Biochemistry and Biotechnology | October2022
The development of new drugs from natural products is still challenging, and the most extensively studied plant material is turmeric, Curcuma longa, which is the chief source of curcumin. Curcumin is a bright yellow solid. Based on the findings, it can be said that curcumin, a natural substance, has good therapeutic qualities when it is isolated.

The Pharmacological Mechanism of Curcumin against Drug Resistance in Non-Small Cell Lung Cancer
Evidence-Based Complementary and Alternative Medicine | October 2022
Curcumin is commonly utilized for the treatment of various cancers (e.g., breast cancer and hematological cancers). It has been found to have anticancer activity in  non-small cell lung cancer. Increasing evidence showed that curcumin could enhance immune function via various mechanisms. It was revealed that curcumin could enhance tumor antigen-specific T-cell induction in cancer cells. Curcumin inhibited CSN5 expression in cancer cells and sensitized them to anti-CTLA4 therapy. Additionally, curcumin could reverse resistance to targeted medicines. Curcumin overcomes primary gefitinib resistance in  non-small cell lung cancercells by causing cell death related to autophagy. Curcumin enhances gefitinib’s sensitivity by inhibiting cell proliferation and suppressing clonogenic capacity in NCI-H1975 cells. Curcumin can also enhance the effect of chemotherapy drugs. A previous study demonstrated that curcumin and doxorubicin work together more effectively in treating Hodgkin lymphoma. Curcumin in combination with immunotherapy, chemotherapy, or targeted drugs has the potential to be effective for drug-resistant non-small cell lung cancer.  Curcumin regulates drug sensitivity in non-small cell lung cancerby interacting with cell cycle, NF-kappa B, MAPK, Th17 cell differentiation signaling pathways, etc. The findings of our study reveal the relevant key signaling pathways and targets of curcumin as an adjuvant therapy in the treatment of non-small cell lung cancer, thus providing pharmacological evidence for further experimental research.

Antitoxic Effects of Curcumin against Obesity-Induced Multi-Organs’ Biochemical and Histopathological Abnormalities in an Animal Model
Evidence-Based Complementary and Alternative Medicine | October 2022
Curcumin exerted potent antitoxic, antioxidant, tissue-protective, and antiobesity effects. Curcumin is recommended to be added to various dietary regimens to prevent or delay the organs’ dysfunction among obese people. The most significant phenolic ingredient in turmeric is called curcumin, and it is yellow in color and is a natural phenolic antioxidant. Due to its biological and pharmacological characteristics, which include antioxidant and anti-inflammatory features, curcumin has received a lot of interest in various research studies, including human or experimental animal models in various diseases, including obesity. Genetic analyses of the related inflammatory signaling pathways (via assessments of adipose tissue expressions of TLR4, IL-6, and TNF-α) were performed to explore the potential mechanistic benefits of curcumin in reversing these metabolic abnormalities. Coadministration of curcumin with a high-fat diet group exhibited significantly decreased serum insulin and glucose levels when compared with the high-fat diet group. In parallel with our results, Hartogh et al. reported that by lowering the harmful effects of liver fat and increasing cell sensitivity to insulin, curcumin can lower blood glucose levels in obese rats. The present results could be attributed to the ability of curcumin to reduce oxidative stress and inflammatory response which contributed to insulin resistance. Similarly, curcumin treatment attenuated glucose intolerance and boost insulin sensitizing response.  Furthermore, curcumin administration caused strong induction of the antioxidant defenses, since SOD, CAT, and GSH-Px activities were significantly increased, reaching values similar to those of the control group. Curcumin’s effects may act by either directly scavenging the reactive oxygen metabolites or due to the presence of various antioxidant principles such as flavonoids, steroids, tannins, glycosides, triterpenoids, and polyphenolic compounds. The anti-inflammatory effects of curcumin form the basis of its potential clinical applications. In the present study, curcumin significantly reduces the inflammation state in high-fat diet group. Curcumin is an excellent antioxidant agent and has an effective role in the regression of DNA damage. Interestingly, the current study demonstrated that administration of curcumin to the high-fat diet group provided protection against hepatic disorders, duodenal and myocardial histopathological changes as confirmed by these results are in line with those of many researchers who found a marked reduction in steatosis of hepatocytes and an improvement in liver histopathology. It is likely to postulate that the antioxidative property of curcumin is the key to its therapeutic effect on gastrointestinal injury as documented by many researchers. Moreover, Gorabi et al. revealed that high-fat diet plus curcumin showed no histopathological changes in the myocardial structure, indicating a preventive effect of curcumin against histological cardiac changes induced by a high-fat diet. There is no doubt that the use of curcumin improved the histological findings as well as modulated metabolic and oxidative stress markers, as well as downregulated inflammatory biomarkers and apoptosis. Therefore, it is advised that curcumin be evaluated as a possible supplemental therapy for metabolic diseases linked to obesity brought on by high-fat diet.

Curcumin strengthens immunity by helping the generation of immune cells such as T cells and B cells
International Curry and Spices Symposium | October 2022
Immune cells such as B cells increased significantly in the lymph glands of rats administered with curcumin. Curcumin helps to produce antibodies and can contribute to the prevention of various infectious diseases such as the flu and colds and cancer. Curcumin is a yellow pigment component of turmeric, the main ingredient in curry, and is known to have excellent antioxidant and anti-inflammatory effects. Curcumin in turmeric has anti-cancer, anti-inflammatory, and antioxidant effects by inhibiting the activity of inflammation-related genes.

Roles of Curcumin on Cognitive Impairment Induced by a Mixture of Heavy Metals
Neurotoxicity Research | October 2022
The most important pathways involved in curcumin's protective activity against heavy metals were categorized as "regulation of neuron apoptotic process” and "negative regulation of apoptotic signaling route”. Curcumin was also well-positioned inside the CASP3 binding region. Three key miRNAs linked to cognitive impairment, mixed heavy metals, and curcumin were observed. These miRNAs were found to be related to the important pathways related to cognitive impairment and involved in curcumin's protective activity against mixed heavy metals such as "apoptosis multiple species”, “apoptosis”, and “Alzheimer’s disease”. Curcumin's physicochemical characteristics and pharmacokinetics are consistent with its therapeutic benefits in cognitive impairment, owing to its high gastrointestinal absorption and ability to cross the blood–brain barrier. Our findings emphasize the protective effects of curcumin in cognitive impairment caused by heavy metal mixtures and pave the way for molecular mechanisms involved in cognitive impairment pathology.

Protective effects of curcumin against traumatic brain injury
Biomedicine & Pharmacotherapy | October 2022
Curcumin has a broad range of clinical properties due to its considerable antioxidative and anti-inflammatory actions. This review discusses the pleiotropic mechanisms, the side effects, curcumin's delivery to the central nervous system (CNS), and its immunomodulatory and protective effects on  traumatic brain injury. Clinical trials, in vivo, and in vitro studies were extracted from different scientific databases, including PubMed, Scopus, and Google Scholar, to assess the effects of curcumin or its derivatives in  traumatic brain injury. Findings reveal that curcumin exhibited some protective effects on  traumatic brain injury via modulation of cell signaling pathways including toll-like receptor-4 (TLR-4), nuclear factor kappa B (NF-κB), and Nod-like receptor family proteins (NLRPs). Moreover, curcumin upregulates the brain-derived Neurotrophic Factor/Tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway, phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), nuclear factor erythroid 2-related factor 2 (Nrf2), which have crucial functions in modulation of TBI pathophysiological-mediated pathways. Curcumin displays beneficial immunomodulatory functions and protective capacities in different  traumatic brain injury models
.

Curcumin: An overview
Journal of Medicinal Plants Studies | October 2022
Curcumin is the active ingredient in the herbal remedy and dietary spice turmeric, having a wide range of therapeutic properties that covers antimicrobial, immune-health, multiple myeloma and cancers of various categories. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. Curcumin inhibits the growth of Helicobacter pylori, which causes gastric ulcers and has been linked with gastric cancers.  Extracts of turmeric and its curcumin component exhibit strong antioxidant activity comparable to vitamins C & E. Several studies have demonstrated curcumin's ability to reduce oxidative stress. It appears that curcumin's role as an antioxidant may be due in part to its ability to down regulate nitric oxide formation. It has been proved already that curcumin down -regulates NF- kappaB in human multiple myeloma cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of multiple myeloma with this pharmacologically safe agent. Pharmacological studies have demonstrated that curcumin from Curcuma longa is an anti-mutagen as well as an anti-promotor for cancer.

The Role of Phytochemicals in the Treatment of Colorectal Cancer
Onco Therapeutics | October 2022
Phytochemicals like curcumin are naturally occurring and are known to exhibit anti-cancer activity against colorectal cancer by regulating various key signaling pathways including the Wnt/β-catenin signaling pathway. By regulating vital molecular pathways, the course of colorectal cancer can be positively altered. The evidence outlined within this literature review suggests the significance of these phytochemicals as preventive agents and their potential role in developing effective therapies. This review emphasizes the molecular mechanisms of curcumin, resveratrol, and sulforaphane that can effectively target colorectal cancer development and progression.

Review On Curcuma Longa Effect On Human Health
Journal of Emerging Technologies and Innovative Research | September 2022
Curcumin is the phytochemical derived from the bulb of the plant Curcuma longa and is the major component of turmeric. The herb has been used for thousands of years. It aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, It may also help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and performance in active people. Most of these benefits can be attributed to its antioxidant and anti-inflammatory effects. Curcumin from the herb turmeric has been used for thousands of years. It aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, It may also help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and performance in active people. Most of these benefits can be attributed to its antioxidant and anti- inflammatory effects. It has also demonstrated hepatoprotective, nephroprotective, neuroprotective, and cardioprotective properties. These characteristics provide the foundation for its therapeutic uses and the rationale for clinical trials. Many other medicinal and pharmacological properties of curcumin used for humans. In Ayurveda, curcumin has been used for various medicinal conditions including rhinitis, wound healing, common cold, skin infections, liver and urinary tract diseases. Curcumin was found to be effective even when given by different routes including topical, oral or by inhalation, dependent on the intended use.

Curcumin Targeting Non-Coding RNAs in Colorectal Cancer: Therapeutic and Biomarker Implications
Biomolecules | September 2022
Curcumin has shown potent anti-tumor and anti-inflammatory effects and is considered a hot spot in the research and development of anti-tumor drugs due to its advantages of precise efficacy, lower toxic side effects, and less drug resistance. Recent studies have revealed that curcumin has anti-tumor effects exerted on the epigenetic regulation of tumor-promoting/tumor-suppressing gene expression through the alteration of expression levels of non-coding RNAs. Curcumin has been approved as a food additive by the World Health Organization and the US Food and Drug Administration and has been listed as a third-generation cancer chemoprevention drug by the National Cancer Institute of the United States due to its safety, non-toxicity, and lack of adverse effects. Curcumin has a non-toxic chemical composition; almost all types of tumor markers can be regulated by it to exert an anti-tumor effect; undoubtedly, this provides a strong theoretical basis for cancer treatment. Studies have shown that curcumin could exert an anti-tumor effect both in vitro and in vivo through different mechanisms, including inhibiting the invasion, metastasis, and proliferation of tumor cells, inducing tumor cell apoptosis and autophagy, and resisting chemotherapy resistance. Recent studies have shown that curcumin is widely used as an anti-tumor agent because it regulates ncRNAs based on an epigenetic regulation mechanism; there are benefits to using curcumin in the treatment of colorectal cancer. Its anti-colorectal cancer effect is essentially through the indirect regulation of target genes or signaling pathways. In summary, these findings could provide favorable evidence for exploring the role of curcumin in the treatment of colorectal cancer via non-coding RNAs, which may provide new directions for the treatment and prognosis of colorectal cancer patients. Curcumin could affect the development of colorectal cancer by targeting oncogenes or tumor-suppressor genes; its anti-colorectal cancer effect is essentially through the indirect regulation of target genes or signaling pathways. Treated by curcumin, Lnc NBR2, Lnc KCNQ1OT1, Lnc PANDAR, and Lnc CCAT1 could prove to be potentially effective target molecules in the treatment progress of colorectal cancer.  In summary, these findings could provide favorable evidence for exploring the role of curcumin in the treatment of colorectal cancer via non-coding RNAs, which may provide new directions for the treatment and prognosis of colorectal cancer patients. Non-coding RNAs can be potential therapeutic targets for the occurrence and development of colorectal cancer, and curcumin-targeted non-coding RNAs have good biomarker and reference significance for the treatment of colorectal cancer.

The effect of eight weeks of Pilates with curcumin supplementation on liver enzymes and lipid profile in overweight and obese women
Obesity Medicine | September 2022
Curcumin supplement significantly improve liver enzymes. Pilates training plus Curcumin supplement significantly decreased anthropometry indices. Pilates and Curcumin alone or in combination led to significant changes in lipid profile. The results showed that weight, BMI, WHR and PBF decreased in the curcumin + Pilates group compared to the other groups. According to the results, an 8-week Pilates and curcumin alone or in combination reduced serum ALT, LDL-C, TG and T-Chol compared with the control group. Also, serum AST levels decreased from 23.75 ± 2.14 to 19.37 ± 1.98 in the curcumin group. Eight weeks of intervention with Pilates and curcumin alone or in combination seemed effective in improving lipid profile and reducing ALT enzyme levels in overweight and obese females. It also appears that the AST enzyme is only affected by curcumin supplementation.

Curcumin in the treatment of urological cancers: Therapeutic targets, challenges and prospects
Life Sciences | September 2022
Curcumin has been widely used in cancer treatment due to its ability to trigger cell death and suppress metastasis. The beneficial effects of curcumin in the treatment of urological cancers is the focus of current review. Curcumin can induce apoptosis in the three types of urological cancers limiting their proliferative potential. Furthermore, curcumin can suppress invasion of urological cancers through EMT inhibition. Notably, curcumin decreases the expression of MMPs, therefore interfering with urological cancer metastasis. When used in combination with chemotherapy agents, curcumin displays synergistic effects in suppressing cancer progression. It can also be used as a chemosensitizer. Based on pre-clinical studies, curcumin administration is beneficial in the treatment of urological cancers and future clinical applications might be considered upon solving problems related to the poor bioavailability of the compound.

The effects of curcumin in learning and memory impairment associated with hypothyroidism in juvenile rats: the role of nitric oxide, oxidative stress, and brain-derived neurotrophic factor
Behavioural Pharmacology | September 2022
Curcumin enhanced the performance of the rats in both MWM and PA tests. In addition, curcumin reduced malondialdehyde concentration and NO metabolites; however, it increased thiol content as well as the activity of catalase and superoxide dismutase enzymes in both the cortex and hippocampus. Curcumin also increased hippocampal synthesis of BDNF in hypothyroid rats. The beneficial effects of curcumin cognitive function in juvenile hypothyroid rats might be attributed to its protective effect against oxidative stress and potentiation of BDNF production.

Curcumin Modulates Oxidative Stress, Fibrosis, and Apoptosis in Drug-Resistant Cancer Cell Lines
Life | September 2022
The present study shows that curcumin induces anticancer activity against resistant cancer cell lines in a concentration and time-dependent manner. The protective activities of curcumin against the growth of cancer cells are mediated by modulating oxidative stress, regulating fibrosis, SIRT1 activation, and inducing cellular apoptosis. The bio-functional properties of curcumin and its derivatives - such as anti-tumor, antioxidant, and anti-inflammatory activities - have gained much attention in combating many human diseases, particularly cancer. Curcumin’s natural phenolic, hydrophobic, and antioxidant properties help it to diffuse through cancer cell membranes into the mitochondria, endoplasmic reticulum, and nucleus to perform chemo-preventive, antimetastatic, and anti-angiogenic actions. Curcumin has been reported to exert its chemotherapeutic efficacy through targeting several molecular pathways involved in mutagenesis, cell cycle regulation, tumorigenesis, apoptosis, and metastasis. Moreover, several studies showed that curcumin significantly reduces fibrosis via suppressing the overproduction of collagen-linked factors such as hydroxyproline, fibronectin, and TGF-β1 in cancer cells. In breast cancer, curcumin is shown to suppress the spread of cancer cells to other parts of the body. In addition, curcumin regulates different signaling pathways, especially breast cancer gene. In colon cancer, curcumin induces FADD (Fas-Associated Protein With Death Domain), triggering apoptosis. Moreover, it inhibits colon cancer metastasis. Similarly, in lung cancer, curcumin modulates the circ-PRKCA/miR-384/ITGB1 pathway, suppressing the malignancy of lung carcinoma. It also reduces migration and invasion of lung carcinoma. Curcumin has been reported to sensitize tumor cells to chemotherapeutic drugs and ionizing radiation therapy. In conclusion, curcumin induces anticancer activity against sensitive and drug-resistant cancer cells in a concentration- and time-dependent manner. The protective activities of curcumin against the growth of cancer cells are mediated by modulating oxidative stress, regulating fibrosis, SIRT1 activation, and inducing cellular apoptosis. Therefore, curcumin could be tested as an auxiliary therapeutic agent for current treatments to improve the prognosis in patients with drug-resistant cancer.

Curcumin as adjuvant treatment in patients with non-alcoholic fatty liver (NAFLD) disease: A systematic review and meta-analysis
Complementary Therapies in Medicine | September 2022
Curcumin has been shown to improve non-alcoholic fatty liver disease’s severity and increase liver steatosis resolution compared to the placebo groups. Curcumin was also found to reduce triglycerides if taken more than eight weeks’ duration.  There is no major side effect, and our findings showed no difference in the adverse effect. Curcumin is acknowledged as a powerful antioxidant and anti-inflammatory agent. A review reported that the consumption of curcumin significantly reduced liver enzymes, decreased low-density lipoprotein and total cholesterol among non-alcoholic fatty liver disease patients. Another review found curcumin showed significant effects on fasting blood sugar, insulin level, and homeostasis model of assessment insulin resistance among women with polycystic ovary syndrome. Curcumin is anticipated to function as antiviral drugs to treat the current COVID-19 virus based on in vitro and in vivo studies as it showed high inhibitory activity towards the virus. Goodarzi and Jalali found that curcumin reduced liver enzymes in non-alcoholic fatty liver disease compared to the placebo group, which is similar to our findings. Mansour-Ghanaei and Wei showed that curcumin reduced aspartate aminotransferase. Our finding is similar to Jalali that curcumin reduced total cholesterol in participants compared to the placebo group. Wei and Jalali showed that curcumin reduced the low-density lipoprotein compared to the placebo group. Wei also showed that curcumin reduces triglycerides compared to the placebo group. Curcumin reduced BMI in participants with the non-alcoholic fatty liver disease compared to the placebo group. Besides improving the liver ultrasonographic findings, curcumin also reduced serum liver enzymes, total cholesterol, and BMI. There is no major side effect, and our findings showed no difference in the adverse effect between the two groups. Our meta-analysis shows that curcumin has favorable effect on liver ultrasonographic findings, reduced serum liver enzymes, total cholesterol, and BMI in participants with non-alcoholic fatty liver disease. Therefore, promoting curcumin as an adjuvant treatment on NAFLD patients might be justified.

Prevention of Female Reproductive Disorders with the Help of Curcumin
Journal of Antimicrobial Agents | September 2022
Various examinations on Curcumin have exhibited its many advantages because of its cell reinforcement, hostile to disease, against joint inflammation, against asthmatic, against microbial, against viral and against parasitic properties. Curcumin shows huge cancer prevention agent properties by breaking the chain response of free extreme creation. Likewise, curcumin diminished the protein reactions engaged with aggravation processes, for example, those of cancer rot factor alpha, interleukin-1, IL-2, IL-6, IL-8 and IL-12.  Curcumin has been displayed to hinder the actuation of TNF-α in the NF-κB pathway and kill the receptive oxygen species, causing oxidative pressure. As oxidative pressure and irritation are in most persistent sicknesses, curcumin supplementation could altogether offer different medical advantages. Coorganization of curcumin with piperine, an alkaloid in dark pepper, improves curcumin's bioavailability by up to 2000 percent.

Anti-migratory effect of curcumin on A-549 lung cancer cells
Hormone Molecular Biology and Clinical Investigation | September 2022
Curcumin inhibited lung cancer cells through various molecular pathways. RECK/MMPs axis as a regulator of cancer cell migration was modulated after curcumin treatment and invasion of lung cancer cells was decreased. The results of MTT assay showed that the cytotoxic effect of curcumin was in a dose dependent manner. Flow cytometry results demonstrated a significant increase in the percentage of apoptotic cells in curcumin treated group. In addition, curcumin inhibited migration rate in lung cancer cells.

A network pharmacology approach to identify the mechanisms and molecular targets of curcumin against Alzheimer's disease
Medicine | September 2022
Curcumin and its metabolites possess anti-inflammatory, antioxidant, antimicrobial, and antiviral activities. Further, in recent years, the literature reports that curcumin has beneficial effects in diseases of the neurological system, including Alzheimer's disease. Curcumin suppresses the formation and promotes the disaggregation of amyloid-β plaques, attenuates the hyperphosphorylation of tau, and enhances its clearance. available studies indicate that curcumin has been widely used in neurodegenerative diseases. A recent study indicated that curcumin could improve lipid metabolic disorders by the ATP binding cassette A1 transmembrane transport system in Alzheimer's disease. In addition, curcumin improves parkinsonian disability scores in vivo and inhibits PC12 cell death in vitro by inhibiting AKT/mTOR signaling pathway, which is mediated by autophagy. As valuable targets for Alzheimer's disease treatment, curcumin can systematically improve the pathological features of stroke through multifactorial, multitarget, and multipathway. In summary, curcumin has the potential to be more effective than current treatments.

Curcumin as a novel approach in improving lipid profile: An umbrella meta-analysis
Nutrition, Metabolism and Cardiovascular Diseases | September 2022
Curcumin supplementation significantly reduced serum levels of LDL-cholesterol, triglycerides and total cholesterol. Curcumin intake significantly increased high-density lipoprotein cholesterol (HDL-cholesterol) levels. Curcumin has ameliorating effects on triglycerides, total cholesterol, LDL-c, and HDL-c levels. Overall, curcumin could be recommended as an adjuvant anti-hyperlipidemic agent. We showed that curcumin supplementation could be effective for lipid profile.

Antitumor effect of infrared whole-body hyperthermia with curcumin in breast cancer
Medical Applications | September 2022
Curcumin has traditionally been used as a food additive or as a remedy in traditional medicine for its anticancer and non-toxic effects. Thus, this research proposed the combination of curcumin and IHT as an alternative to chemotherapy in breast cancer treatment. Results showed that tumor growth inhibition and body weight gain in the combination treatment group are significantly different compared to control. The group also had the longest median survival time (42 days) with no mortality observed during the experiment. This result indicates that the combination treatment is well tolerated by the mice and has negligible levels of toxicity. Platelet to Lymphocyte Ratio) and Neutrophils to Lymphocytes Ratio results indicate that the combination treatment has better prognosis outcome than single treatment and may become a potential alternative antitumor treatment of breast cancer.

Synergistic anticancer effects of curcumin and crocin on human colorectal cancer cells
Molecular Biology Reports | September 2022
Curcumin, a polyphenol compound derived from the Curcuma longa L, and crocin, a hydrophilic carotenoid from Crocus Sativus Linnaeus, are traditionally used in food preparations in many countries and could act as chemopreventive compounds against several diseases, including cancer.  Based on the obtained results, curcumin and crocin treatment could cooperatively reduce cell viability and induce apoptosis in SW-480 cells by modulating the expression of Bax, Bcl-2, Caspase-3, Caspase-8, Caspase-9, Jak2, Stat3, and Akt1 genes. Besides, curcumin and crocin were able to synergistically increase the cell cycle arrest at the sub G1 phase, induce autophagy and decrease the clonogenic ability of SW-480 cells. These results suggested that curcumin and crocin combination could be considered a more effective therapeutic strategy for inhibiting colorectal cancer.

Curcumin against gastrointestinal cancer: A review of the pharmacological mechanisms underlying its antitumor activity
Frontiers in Pharmacology | September 2022
Gastrointestinal cancer poses a serious threat to human health globally. Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, has shown reliable anticancer function and low toxicity, thereby offering broad research prospects. Numerous studies have demonstrated the pharmacological mechanisms underlying the effectiveness of curcumin against GIC, including the induction of apoptosis and autophagy, arrest of the cell cycle, inhibition of the epithelial–mesenchymal transition processes, inhibition of cell invasion and migration, regulation of multiple signaling pathways, sensitization to chemotherapy and reversal of resistance to such treatments, and regulation of the tumor survival environment. It has been confirmed that curcumin exerts its antitumor effects on GIC through these mechanisms in vitro and in vivo. Moreover, treatment with curcumin is safe and tolerable. It has been reported that curcumin promoted pyroptosis in liver cancer cells (Li W.-f. et al, 2021), induced necroptosis in prostate and lung cancer cells (Lee et al., 2021), and induced ferroptosis in breast (Li et al., 2020) and lung cancer cells (Tang et al., 2021). Curcumin has exhibited good antitumor activity and low toxicity.  Newly discovered types of regulated cell death, such as pyroptosis, necroptosis, and ferroptosis, may provide a new direction for research on the efficacy of curcumin against GIC. Curcumin is the most important component of the rhizomes of turmeric (Curcuma longa) (Waly et al., 2018). Curcumin is a hydrophobic polyphenol that has been approved by the US Food and Drug Administration based on its bio-safety (Mashayekhi-Sardoo et al., 2021). Moreover, it has demonstrated a wide range of pharmacological activities, such as antibacterial (Ibarra-Martinez et al., 2022), anti-inflammatory (Yan et al., 2021), antioxidant (Xu et al., 2021), and antitumor (Zhang et al., 2020). Curcumin has been widely reported to inhibit the proliferation of tumor cells in a concentration-and time-dependent manner in vitro (Li et al., 2017a; Fan et al., 2020; Mao et al., 2021). In numerous studies, curcumin, a plant extract with a good safety profile, has exhibited pharmacological effects on GIC both in vivo and in vitro. As demonstrated in the present review, curcumin can effectively inhibit GlC through multiple targets, mechanisms, and pathways.

Curcumin Remedies Testicular Function and Spermatogenesis in Male Mice with Low-Carbohydrate-Diet-Induced Metabolic Dysfunction
International Journal of Molecular Sciences | September 2022
Low carbohydrate diet and ketogenic diet groups had significantly lower testosterone concentrations than the normal diet group. In contrast, the diet treated with curcumin supplementation group had an increased testosterone concentration level. Curcumin increases the testosterone level through upregulating 17β-HSD expression. Curcumin, a powdered rhizome of Curcuma longa, is considered a powerful antioxidant. The antioxidant capacity of curcumin can be divided into the direct removal of reactive oxygen species (ROS) and indirect activation of antioxidant enzymes activities. These properties are related to the chemical structure of curcumin, which includes bios-α, β-unsaturated β-diketone, two methoxy groups, two phenolic hydroxy groups and two conjugated bonds, which might play important roles in anti-inflammatory and antiproliferative activities. A randomized, double-blind, placebo-controlled clinical trial showed that curcumin supplementation could increase sperm quality, including total sperm count, sperm concentration and motility, and improved the total antioxidant capacity of plasma, malondialdehyde, C-reactive protein and tumor necrosis factor (TNF). Curcumin, a phenolic compound extracted from the Curcuma longa rhizome, has antioxidant, anti-inflammatory, and anti-mutative properties. The present study shows that curcumin improved the percentage of morphologically normal sperm and testicular morphology. Alizadeh et al. showed that curcumin could improve sperm count, concentration and motility in patients with asthenoteratospermia. It is speculated that curcumin, with a conjugated structure and an enol form, could scavenge free radicals and increase the activity of antioxidant enzymes, thereby improving sperm quality. The study shows that oral curcumin (80 mg/kg) can lower lipid accumulation in liver and adipose tissue and improve the insulin sensitivity of male C57BL/6 mice with a 60% high-fat diet. Oral administration of curcumin (80 mg/kg) in Sprague Dawley rats with a 60% high-fat diet feeding showed anti-hyperglycemic, anti-lipolytic and anti-inflammatory effects by attenuating TNF-α levels. In ICR mice with spermatogenic disorders induced by scrotal heat stress, administrating curcumin (80 mg/kg) by intragastric intubation, also had antioxidative, anti-apoptotic and androgen synthesis effects.  Our results show that a low-carbohydrate diet caused a lower sperm quality and a damaged testicular histology. Administrating curcumin (80 mg/kg) could partially reverse this condition.  Mu et al. showed that curcumin reversed high-fat-diet-induced decreased expressions of Fas, Bax and cleaved caspase 3, and increased the expression of Bcl-xl. In summary, the results of our study confirmed that a low-carbohydrate diet led to a lower sperm quality and damaged testicular histology. Supplementation with curcumin may improve the impaired sperm and testis function via decreasing oxidative stress, inflammation and apoptosis.

Anti-proliferation effects of apatinib in combination with curcumin in breast cancer cells
Hormone Molecular Biology and Clinical Investigation | September 2022
The obtained results showed that all treatments of apatinib, curcumin, and apatinib-curcumin significantly decreased viability and proliferation of the breast cancer cells in a concentration‐ and time‐dependent manner. Curcumin and Apatinib-Curcumin increased apoptosis percentage in the treated cancer cells through regulation of apoptosis-related genes expression.

ERK1/2-Dependent Inhibition of Glycolysis in Curcumin-Induced Cytotoxicity of Prostate Carcinoma Cells
BioMed Research International | September 2022
Curcumin exerts chemotherapeutic effects on various types of cancers by disrupting mitochondrial homeostasis and enhancing cellular oxidative stress. Inhibition of ERK1/2 activation seems to serve as an upstream event explaining the antiglycolytic and cytotoxic roles of curcumin in prostate carcinoma cells preadapted to acidic conditions. Numerous studies have shown that the growth inhibitory effect of curcumin on various tumor cells is mediated through actions on numerous molecules in the signaling pathway, including p53, NF-κB, mitogen-activated protein kinases (MAPK), Akt/mammalian target of rapamycin (mTOR), Notch-1, nuclear factor erythroid 2-related factor 2 (Nrf2), Wnt/β-catenin, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and AMP-activated protein kinase (AMPK). Recently, curcumin has been reported to suppress the Warburg effect in various cancer cell lines by downregulating PKM2 expression through inhibition of the mTOR/HIF-1α axis. In a previous study, we reported the preferential cytotoxicity and mechanism of curcumin on PC-3AcT cells that showed high resistance to docetaxel, compared to parental PC-3 cells. Interestingly, curcumin was shown to have the activity of co-inducing apoptosis and necroptosis by increasing reactive oxygen species (ROS) production and decreasing intracellular ATP content in human prostate carcinoma cells preadapted to lactic acid-containing media. Results provide mechanistic evidence for the antiglycolytic and cytotoxic roles of curcumin through inhibition of the MEK/ERK signaling pathway in prostate carcinoma cells preadapted to acidic conditions. It is important to note that curcumin promotes both apoptosis and necroptosis for prostate cancer cells exhibiting the Warburg phenotype by acting as a dual inhibitor of glycolysis and mitochondrial function.

Piperine Enhances the Antimalarial Activity of Curcumin in Plasmodium berghei ANKA-Infected Mice: A Novel Approach for Malaria Prophylaxis
Evidence-Based Complementary and Alternative Medicine | September 2022
Curcumin has numerous pharmacological, antioxidant, anti-inflammatory, and anticarcinogenic activities. Previous studies have reported the health beneficial effects of dietary polyphenols, e.g., curcumin from turmeric for preventive or therapeutic purposes in various types of cancer. Furthermore, curcumin has well-known cytotoxic and parasiticidal effects on protozoan parasites in vitro (e.g., Leishmania, Giardia, Trypanosoma, and Plasmodium falciparum). Several studies have shown the beneficial impacts of curcumin as an antimalarial agent. For example, curcumin plays a role in disrupting Plasmodium organelles such as apicoplast, microtubules, and PfATP6 as well as affecting parasite chromatin modification through HAT inhibition. In addition, curcumin may promote the immune response against Plasmodium via increasing the reactive oxygen species. Furthermore, curcumin inhibits glycogen synthase kinase-3β (GSK3β), which affects the production of the proinflammatory cytokines by inhibiting the transcriptional activity of NF-κB. Nonetheless, the poor bioavailability of curcumin due to expansive intestinal and hepatic metabolism along with rapid elimination restricts its clinical use. However, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a therapeutic could be achieved by combining with bioenhancers like piperine.  The combination of piperine and curcumin can enhance the bioavailability of curcumin in human and animal models.  Recent studies reviewed that the curcumin and piperine combination possibly has prophylactic activity. The combination of curcumin and piperine provided a good antimalarial activity with a synergistic effect on Plasmodium berghei ANKA-infected mice, including inhibition of parasitemia, delayed onset of clinical signs, and prolonged survival rate. In addition, the low parasitic load in the liver, lack of elevation in ALT and AST serum, and good histopathological features of the liver suggest that piperine may serve as a potential partner that can be combined with curcumin as malaria prophylaxis.

Curcumin improves the ability of donepezil to ameliorate memory impairment in Drosophila melanogaster
Drug and Chemical Toxicology | September 2022
Curcumin and donepezil, especially at lower dose of donepezil, significantly improved the memory index and biochemical parameters compared to donepezil alone. Thus, curcumin plus donepezil offers unique therapeutic effects during memory impairment in the D. melanogaster model of neurotoxicity.

Curcumin-mediated transcriptional regulation of human N-acetylgalactosamine-α2,6-sialyltransferase which synthesizes sialyl-Tn antigen in HCT116 human colon cancer cells
Frontiers in Molecular Biosciences | September 2022
Curcumin, a natural polyphenolic compound, increases gene expressions of ganglioside-specific human sialyltransferases, hST3Gal V and hST8Sia I, in human cancer cell lines (Lee at al., 2018 a, 2018b). In this study, we investigated the effect of curcumin on hST6GalNAc I gene expression in four kinds of human cancer cell lines (colon cancer cell HCT116, lung cancer cell line A549, glioblastoma cell line U-87 MG and breast cancer cell MCF-7). As shown in Figure 1, gene expression of hST6GalNAc I assessed by RT-PCR after treatment for 24 h with different concentration of curcumin was increased remarkably in HCT116 cells, which began to increase at 30 μM curcumin and showed about 14-fold enhancement at 50 μM curcumin compared to untreated control cells.

An examination of the protective effects and molecular mechanisms of curcumin, a polyphenol curcuminoid in diabetic nephropathy
Biomedicine & Pharmacotherapy | September 2022
The anti-inflammatory, antioxidative, anti-apoptotic, and anti-fibrosis properties of curcumin, a polyphenol curcuminoid, have been demonstrated in research on diabetic nephropathy. Curcumin may have clinical protective effects on diabetic nephropathy. Curcumin played anti-inflammatory, antioxidant and anti-fibrosis effects in diabetic nephropathy. Curcumin played anti-apoptosis and promoted autophagy effects in diabetic nephropathy. Curcumin is the most active ingredient of the curcuminoids and has been shown to be safe and non-toxic in both pharmacological trials and in vivo experiments. In addition, numerous studies have demonstrated that curcumin exhibits positive biological properties such as anticancer, anti-inflammatory, hypoglycemic, antioxidant, and anti-apoptotic effects. Based on the remarkable efficacy of curcumin, researchers have begun to focus on how it can be applied to diabetes and its associated chronic complications. Curcumin has been shown to play an essential role in regulating hyperglycemia and lipid metabolism, alleviating insulin resistance], inhibiting AGEs formation and AGEs-mediated destruction, improving oxidative stress, inflammatory pathways and apoptosis. Accumulating evidence indicates that curcumin plays a vital role in the protection of multiple pathologic mechanisms in diabetes retinopathy, diabetes cardiomyopathy and diabetic neuropathy. Both clinical trials and preclinical studies have verified that curcumin is beneficial to the hypoglycemic process as well as insulin resistance improvement, and more research on diabetic nephropathy has recently emerged. A review of the underlying mechanisms of curcumin in diabetic nephropathy examined its anti-inflammation, antioxidation, anti-fibrosis, anti-apoptosis, and autophagy-promoting properties. Notable progress has been made in preclinical studies; however, clinical trials are still lacking. As a natural polyphenol curcuminoid, curcumin is safe and effective as a promising alternative therapeutic agent for the treatment of diabetic mellitus and diabetic nephropathy.

The aphrodisiac potential of β-cyclodextrin–curcumin via stimulating cAMP-PKA pathway in testicular Leydig cells
Nature | September 2022
Recent studies have confirmed the potential pharmacological actions of curcumin in inflammatory disorders, metabolic syndrome, cardiovascular disease, and neurological disorders. Beyond these beneficial properties, recent studies also revealed that curcumin potentially impacts the reproductive system. Besides, curcumin was found to have curative potential on the reproductive system function and its impairment, regulated by stress and reproductive-related hormones. Of note, researchers also demonstrated that curcumin could increase spermatozoon motility in metronidazole-treated mice.

 Combined Treatment with Curcumin and Ferulic Acid Suppressed the Aβ-Induced Neurotoxicity More than Curcumin and Ferulic Acid Alone
International Journal of Molecular Sciences | September 2022
Curcumin has been studied for its antioxidant and anti-inflammatory effects. Curcumin is a fat-soluble polyphenol abundant in turmeric, traditionally used in Indian medicine. In some in vivo and in vitro studies, curcumin has been found to have antioxidant and anti-inflammatory effects, and it is therefore attracting attention as a preventative action for Alzheimer’s disease by inhibiting Aβ aggregation including oligomerization in vitro and in vivo. Furthermore, the administration of curcumin to APPswe/PS1dE9 double transgenic mice has been found to reduce the γ-secretase component presenilin-2 and promote the degradation of aggregated Aβ.We find that combination treatment of curcumin and FA exerts a cytoprotective effect on Aβ-induced cytotoxic effects, through multiple mechanisms. These mechanisms include the suppression of Aβ aggregation and antioxidant effects, as compared to single treatment with either curcumin or FA alone. The protective effects of the combination treatment we observed were complementary and cooperative. These findings suggest that the combination of curcumin and FA may provide an effective and superior strategy for the prevention and therapeutics of Alzheimer’s disease in humans.

Specific Irreversible Cell-Cycle Arrest and Depletion of Cancer Cells Obtained by Combining Curcumin and the Flavonoids Quercetin and Fisetin
Genes | September 2022
Curcumin treatment specifically triggers senescence in cancer cells by inducing mitotic slippage and DNA damage. We show that curcumin-induced senescence is p21-dependent and characterized by heterochromatin loss. Finally, we found that flavonoids clear curcumin-induced senescent cancer cells. Our findings expand the characterization of curcumin-induced cellular senescence in cancer cells and lay the foundation for the combination of curcumin and flavonoids as a possible anti-cancer therapy.

Curcumin and capsaicin regulate apoptosis and alleviate intestinal inflammation induced by Clostridioides difficile in vitro
Annals of Clinical Microbiology and Antimicrobials | September 2022
Curcumin is found to possess a wide array of biological features including anti-oxidant, anti-tumor and also anti-inflammatory properties. Furthermore, curcumin and its derivatives, bisdemethoxycurcumin and demethoxycurcumin have been shown to exert antimicrobial activities against different bacterial species particularly multidrug resistant (MDR) strains. Curcumin has anti-inflammatory and also anti-fibrosis effects by suppressing the NF-κB and TGF-β1/SMAD-3 signaling pathways, respectively. Vasanthkumar et al. demonstrated that curcumin and CAP alone or in combination cause considerable reduction in LPS-induced overexpression of COX-2, IL-6 and TGF-β. Consistent with previous studies, findings of the present work revealed that curcumin could decrease the C. difficile-induced gene expression level

The Regenerated Capacity of Curcumin in the Migration of Epidermal Stem Cells Promotes Skin Wound Healing in a Wistar Rat
International Journal of Pharmacology | September 2022
Turmeric contains a polyphenol called curcumin, which is similar to stem cells in that it can renew identical cells and preserve proliferation and multipotency. Curcumin’s anti-inflammatory and stemness properties as well as regenerative benefits, were investigated in this study. The curcumin decreased granulation tissue intensity vs. the control group on days 7 and day 14. Curcumin significantly reduced the mean of angiogenesis vs. the negative-control group. However, curcumin significantly improves epidermal thickening vs. the negative-control group (score 1 vs. 2, p<0.05), respectively at days 21 and 28. Curcumin improves the collagen fibre, on day 21 as fascicle vs. mixed when compared to the negative-control group. While, on days 21 and 28 the mature collagen was profoundly deposited vs. moderately in the curcumin vs. control groups. Conclusion: we conclude that curcumin significantly accelerated the healing course via modulation in the amount, maturation and arrangement of collagen fibre. Curcumin had a putative regenerative property upon upregulation of CD34 as epidermal stem cell marker expression in epidermis and hair follicles.

Cocktail of isobavachalcone and curcumin enhance eradication of Staphylococcus aureus biofilm from orthopedic implants by gentamicin and alleviate inflammatory osteolysis
Microbiology | September 2022
The combination of isobavachalcone and curcumin can enhance the susceptibility of MRSA to gentamicin, thus promoting the eradication of MRSA biofilm. When administrated as cocktail in vivo, they can significantly modify local inflammation in orthopedic device-related infection and maintain trabecular bone microstructure while substantially eradication MRSA in ODRI. Although our current study did not reveal specific mechanism about the synergy of this cocktail of gentamicin, isobavachalcone and curcumin against S. aureus, their bone microarchitecture maintenance characteristic did provide us the insight and evidence for future potential topical application by incorporating the mixture of these two small molecules with conventional antibiotics, like gentamicin bone cement chain beads and antimicrobial biomaterials, etc. The combination of isobavachalcone and curcumin as adjuvants administrated together with gentamicin to significantly enhance its antimicrobial effect, which may serve as a new potential treatment strategy especially for MRSA-induced ODRI, to rationalize the use of high-level antibiotics and reduce the emergence of drug-resistant strains of bacteria.

Curcumin and Curcuma longa Extract in the Treatment of 10 Types of Autoimmune Diseases: A Systematic Review and Meta-Analysis of 31 Randomized Controlled Trials
Frontiers in Immunology | August 2022
Curcumin and Curcuma longa Extract had good clinical efficacy in the treatment of psoriasis, ulcerative colitis and rheumatoid arthritis, so Curcumin and Curcuma longa Extract could be used in the treatment of the above diseases in the future. Curcumin is the most effective ingredient extracted from the rhizomes of ginger plants such as turmeric. A number of in vitro and in vivo experiments showed that Curcumin has various pharmacological effects such as regulating immunity, anti-oxidation, inhibiting inflammation, anti-tumor, anti-angiogenesis, anti-coagulation, and scavenging free radicals. These studies suggest that Curcumin may play a regulatory role by altering the activities of enzymes, receptors, and related transcription factors. Numerous randomized controlled trials have shown that curcumin can alleviate many human diseases, including autoimmune diseases, with the main mechanisms in regulating immunity and inhibiting inflammation. Also, Curcumin is administered with few side effects, making it a potential alternative to NSAIDs and other drugs with known severe side effects. Curcumin has been shown to be a potent immunomodulator, which can modulate the activity of T cells, B cells, macrophages, neutrophils, NK cells, and dendritic cells. The diverse pharmacological activities of Curcumin stem from its ability to interact with different biological targets and signaling pathway.  Current pharmacological studies have shown that Curcumin and Curcuma longa Extract seems to reverse some clinical symptoms of many autoimmune diseases by regulating immune inflammatory biological modules, such as inflammatory factors and immune inflammatory cell activation, differentiation and immune function regulation. Curcumin and Curcuma longa Extract is an effective natural compound with a variety of therapeutic pharmacological properties and almost no side effects. Recent studies have shown that curcumin can synergistically enhance the synergistic effect of glucocorticoids and alleviate glucocorticoid-induced osteoporosis. Because of its good clinical safety, the dose of curcumin in the treatment of autoimmune diseases is mainly between 80 mg and 6000 mg. The results of Meta-analysis showed that Curcumin and Curcuma longa Extract had good clinical efficacy in the treatment of Psoriasis, UC and RA, so Curcumin and Curcuma longa Extract could be used in the treatment of the above diseases in the future.

Protective and anti-oxidative effects of curcumin and resveratrol on Aβ-oligomer-induced damage
Journal of the Neurological Sciences | August 2022
Results suggest that curcumin and resveratrol decreased ROS generation, attenuated oxidative stress, inhibited tau hyperphosphorylation, and protected SH-SY5Y cells from AβO damage. Both curcumin and resveratrol are promising supplements or medicine as therapeutic agents for the treatment of Alzheimer's disease.

Curcumin Suppresses the Progression of Colorectal Cancer by Improving Immunogenic Cell Death Caused by Irinotecan
 Chemotherapy Anticancer Section | August 2022
Curcumin, an adjuvant drug with anti-inflammatory and antitumor effects, has been studied extensively, although its synergistic antitumor effect remains unclear. Results: Irinotecan in combination with curcumin had synergistic antitumor effects in CT-26 colon carcinoma cells. Combination treatment with Irinotecan and curcumin was more effective than Irinotecan or curcumin alone. Irinotecan and curcumin combination treatment significantly upregulated ICD-related proteins including CALR and HMGB1 and had a greater antitumor effect than Irinotecan or curcumin single treatment in vivo. Curcumin may synergistically improve the antitumor effect of Irinotecan by promoting the ICD effect. Conclusion: Combination therapy with Irinotecan and curcumin may be an option for first-line chemotherapy in some patients with advanced colorectal cancer.

Effects and Mechanisms of Curcumin for the Prevention and Management of Cancers: An Updated Review
Antioxidants | August 2022
Curcumin possesses various biological activities, such as antibacterial, anti‐inflammatory, antioxidant and anticancer effects. Curcumin has shown anticancer effects on various cancers, such as breast, liver, lung, gastric and prostate cancers. For example, curcumin inhibited breast cancer cells proliferation and induced apoptosis by increasing reactive oxygen species (ROS) production. Curcumin also inhibited liver cancer. Curcumin has been selected as a third‐generation cancer chemopreventive agent by the National Cancer Institute. The anticancer effects of curcumin have been extensively studied in different cancers, such as breast, lung, colorectal, head and neck, gastric, bladder, prostate, thyroid, liver, ovarian, oral, pancreatic, cervical, tongue and brain cancers. Many studies have reported the effectiveness of curcumin in the prevention and management of various cancers, such as thyroid, breast, gastric, colorectal, liver, pancreatic, prostate and lung cancers. The potential mechanisms include inhibiting cancer cell proliferation, suppressing invasion and migration, promoting cell apoptosis, inducing autophagy, decreasing cancer stemness, increasing reactive oxygen species production, reducing inflammation, triggering ferroptosis, regulating gut microbiota, and adjuvant therapy.

Curcumin activates autophagy and attenuates high glucose‑induced apoptosis
Experimental and Therapeutic Medicine | August 2022
Curcumin is well known for its anti‑inflammatory and antioxidant effects. Accumulating evidence suggests that curcumin can act as an agent with anti‑inflammatory, antioxidant, anticarcinogenic and antilipidemic effects. Curcumin can improve gastric emptying in rats by blocking the production of oxidative stress. In addition, curcumin also induces autophagy to protect the vascular endothelial cells and reduces the cell apoptosis from the oxidative stress damage, suggesting a potential mechanism underlying the anti‑apoptosis effects of curcumin. Overall, previous studies have confirmed that curcumin has a strong antioxidant and antiapoptosis effect. Curcumin alleviated apoptosis by promoting autophagy and inhibiting the ROS/NF‑κB signaling pathway.

Identifying the Antitumor Effects of Curcumin on Lung Adenocarcinoma Using Comprehensive Bioinformatics Analysis
Drug Design, Development and Therapy | July 2022
The results of this study suggest that the therapeutic effects of curcumin on Lung Adenocarcinoma may be achieved through the intervention of INS and GCG, which may act as potential biomarkers for Lung Adenocarcinoma prevention and treatment. Curcuma longa L., also known as turmeric, has been widely used as a traditional medicine in China, India, and Southeast Asia. As the main component of turmeric, curcumin was first used to treat cholecystitis in 1937. Curcumin mediates its anticancer activity by modulating molecular targets including transcription factors, micro-RNAs, cytokines, and interfering with genes related to apoptosis and proliferation—thus inhibiting tumor cell proliferation and migration, inhibiting angiogenesis, inducing apoptosis, and increasing sensitivity to antitumor therapy. Due to its excellent pharmacological activity, curcumin is widely used in the treatment of many diseases, including gastrointestinal disease, liver cirrhosis, cardiovascular disease, diabetes, and cancer. Increasing studies suggest that curcumin inhibits the growth of lung cancer cells through multiple pathways by inducing apoptosis, inhibiting cell proliferation, and epigenetic changes. These studies have indicated that curcumin has great potential in the treatment of various diseases. We found that curcumin significantly inhibited the proliferation, migration and invasion of Lung Adenocarcinoma A549 and NCI-H1299 cells and significantly decreased the expression of INS and GCG genes.

Curcumin reduces blood-nerve barrier abnormalities and cytotoxicity to endothelial cells
Folia Morphologica | July 2022
Curcumin, a polyphenol found in the root of Curcuma longa, had favorable effects on cisplatin neuropathy in previous work. Curcumin alleviated pericyte detachment, cytotoxicity, oxidative stress, TEER reduction and tight junction protein expression. Curcumin might improve neuropathy via the restoration of BNB. Whether alterations in the BNB occur and curcumin is effective in patients with cisplatin neuropathy remain to be investigated.

The protective effect of curcumin on testicular tissue in a cryptorchid rat model
Journal of Pediatric Urology | July 2022
Curcumin administration ameliorated the histological appearance of the testis and greatly reduced the level of apoptosis in cryptorchidism rats' testicular cells. After curcumin treatment, the expression of proliferating cell nuclear antigen (PCNA) was restored in the testis tissues of cryptorchidism rats. Curcumin therapy reduced Bax expression while increasing Bcl-2 expression, according to the molecular study. Curcumin therapy also reduced malondialdehyde (MDA) levels and enhanced superoxide dismutase (SOD) levels in cryptorchidism rats' testis tissue.

Exploring the Mechanism of Curcumin on Retinoblastoma Based on Network Pharmacology and Molecular Docking
Evidence-Based Complementary and Alternative Medicine | July 2022
Curcumin shows great effects of inhibiting tumor cell proliferation, inducing apoptosis, inhibiting tumor metastasis, and inhibiting angiogenesis on a variety of tumors. Curcumin is a yellow phenolic pigment with low toxicity, wide medicinal source and low price extracted from the rhizome of Curcuma longa of the ginger family, such as turmeric, which has a wide application prospect and value in clinical treatment. We initially revealed that curcumin exerts its therapeutic effects on retinoblastoma with multitarget, multipathway, and multibiological functions, providing a theoretical basis for subsequent studies. In conclusion, this comprehensive network-based pharmacological analysis suggests a number of testable speculations on the potential molecular mechanisms of curcumin in the treatment of retinoblastoma and predicts RB1, STAT3, and CDKN2A as potential therapeutic targets.

Curcumin, thymoquinone, and 3, 3′-diindolylmethane combinations attenuate lung and liver cancers progression
Frontiers in Pharmacology Sec. Ethnopharmacology | July 2022
Results showed that triple (Curcumin  + TQ + DIM) and double (Curcumin + TQ, curcumin + DIM, and TQ + DIM) combinations of Curcumin, TQ, and DIM significantly increased apoptosis with elevation of caspase-3 protein levels. Also, these combinations exhibited significantly decreased cell proliferation, migration, colony formation activities, phosphatidylinositol 3-kinase (PI3K), and protein kinase B (AKT) protein levels with S phase reduction. Triple and double combinations of Curcumin, TQ, and DIM hindered tumor weight and angiogenesis of A549 and HepG2 implants in the chorioallantoic membrane model. Interestingly, Curcumin, TQ, and DIM combinations are considered promising for suppressing cancer progression via inhibiting tumor angiogenesis. Curcumin, the active ingredient of Curcuma longa L is the most studied compound described as a potential anticancer agent due to its multi-targeted signaling/molecular pathways (Sharma and Martins, 2020; Shah et al., 2021). Generally, Curcumin has the highest binding affinities with target proteins, followed by DIM and then TQ. Furthermore, because Curcumin, TQ, and DIM have different and common targets, we suggest treating different cancer cells. In the same context, we encourage researchers to investigate Curcumin, TQ, and DIM combination with chemotherapeutic agents investigating the effect of natural products combined with commonly used chemotherapeutics for cancer therapy.

Curcumin Alleviates D-Galactose-Induced Cardiomyocyte Senescence
Natural Products and Herbal Medicine: Safety, Efficacy, and Bioactivity | July 2022
Curcumin could be an effective anticardiac aging drug. The polyphenolic compound curcumin is derived from turmeric and possesses therapeutic and biological properties against many human health issues. Experiments in vitro and in vivo suggest that curcumin could prevent cardiovascular diseases, alleviate cardiovascular aging, and induce autophagy via various signaling pathways, including SIRT, AMPK, and mTOR. Curcumin has antioxidant, autophagy-promoting, and antiaging properties. The polyphenol compound, curcumin, extracted from turmeric, has various therapeutic uses in humans. It induces antioxidant, anti-inflammatory, anticancer, and antiaging effects. Curcumin protects against cardiovascular diseases, such as cardiac hypertrophy, heart failure, and atherosclerosis. The role of curcumin in regulating apoptosis and autophagy is well-studied, including its role in reversing the aging process and reducing oxidative stress. Curcumin ameliorates aging by promoting autophagy and reducing oxidative stress during oxidative stress-induced cardiac aging. These protective effects of curcumin in cardiac aging is consistent with the interaction between autophagy and oxidative stress. In addition, curcumin could be used as a potential pharmacological candidate for treating cardiac aging. Curcumin alleviated cardiac aging by promoting autophagy and reducing oxidative stress in vivo. The experimental results also revealed that curcumin acted as a cardioprotective agent.

The Effect of Curcumin on Lipid Profile and Glycemic Status of Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Evidence-Based Complementary and Alternative Medicine | July 2022
Curcumin supplementation had beneficial effects on glycemic status and some lipid parameters in patients with type 2 diabetes mellitus (T2DM).  Curcumin has a wide range of pharmacological effects, including antioxidant, anti-inflammatory, antibacterial, antiviral, antifungal, and antitumor properties. Experimental and clinical studies also have reported the beneficial effects of curcumin supplementation on lipid profile and glycemic status.  In conclusion, this meta-analysis provided evidence that curcumin has promising effects on the lipid profile and glycemic status in patients with T2DM. It indicated that curcumin might be a favorable therapeutic option for T2DM patients with mixed dyslipidemia.

Curcumin attenuates development of depressive-like behavior in male rats after spinal cord injury: involvement of NLRP3 inflammasome
Journal of Contemporary Medical Sciences | July 2022
Curcumin appears to constitute a suitable agent to reduce neuroinflammation and through it, relieve a depressive-like state.  Curcumin is a multifunctional drug and it has a lot of pharmacologic effects, like anti-inflammatory, anti-oxidant, and anti-infectious activities. Studies have reported that curcumin  improves neurological defects by inhibiting apoptosis and neuronal cell death and reducing inflammation. Considering the role of curcumin in reducing inflammation after spinal-cord injury and the role of NLRP3 inflammasome in starting of inflammation and also the role of the inflammatory process in depression after spinal-cord injury, the purpose of this study is investigating curcumin role in mood alterations in male rats after spinal-cord injury through focusing on the involvement of NLRP3 inflammasome. Our results suggested that administration of curcumin  decreased neuroinflammation. Based on the findings of the behavioral tests in the present study, because of safety and high ability to enhance the parameters related to depression, curcumin can be considered as a treatment for depression.

The Role of Curcumin in Prostate Cancer Cells and Derived Spheroids
Cancers | July 2022
Curcumin can suppress the proliferation of both androgen-dependent and androgen-independent PC cell lines. Consequently, curcumin administration seems to be useful in PC prevention, and in co-treatment with conventional therapy to halt PC progression towards mCRPC. Despite its widely reported health benefits, the use of curcumin is hampered by its poor bioavailability which limits its clinical application. In this regard, several strategies were developed to overcome these limitations, including improving the delivery system by encapsulating curcumin in the form of nanoparticles, designing novel structural analogs, and liposomal encapsulation and emulsions. Our study provides evidence that curcumin supplementation can be used as a preventative strategy and opens up new frontiers for further studies aimed at implementing the diet with nutraceuticals. In conclusion, despite different studies being carried out to identify the potential synergistic curcumin combinations with chemopreventive/therapeutic ef ficacy for inhibiting PC growth, to our knowledge, this study is the first to show the ability of curcumin used alone or in combinatorial approaches to impair the size and the viability of PC-derived spheroids.

Therapeutic Potential of Curcumin and its Derivatives on Brain Tumor Glioma Biology
Neurochemical Research | July 2022
Curcumin is a natural polyphenolic compound with several anti-tumor effects which potentially inhibit tumor growth, development, proliferation, invasion, dissemination, and angiogenesis in different human malignancies. Experimental model studies have demonstrated that curcumin attenuates glioma cell viability by G2/M cell cycle arrest, apoptosis, induction of autophagy, gene expression alteration, and disruption of multi-molecular pathways. Moreover, curcumin has been reported to re-sensitize cancer to chemotherapeutics as well as augment the effect of radiotherapy on glioma cells. In this review, we have provided an update on the in vitro and in vivo effects of curcumin-based therapy on gliomas. We have also discussed the use of curcumin in combination therapies, its effectiveness on drug-resistant cells, and new formulations of curcumin in the treatment of gliomas.

The Effect of Curcumin on Lipid Profile and Glycemic Status of Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Evidence-Based Complementary and Alternative Medicine | July 2002
Curcuma longa L. is a traditional medicinal plant, which is widely distributed in China and some Asian countries. Turmeric, the rhizome of Curcuma longa L, is used as a spice to improve taste and also as medicine because of its therapeutic properties. Curcuminoids, the main bioactive agents extracted from the rhizome of Curcuma longa L, is responsible for the major biological effects of turmeric. As the main present form of curcuminoids, curcumin has a wide range of pharmacological effects, including antioxidant, anti-inflammatory, antibacterial, antiviral, antifungal, and antitumor properties. Experimental and clinical studies also have reported the beneficial effects of curcumin supplementation on lipid profile and glycemic status. The results of this study showed that curcumin supplementation had beneficial effects on glycemic status and some lipid parameters in patients with Type 2 diabetes mellitus. In conclusion, this meta-analysis provided evidence that curcumin has promising effects on the lipid profile and glycemic status in patients with Type 2 diabetes mellitus. It indicated that curcumin might be a favorable therapeutic option for Type 2 diabetes mellitus patients with mixed dyslipidemia.

The Effect of Curcumin on Renal Ischemia/Reperfusion Injury in Diabetic Rats
Nutrients | July 2022
Curcumin has shown to be effective in the regulation of glycemia and lipidemia with an action mechanism similar to antidiabetic medications. In addition, recent studies have demonstrated promising effects of curcumin for the treatment of autoimmune diseases, such as type 1 diabetes. It has been also demonstrated that it could have a potential role in preventing and treating several diseases due to its antibacterial, antiviral, anti-ischemic, hepatoprotective, nephroprotective, antirheumatic and anticancer activities. his study proved the effectiveness of curcumin as a renoprotective agent in DM with I/R, becoming a promising agent for the suppression of the morbidity of DM. In addition, the study suggests that, after other preclinical studies with different formulations and administration routes designed to obtain products with higher bioavailability, with a larger sample and other methodologies for evaluating renal function and also clinical studies, curcumin can be considered a therapeutic possibility to be incorporated into the clinical treatment of diabetic patients at risk for complications of renal function. Early treatment with curcumin improved renal function in diabetic rats submitted to I/R with beneficial repercussions on renal hemodynamics and renal oxidative profile.

Curcumin as a Promising Neuroprotective Agent for the Treatment of Spinal Cord Injury: A Review of the Literature
Neurospine | July 2022
Curcumin is a promising therapeutic drug for  spinal cord injuries (SCIs)treatment because it reduces the incidence of secondary injuries.  Curcumin has antioxidant and nonsteroidal anti-inflammatory pharmacological properties. Preclinical and clinical trials have revealed its various pharmacological activities, including its anti-inflammatory, antibacterial, anticancer, and neuroprotective effects on neurodegenerative disorders. Curcumin also has hepatoprotective, nephroprotective, cardioprotective, neuroprotective, hypoglycemic, and antirheumatic activities, and its neuroprotective activity against several neurodegenerative disorders is gaining researchers’ attention. As an anti-inflammatory agent, curcumin suppresses the production of many proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-8, and monocyte chemoattractant protein 1 [8,9]. In a recent study, curcumin inhibited the hypoxia-induced upregulation of glial fibrillary acidic protein (GFAP) and neurofilament-H following hypoxia and downregulated the expression of proinflammatory cytokines, such as TNF-α and IL-1. It also suppresses glial scar formation and GFAP expression, contributing toward the development of a more favorable environment for neurological recovery. Curcumin is a neuroprotective polyphenolic compound that has benefits such as pluripotency, oral safety, long usage history, and low cost. Several animal experiments have shown that curcumin can minimize secondary injury following primary SCIs through its anti-inflammatory, antioxidant, and stem cell mobilization properties. Curcumin is an influential therapeutic agent that can potentially treat catastrophic secondary injuries in the spinal cord, including inflammation, edema, free radical injury, fibrosis, and glial scar formation. It can enhance neurological function in rats, as measured using the BBB locomotor rating scale.

Antioxidant Potential of Phytoconstituents with Special Emphasis on Curcumin
Antimicrobial and Pharmacological Aspects of Curcumin | July 2022
The medicinal properties of turmeric, the source of curcumin, have been known for thousands of years; however, the ability to determine the exact mechanism(s) of action and to determine the bioactive components have only recently been investigated. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), also called diferuloylmethane, is the main natural polyphenol found in the rhizome of Curcuma longa (turmeric). Curcumin, a polyphenol, has been shown to target multiple signaling molecules while also demonstrating activity at the cellular level, which has helped to support its multiple health benefits such as antioxidant, anti-inflammatory, antimutagenic, antimicrobial and anticancer properties.

Curcumin improves D-galactose and normal-aging associated memory impairment in mice: In vivo and in silico-based studies
Plos One | July 2022
Curcumin, a natural flavonoid, has potent antioxidant and anti-aging properties. Curcumin significantly increased retention time (p < 0.05) and freezing response (p < 0.05) in PA and CFC, respectively. Curcumin profoundly ameliorated the levels of glutathione, superoxide dismutase, catalase, advanced oxidation protein products, nitric oxide, and lipid peroxidation in mice hippocampi. In silico studies revealed favorable binding energies of curcumin with GSTA1, GSTO1, KEAP1, BACE1, and MAOA. Curcumin improves retention and freezing memory in D-gal and nature-induced aging mice. Curcumin ameliorates the levels of oxidative stress biomarkers in mice. Anti-aging effects of curcumin could be attributed to, at least partially, the upregulation of antioxidant enzymes through binding with GSTA1, GSTO1, KEAP1, and inhibition of oxidative damage through binding with BACE1 and MAOA. We investigated the detailed effects of curcumin on oxidative stress in the D-gal and nature-induced aging mice model. Our in vivo study suggested that curcumin improves memory and rescues learning impairment by modulating oxidative stress levels. Furthermore, our in-silico study demonstrated that curcumin has good binding affinities for several molecular targets implicated in redox homeostasis. Finally, based on our in vivo and computational studies, it can be stated that curcumin improves aging-associated memory impairment by reducing oxidative overload in mice.

Effects of curcumin on low-density lipoprotein (LDL) oxidation from experimental studies to clinical practice
Excli journal | July 2022
Curcumin is a potent antioxidant and has a strong track record in the treatment of numerous diseases. Recent studies indicate that Curcumin exerts a lipid-lowering effect, and can modulate the formation of atherosclerotic plaque. Curcumin has a long history in the treatment of diseases, such as gastric and hepatic disorders, dental problems, menstrual difficulties, infectious diseases, malignancies, immune-related and metabolic disorders (Sahebkar and Henrotin, 2016; Panahi et al., 2017; Bagherniya et al., 2018; Parsamanesh et al., 2018; Gorabi et al., 2019; Mortezaee et al., 2019; Shakeri et al., 2019; Zahedipour et al., 2020; Afshari et al., 2021; Fu et al., 2021; Mohammed et al., 2021). Anti-inflammatory and antioxidant properties of Curcumin, a polyphenol, have been reported in numerous studies (Menon and Sudheer 2007; Shehzad et al., 2011; Momtazi-Borojeni et al., 2018; Farhood et al., 2019). Curcumin can improve the lipid profile of patients by reducing serum triglyceride (TG), LDL and total cholesterol levels significantly in subjects with coronary artery disease. Curcumin decreases the aortic lipid lesions and inhibits development of atherosclerotic plaques (Wongcharoen and Phrommintikul 2009). Curcumin demonstrates antioxidant activity because the benzene rings in the structure of the Curcumin molecule eliminate reactive oxygen species (ROS) (Joe and Lokesh, 1994). According to cardiac-related studies, serum levels of lipid peroxides are higher in patients with IHD; Curcumin is able to reduce lipid peroxide concentration (Stringer et al., 1989; Soni and Kuttan 1992). These actions could indicate that curcumin also inhibits ox-LDL elevation. Overall, our results suggest that curcumin could be effective in reducing LDL oxidation.

Curcumin inhibits the replication of rotavirus in vitro
Acta Virologica | July 2022
The present study aims to determine the effect of curcumin, a natural polyphenol compound, on rotavirus in a cell culture model. The anti-viral activity of curcumin was evaluated by reverse-transcriptase quantitative PCR (RT-qPCR), TCID50, and western blot techniques to assess CC50 in curcumin-treated MA104 cells as well as EC50 and SI within the infected MA104 cell line. Our findings supported that curcumin exerted an inhibitory influence against rotavirus in a dose-dependent manner and decreased the viral titer and VP6 expression by ~99% at a concentration of 30 μM.

How Curcumin Targets Inflammatory Mediators in Diabetes: Therapeutic Insights and Possible Solutions
Molecules | July 2022
Curcumin, a polyphenol derived from turmeric, is well known for its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Curcumin’s anti-inflammatory and anti-oxidative activities against a wide range of molecular targets have been shown to have therapeutic potential for a variety of chronic inflammatory disorders, including diabetes. Curcumin’s biological examination has shown that it is a powerful anti-oxidant that stops cells from growing by releasing active free thiol groups at the target location. Curcumin is a powerful anti-inflammatory agent that targets inflammatory mediators in diabetes, and its resistant form leads to better therapeutic outcomes in diabetes complications. Moreover, Curcumin is an anti-oxidant and NF-B inhibitor that may be useful in treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase and aldose reductase inhibitors. Through its anti-oxidant and anti-inflammatory effects, and its suppression of vascular endothelial development and nuclear transcription factors, curcumin has the ability to prevent, or reduce, the course of diabetic retinopathy. Curcumin improves insulin sensitivity by suppressing phosphorylation of ERK/JNK in HG-induced insulin-resistant cells and strengthening the PI3K-AKT-GSK3B signaling pathway. Curcumin is an anti-oxidant and NF-κB inhibitor that may be useful in preventing and treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase, and aldose reductase inhibitors . Curcumin has been shown to have therapeutic potential in the prevention, or delaying, of diabetic retinopathy, by acting as an anti-oxidant and an anti-inflammatory, and inhibiting vascular endothelial development and nuclear transcription factors. Curcumin’s current applications for glycemia and diabetes-related liver illnesses, neuropathy, adipocyte dysfunction, vascular diseases, nephropathy, and pancreatic disorders were described in. Curcumin has shown efficient anti-inflammatory, anti-apoptotic and anti-oxidant potential. In patients with metabolic syndrome, short-term treatment with a curcuminoid-piperine combination reduced inflammatory status dramatically. Curcuminoids are effective, safe and natural CRP-lowering compounds. In addition, curcumin reduces levels of inflammatory mediators and factors, such as TNF-α, INF-γ, reduces systemic inflammatory biomarkers. such as RANTES. and other cytokine levels. Curcumin also reduces the levels of inflammatory cytokines, such as IL-6 and IL-1β, and targets inflammatory mediators in insulin diabetes resistance. Curcumin restores dysfunction associated with Nrf2 that helps in diabetes resistance management. Similarly, curcumin inhibits inflammatory signaling and the expression of Kelch-like ECH-associated protein 1 (Keap1), resulting in activation of the Nrf2 system. Curcumin metabolites have shown significant results in diabetes mellitus treatment focusing on inflammatory mediators.

Curcumin Increased the Sensitivity of Non-Small-Cell Lung Cancer to Cisplatin through the Endoplasmic Reticulum Stress Pathway
Evidence-Based Complementary and Alternative Medicine | July 2022
Curcuma longa was reported to possess antitumor activity through regulating oncogene expression, cell cycle regulation, apoptosis, tumorigenesis, and metastasis. Recently, curcumin was found to promote chemotherapeutic efficiency in various cancers and diseases. For instance, Zou et al. reported that curcumin increases breast cancer cell sensitivity to cisplatin by decreasing FEN1 expression. Lu et al. found that curcumin can increase the sensitivity of paclitaxel-resistant non-small-cell lung cancer cells to paclitaxel through microRNA-30c-mediated MTA1 reduction. Recently, curcumin was found to increase effects of irinotecan through mediating the ER stress pathway in colorectal cancer cells. Misra et al. found that curcumin regulates ER stress through cAMP responsive element-binding protein H.  Curcumin can enhance the chemosensitizing effect of non-small-cell lung cancer cells by targeting the ER stress pathway. Taken together, this study demonstrated curcumin can increase DDP sensitivity of non-small-cell lung cancer cells through mediating the ER stress pathway. The results of this study proposed a possible mechanism of curcumin improving DDP sensitivity in non-small-cell lung cancer cells and may shed a little light on developing the molecular targets in the ER stress pathway to overcome the DDP resistance in non-small-cell lung cancer.

Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain
Scientific Reports | June 2022
Curcumin is a natural polyphenol and has beneficial therapeutic effects on pain. Curcumin has been used as an analgesic adjuvant with several analgesic drugs, allowing synergistic antinociceptive effects. Coadministration of curcumin and metformin at a 1:1 fixed ratio of their ED50 doses significantly reduced the dose required to produce a 50% effect compared to the theoretically required dose in phase II of the formalin test with a combination index value of 0.24. Our findings suggest that curcumin exerts synergistic anti-inflammation with metformin with no potential CNS adverse effects. Curcumin has been used as a traditional herbal remedy for centuries throughout Asia due to its pleiotropic activities, including anti-inflammatory, antioxidant, and anticancer. It is a well‐tolerated natural product causing no or minimal toxicity in short- and long-term use. Consequently, it was declared “generally recognized as safe” by the US Food and Drug Administration (FDA)21. Moreover, the therapeutic effectiveness of curcumin in nociceptive, inflammatory, and neuropathic pain has been reported in numerous animal models and humans. Dual treatment with curcumin and metformin has been reported in diabetic mellitus, diabetes-induced comorbidities, nephrotoxicity, hepatocellular carcinoma, pancreatic cancer cells, and breast cancer, with the results suggesting synergistic effects. Moreover, metformin and curcumin have different mechanisms of action in pain modulation, which indicates the potential for exerting greater analgesia when administered together.  In summary, this study suggests for the first time that curcumin combined with metformin exerts synergistic anti-inflammatory effects in both in vitro and in vivo conditions. Curcumin synergistically augmented the inhibition of nitric oxide and proinflammatory cytokines by metformin both in RAW 264.7 macrophage and BV-2 microglial cells.  Moreover, the combined therapy using curcumin and metformin showed no considerable CNS adverse effects in naïve mice. Hence, this study supports the possibility of combined use of curcumin and metformin in the treatment of pain with the least amount of medication while taking the easiness of administration, cost of the therapy, and side effect profile of medicines into the account.

 Combined Curcumin and Luteolin Synergistically Inhibit Colon Cancer Associated with Notch1 and TGF-β Signaling Pathways in Cultured Cells and Xenograft Mice
Cancers | June 2022
A combination of luteolin (30 µM) and curcumin (15 µM) was selected as the optimum combination for the study due to a low combination index of 0.25 and its highest synergistic inhibitory effect on the growth of two human colon cancer cell lines CL-188 and DLD-1. Consistent with in vitro results, intraperitoneal injection of luteolin at 10 mg/kg body weight and curcumin at 20 mg/kg body weight in BALB/C Foxn nude mice for a 2-week period synergistically inhibited CL-188 cell-derived tumor growth. Further analysis showed that the synergistic anti-colon cancer effect exhibited by curcumin and luteolin was mediated through the downregulation of the effector protein Notch1, to induce growth cycle arrest, promote apoptosis, and TGF-β signaling inhibits angiogenesis and invasion in vitro and in vivo. These data demonstrate that a combination of curcumin and luteolin exerts an anti-colon cancer effect through the modulation of Notch1 and TGF-β signaling pathways, well-known in cancer growth, invasion, and metastasis.

Antioxidant Potential of Phytoconstituents with Special Emphasis on Curcumin
Antimicrobial and Pharmacological Aspects of Curcumin | June 2022
Curcumin, a polyphenol, has been shown to target multiple signaling molecules while also demonstrating activity at the cellular level, which has helped to support its multiple health benefits such as antioxidant, anti-inflammatory, antimutagenic, antimicrobial and anticancer properties. Curcumin has received worldwide attention for its multiple health benefits, which appear to act primarily through its anti-oxidant and anti-inflammatory mechanisms. Many major diseases such as liver problem, myocardial infarction, diabetes, cancer are believed to be associated with lipid peroxidation and thus causing major cell damage. Curcuminoids and other polyphenols in turmeric can ameliorate and prevent lipid peroxidation, can stabilize the cell membrane, hence proving its significant role in prevention of atherosclerosis. Inhibitory action of   curcumin  on lipid accumulation, oxidation, nitric oxide as well as the formation of inflammatory molecules, nuclear factor-kappa B- (NF-kB-) dependent gene expression, and its activation can thus influence therapeutic potential of turmeric in the treatment of pancreatic, hepatic, cancer and intestinal diseases. Curcumin can produce promisable symptomatic relief on external cancerous lesions in human. Along with this, curcumin has resulted to be effective in preventing and treatment of many of the neurodegenerative disorders as a free radical scavenger including Alzheimer’s disease. Also after giving short-term supplementation it has proved to reduce hematuria, proteinuria, including systolic blood pressure in patients with relapsed or refractory lupus nephritis. By referring all the literature, Curcumin can be considered as a safe adjuvant therapy. The previous studies had indicated that the high antioxidant properties of turmeric was found to inhibit cellular lipid peroxidation and can also ameliorate other oxidative damage caused by free radicals. Thus Turmeric is proven to be an important source of high contents of flavonoids, polyphenols, tannins and ascorbic acid. Curcumin as important phytoconstituent of turmeric varieties is and effective and important antioxidant compound and which can be effective in management of various diseased conditions.

Efficacy of Curcumin on Treating Cancer Anorexia-Cachexia Syndrome in Locally or Advanced Head and Neck Cancer: A Double-Blind, Placebo-Controlled Randomised Phase IIa Trial
Journal of Nutrition and Metabolism | June 2022
Curcuminoids are the extracts from curcumin, which both in vitro and in vivo studies have shown the inhibitory effect of NF-kB through intracellular phosphorylation. Siddiqui et al. demonstrated that 100 mg/kg of curcumin prevented weight loss in MAC16 colon tumour mice. Moreover, the increasing dose of curcuminoid (up to 250 mg/kg) showed a 25% increase in body weight in mice. Additionally, Gil da Costa et al. discovered preventing myolysis in HPV-16-infected mice from curcuminoids by the mechanism of downregulation of NF-kB synthesis resulted in increased muscle mass or delayed muscle wasting compared with controlled mice. For curcumin in clinical studies, Gupta et al. showed that patients with solid cancer receiving chemotherapy and curcumin for eight weeks showed a significant improvement in their quality of life and a declined NF-kB level compared with the controlled arm. Recently, our previous study showed that 800 mg/day of curcumin delayed the progression of handgrip muscle strength loss and basal metabolic rate significantly among patients with solid cancer, as well as there were no serious adverse events. Our study results showed significantly improved skeletal muscle mass with the use of curcumin compared with matching placebo, in which the difference in the percent change in muscle mass between the groups was significant. Moreover, body fat mass among patients treated with curcumin showed a slower decline than patients treated with matching placebo, even though no statistically significant difference was noted between the two groups, but the trend seems to favour curcumin. Our study showed that patients treated with curcumin improved handgrip strength at week 8, but loss of handgrip strength was observed in the matching placebo group. Furthermore, in vivo studies demonstrated curcumin's crucial significant immunomodulatory effect by stimulating PBMC proliferation and cytokine production. Our study results supported the related in vivo study that curcumin administration for eight weeks resulted in less lymphocyte suppression compared with the matching placebo group. The potential role of curcumin regarding the immunomodulatory effect should be further investigated among patients with cancer during treatment with chemotherapy or immunosuppressive agents. For safety endpoint, phase I studies suggested that curcumin at a dose up to 8,000 mg once daily orally can be safely administered without dose-limiting toxicity. Our study results demonstrated that curcumin was well tolerated at a dose of 4,000 mg/day and showed only mild grade of adverse events. No serious adverse events were reported.

Review of the Effects and Mechanism of Curcumin in the Treatment of Inflammatory Bowel Disease
Frontiers in Pharmacology | June 2022
Curcumin has been used as a traditional herbal medicine in India and Southeast Asia for thousands of years. It is often used to treat biliary tract diseases, anorexia, rhinitis, cough, rheumatism, and various chronic inflammatory diseases. Due to its extensive biological activities, it has received widespread attention from researchers in recent years. Current researching indicates that curcumin has high medical value, including anti-inflammatory, antioxidant, anti-tumor, anti-apoptotic, anti-fibrosis, immune regulation and other effects, and can be used to treat a variety of diseases (Salehi et al., 2019). It is involved in many significant genetic and biochemical pathways (Karthikeyan et al., 2020; Moniruzzaman and Min, 2020; Beyene et al., 2021). Curcumin is associated with many cellular targets (i.e., NF-κB, JAKs/STATs, MAPKs, TNF-γ, IL-6, PPARγ, and TRPV1) that effectively reduce the progression of IBD. The research of curcumin and related formulations for IBD treatment has surged over the decade (Kahkhaie et al., 2019; Sharma et al., 2019; Patel et al., 2020). So far, a large number of basic and clinical studies have shown that curcumin has the effect of treating IBD and also can maintain the remission of IBD (Yang H. et al., 2017). In this review, the researches of IBD genetics and pathogenesis and curcumin molecular targets in IBD in recent years are summarized in order to provide reference for further research and application of curcumin. Current researching indicates that curcumin has high medical value, including anti-inflammatory, antioxidant, anti-tumor, anti-apoptotic, anti-fibrosis, immune regulation and other effects, and can be used to treat a variety of diseases. A large number of basic and clinical studies have shown that curcumin has the effect of treating IBD and also can maintain the remission of IBD. In this review, the research of curcumin on IBD in recent years is summarized in order to provide reference for further research and application of curcumin. At present, many researches have proved that curcumin is safe and effective through DBPC test (Heger, 2017). Curcumin may not fit medical chemists’ definition of the perfect drug, but many in vitro, in vivo and clinical trials have irrefutably confirmed its medicinal potential (Li et al., 2015; Beloqui et al., 2016; Yang et al., 2018; Yue et al., 2019; Wei et al., 2021). We searched ClinicalTrials.gov to identify current clinical trials evaluating curcumin treatment for IBD. A total of 10 trials were included. Three of them have been completed and five are in phase 3. Curcumin has less adverse reactions and high safety during use. As a potential chemotherapeutic drug, it shows a good application prospect in both basic experimental researches and clinical trials of IBD over the decades (Shapira et al., 2018; Sadeghi et al., 2020; Sugimoto et al., 2020; Banerjee et al., 2021).

A study on the effects of inhibition mechanism of curcumin, quercetin, and resveratrol
Journal of Biomolecular Structure and Dynamics | June 2022
Curcumin is the much better inhibitor than quercetin and resveratrol for hGR according to both in vitro and in silico studies. Curcumin, a potential inhibitor of hGR, can be used in drug design to target the glutathione system in cellular injury.

Curcumin as adjuvant treatment in patients with non-alcoholic fatty liver (NAFLD) disease: A systematic review and meta-analysis
Complementary Therapies in Medicine | June 2022
Turmeric (Curcuma longa) has active constituents in its rhizome called curcuminoids, with the most prominent curcuminoid called curcumin. Curcumin is acknowledged as a powerful antioxidant and anti-inflammatory agent. Curcumin is given through an oral capsule and taken daily.  Two trials’ participants received 500 mg curcumin and 5 mg piperine/day as intervention. A review reported that the consumption of curcumin significantly reduced liver enzymes, decreased low-density lipoprotein and total cholesterol among non-alcoholic fatty liver disease (NAFLD) patients. Another review found curcumin showed significant effects on fasting blood sugar, insulin level, and homeostasis model of assessment insulin resistance8 among women with polycystic ovary syndrome. Curcumin is anticipated to function as antiviral drugs to treat the current COVID-19 virus based on in vitro and in vivo studies as it showed high inhibitory activity towards the virus. Computer simulation and molecular docking showed the good ability of this monomer to bind to the COVID virus and host target so that they could block the virus-host binding sites. Curcumin has been shown to improve non-alcoholic fatty liver disease (NAFLD) severity and increase liver steatosis resolution compared to the placebo groups. Besides improving the liver ultrasonographic findings, curcumin also reduced serum liver enzymes, total cholesterol, and BMI. There is no major side effect, and our findings showed no difference in the adverse effect between the two groups. Curcumin was also found to reduce triglycerides if taken more than eight weeks’ duration.  Our meta-analysis shows that curcumin has favorable effect on liver ultrasonographic findings, reduced serum liver enzymes, total cholesterol, and BMI in participants with non-alcoholic fatty liver disease (NAFLD). Therefore, promoting curcumin as an adjuvant treatment on non-alcoholic fatty liver disease (NAFLD) patients might be justified.

Profiling of curcumin-treated T47D human breast cancer cells by a system-based approach
Gene Reports | June 2022
This study investigated the regulatory mechanism of curcumin in breast cancer cells. Curcumin triggers cell death-related pathways and regulates the metabolism of lipids and apoptotic processes in T47D cells. Curcumin signature had significant prognostic power. Regulatory network analyses found specific proteins, microRNAs and transcription factors as the hub nodes, which corresponded to the effects of curcumin treatment. This work provides a picture of the cytotoxicity mechanism of curcumin and potential therapeutic targets for treatment optimization of breast cancer.

The efficacy of curcumin-piperine co-supplementation on clinical symptoms, duration, severity, and inflammatory factors in COVID-19 outpatients: a randomized double-blind, placebo-controlled trial
Trials | June 2022
Curcumin as an anti-inflammatory agent can have a positive effect on the control of COVID-19 complications. This study aimed to assess the efficacy of curcumin-piperine supplementation on clinical symptoms, duration, severity, and inflammatory factors in patients with COVID-19. Forty-six outpatients with COVID-19 disease were randomly allocated to receive two capsules of curcumin-piperine; each capsule contained 500 mg curcumin plus 5 mg piperine or placebo for 14 days. The present study results showed that curcumin-piperine co-supplementation in outpatients with COVID-19 could significantly reduce weakness.

Curcumin attenuates vascular calcification via the exosomal miR-92b-3p/KLF4 axis
Experimental Biology and Medicine | June 2022
Curcumin is a natural polyphenolic compound that has hypolipidemic, anti-inflammatory, and antioxidant effects on the cardiovascular system. Exosomes are known to have extensive miRNAs for intercellular regulation. Our study suggests that curcumin  attenuates vascular calcification.

Role of Curcumin in the Management of Schizophrenia: A Narrative Review
Indian Journal of Psychological Medicine | June 2022
Curcumin is a polyphenolic molecule derived from Curcuma longa. In traditional medicine, turmeric is commonly used as an anti-inflammatory and antiseptic agent. Its antioxidant property and low toxicity potential are utilized in physical disorders like rheumatioid arthritis, cardiovascular disorders, asthma, and neuropsychiatric disorders like Alzheimer’s dementia and Parkinsonism. There are no available reports of toxicity in humans following long-standing use of curcumin. An exploratory proof-of-concept study examined the effects of curcumin combined with piperine (from black pepper extract–used to improve the bioavailability of curcumin) as an add-on to the ongoing antipsychotic treatment. Fifteen chronic schizophrenia patients were randomized to receive 1 g vs 4 g of add-on curcumin and piperine compounds. At the end of 16 weeks, both groups showed significant improvements in total scores and general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS). Both the doses were tolerated well without much adverse effects. The role of curcumin in the management of depression and bipolar disorder has been proposed recently. Curcumin as an add-on to antidepressant drugs has been convincingly shown to reduce depressive symptoms, compared to placebo add-on. A recent meta-analysis supported the utility of adjunctive curcumin in the management of depression and anxiety disorders. Notably, curcumin was tolerable and safe in all those randomized human clinical trials.  Preclinical studies support curcumin’s role in ameliorating the metabolic side effects of antipsychotics such as olanzapine 28 and clozapine. Also, pretreatment with curcumin prevented the development of tardive extrapyramidal syndromes. In both haloperidol and clozapine exposed rats, pretreatment with curcumin successfully prevented the development to tardive orofacial movements. Curcumin’s antioxidant, free radical scavenging, and antiapoptotic properties are postulated to underlie this preventive mechanism. Preclinical studies also reported curcumin’s beneficial effects in preventing and reducing extrapyramidal and metabolic side effects. Preclinical and clinical trials reported curcumin’s potential role in the management of schizophrenia.

Comparative Study of the Anticoagulant Activity of Zingiber Officinale and Curcuma longa Rhizomes Extracts in Blood Samples of Normal Individuals
Pakistan Journal of Medical & Health Sciences | June 2022
The in vitro anticoagulant effect demonstrated that ginger and curcumin extracts had equal anticoagulant activity, but curcumin has a higher anticoagulant impact with considerable PT prolongation.

Curcumin and Related Compounds in Cancer Cells: New Avenues for Old Molecules
Frontiers in Pharmacology | June 2022
Curcumin and related compounds are bioactive compounds mainly derived from natural sources and known for years for their pleiotropic effects. These compounds show anti-viral, anti-fungal, anti-microbial and anti-tumor effects (Chiao et al., 1995; Beauregard et al., 2015; Balaha et al., 2021), mainly ascribable to anti-inflammatory and antioxidant activities. Curcumin and derivatives have been proposed as potential therapeutic agents in selected cancer types such as prostate, colon, breast and thyroid cancer (Schwertheim et al., 2017; Mbese et al., 2019) and their anticancer effects have been tested in vitro and in vivo in combination with chemotherapeutic agents and radiotherapy (Yu et al., 2021). Curcumin has shown to amplify the anticancer effects of drugs (e.g., doxorubicin, cisplatin, gefitinib) and radiotherapy (Tan and Norhaizan, 2019; Ashrafizadeh et al., 2020). For instance, curcumin displays a synergistic effect with some chemotherapeutic agents such as 5-fluorouracil and oxaliplatin (Farhood et al., 2019) while protecting normal tissues from cell death, and therefore without side effects.

Effect of Interval Training and Curcumin on BAX, Bcl-2, and Caspase-3 Enzyme Activity in Rats
Gene, Cell and Tissue | June 2022
Curcumin is a polyphenol used as a painkiller, anti-inflammatory agent, and a source of powerful antioxidants. Numerous studies have confirmed the biological effects of curcumin and introduced it into various pathological conditions. It contains many anti-diabetic, anti-tumor, anti-inflammatory, and antioxidant agents. Curcumin activates the caspase-3 enzyme and releases cytochrome c from the mitochondria to the cytosol. Also, curcumin can improve athletic performance and delay exercise fatigue. Studies have shown that curcumin synergizes with 5-fluorouracil and enhances apoptosis in cancer cells in xenograft mice. If curcumin enters cancer cells, it activates programmed cell death pathways.  High-intensity interval training did not reduce BAX protein, but the training and curcumin supplementation increased Bcl-2 protein expression and neutralized the BAX effect. Curcumin supplementation combined with intense interval training resulted in synergy and reduced cell programming mortality. Therefore, curcumin supplementation and intermittent exercise can reduce cell apoptosis and programmed cell death.

Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway
Frontiers in Cell and Developmental Biology | June 2022
Curcumin, a natural hydrophobic polyphenol compound responsible for the yellow color in Curcuma longa, has gathered attention from various research fields due to its natural antioxidant, anticancer, anti-inflammatory, antiangiogenic, and antiapoptotic effects (Gururaj et al., 2002; Majithiya and Balaraman, 2005; Koeberle et al., 2009; Perrone et al., 2015; Zhang et al., 2020). The effect of curcumin on high glucose-induced podocyte injury has been discussed in few studies, mainly focusing on curcumin’s antioxidant and anti-inflammatory properties (Kanitkar et al., 2008; Meng et al., 2013; Den Hartogh et al., 2019). Curcumin has recently been reported to have a protective effect on hepatocyte or neuronal cells prone to necroptosis (Dai et al., 2013; Lu et al., 2016). Our study showed that curcumin had protective effects against oxidative stress, inflammatory response, and fibrosis in high glucose-induced podocyte injury, eventually improving podocyte function. These renoprotective effects of curcumin might be associated with its ability to inhibit high glucose-induced RIPK3 expression by inhibiting oxidative stress. Our observations suggest that curcumin might be a potential therapeutic agent to minimize the progression of podocytopathy caused by diabetes as an inhibitor of RIPK3. Results indicate that curcumin treatment can protect against high glucose-induced podocyte injuries by suppressing the abnormal expression of ROS and RIPK3. Thus, curcumin might be a potential therapeutic agent for diabetic nephropathy as an inhibitor of RIPK3.

Curcumin activates NLRC4, AIM2, and IFI16 inflammasomes and induces pyroptosis by up-regulated ISG3 transcript factor in acute myeloid leukemia cell lines
Cancer Biology & Therapy | June 2022
Curcumin, an active ingredient derived from turmeric, has been recognized for its medicinal properties, including antioxidant, anti‐inflammation, radical‐scavenging, anti-solid and -blood tumor, and so on. The anticancer effects of curcumin mainly result from multiple biochemical mechanisms that are involved in the regulation of programmed cell death, such as apoptosis, autophagy. Recent studies have found that curcumin can induce pyroptosis of solid tumor cells. Prior studies have shown that curcumin exert anti-cancer effects by induction of apoptosis and autophagy. We have discovered that curcumin can induce leukemia cell death by increasing apoptosis and pyroptosis and that activated AIM2, IFI16, and NLRC4 inflammasomes play a key role in this process. In addition, the anti-leukemia effect of curcumin is affected by the expression of GSDMD. Thus, pyroptosis may be a potential new strategy for treating leukemia, and GSDMD is a biomarker to evaluate curcumin sensitivity in the leukemia therapy.

Effect of Curcumin on Apoptosis of Acute T-Lymphoblastic Leukemia Cells
CNKI | June 2022
Curcumin can enhance the apoptosis of T-cell acute lymphoblastic leukemia (T-ALL) cells induced by Mcl-1 small molecule inhibitor UMI-77 by reducing the mitochondrial membrane potential, the mechanism may be related to the inhibition of Notch1 signaling pathway.

Curcumin inhibits the cancer‑associated fibroblast‑derived chemoresistance of gastric cancer
International Journal of Oncology | June 2022
Curcumin abrogated the CAF‑mediated activation of the JAK/STAT3 signaling pathway in GC cells. In vivo data revealed the synergistic effects of curcumin with 5‑FU treatment in xenograft GC tumors. These data strongly suggest that the suppression of the JAK/STAT3 signaling pathway counteracts the CAF‑induced chemoresistance of GC cells. It is suggested that curcumin may be a suitable natural product which may be used to overcome chemoresistance by inhibiting the CAF‑induced activation of the JAK/STAT3 signaling pathway in GC.

The effect of curcumin supplementation on delayed-onset muscle soreness, inflammation, muscle strength, and joint flexibility: A systematic review
Phytotherapy Research | May 2022
Curcumin supplementation significantly reduced serum creatine kinase activity, muscle soreness, and TNF-α concentration. Also, curcumin supplementation elicited significant improvements in maximal voluntary contraction (MVC) and range of motion (ROM). Curcumin supplementation may improve some aspects of delayed-onset muscle soreness (DOMS), including muscle damage, muscle soreness, inflammation, muscle strength, and joint flexibility.

Antiproliferative Effects of Curcumin Different Types of Breast Cancer
Journal of Cancer Prevention | May 2022
Breast cancer is one of the most frequently diagnosed malignancy among women. Turmeric is isolated from Curcuma longa. Curcumin is main curcuminoid of the turmeric which is a member of Zingiberaceae. In this current study antiproliferative effects of curcumin were investigated in luminal A breast cancer cell line MCF-7 and triple negative breast cancer cell line MDA-MB-231. Curcumin, which has antiproliferative effects on breast cancer cells, is thought to be effective in cancer treatment.

Effect of Curcumin on Hippocampal Neurons, Learning, and Spatial Memory in a Model of Global Cerebral Ischemia
Red Crescent Medical Journal | May 2022
Curcumin administration reduced spatial memory impairment in the treatment group compared to the ischemia group. These results suggest that pretreatment with curcumin can improve memory and learning disorders and hippocampal neuron damage following ischemia.

Role of curcumin in ameliorating hypertension and associated conditions: a mechanistic insight
Molecular and Cellular Biochemistry | May 2022
Since ancient times, curcumin has been in use as food spices and folk remedy to treat cough, cold, cuts and wounds, and skin diseases. Preclinical and clinical studies have indicated that curcumin acts a promising therapeutic agent in the management of a wide array of health issues, viz., hyperlipidemia, metabolic syndrome, anxiety, arthritis, cancer and inflammatory diseases. Owing to its enormous potential, recent research has been focused on the synthesis of curcumin and its analogues for the management of metabolic disorders. In the current scenario, hypertension is considered as a key risk factor due to its involvement in various pathogeneses. Mechanistically, curcumin and its analogues have been reported to elicit anti-hypertensive effect through diverse signalling pathways.

The effects of curcumin as dietary supplement for patients with COVID-19: A systematic review of randomized clinical trials.
Drug Discoveries & Therapeutics | May 2022
Accumulating evidence has been reported regarding the effect of curcumin as a dietary antiviral on patients with COVID-19. Our review revealed that curcumin might have a positive effect on relieving COVID-19 related inflammatory response due to its powerful immune-modulatory effects on cytokines production, T-cell responses, and gene expression. These findings suggest that curcumin confers clinical benefits in patients with COVID-19.

Molecular Mechanism of Curcumin and Its Analogs as Multifunctional Compounds against Pancreatic Cancer
Nutrition and Cancer | May 2022
Curcumin is a natural chemical substance obtained from plants with a wide range of pharmacological activities. Research evidence suggests that curcumin can influence PC development through multiple molecular mechanisms.  This review aims to summarize the mechanisms of action of curcumin in preclinical and clinical studies on PC and research progress in enhancing its bioavailability.

An Overview of Parkinson's Disease: Curcumin as a Possible Alternative Treatment
Cureus | May 2022
Curcumin, turmeric's active ingredient, has antioxidant, anti-apoptotic, and anti-inflammatory properties that protect tissues from the harmful effects of reactive oxygen species (ROS).  Curcumin's protective properties start with its ability to cross the blood-brain barrier due to its lipophilic nature. Curcumin has various protective properties in the brain, including protection against toxic metals and ROS. Toxic metal ions can interfere improperly with tissues in the brain, causing neurological damage. Curcumin, as a flavonoid, has antioxidant properties that are potentially stronger than typical antioxidants such as vitamins C and E. Curcumin also protects against A53T α-synuclein aggregation and monoamine oxidase B, becoming a compound of interest in treating neurodegenerative disorders such as Parkinson's disease. Curcumin has been found to protect nigrostriatal dopaminergic neurons from damage in animal models. Curcumin had protective effects on alpha7-nicotinic acetylcholine receptors after administration of 6-hydroxydopamine (6-OHDA) in rats with a curcumin dose of 200 mg/kg. Curcumin restored nigrostriatal dopamine neurons to 87.3% and 84.8%. Curcumin's ability to donate an H ion from the beta-diketone moiety is thought to be responsible for its anti-ROS properties. Curcumin protects mitochondria and neurons from the damaging effects of ROS by donating an H ion. Curcumin's powerful antioxidant capabilities, including chelation of harmful metals and lowering ROS, may help reduce inflammation and apoptosis. Because neurons are terminal tissues, reducing ROS may improve their longevity and the efficacy of pharmaceutical therapies. These findings imply that curcumin could be used in conjunction with standard Parkinson's disease medication to improve treatment and results. 

Antitumor Properties of Curcumin in Breast Cancer Based on Preclinical Studies: A Systematic Review
Cancers | May 2022
Studies have shown that curcumin administered at different concentrations inhibited proliferation, decreased viability, and induced apoptosis in human and animal breast cancer cells.  This review assesses the antitumor effects of curcumin on breast cancer reported in preclinical in vitro and in vivo animal models. We used five databases to search for preclinical studies published up to May 2021. The assessments included the effects of curcumin on the proliferation, viability, and apoptosis of breast cancer cell lineages and on tumor volume. In total, 60 articles met the inclusion criteria. Curcumin administered at different concentrations and via different routes of administration inhibited proliferation, decreased viability, and induced apoptosis in human and animal breast cancer cells.

Docking Analysis of Some Bioactive Compounds from Traditional Plants against SARS-CoV-2
Molecules | May 2022
Curcumin and its analogues are the main phytonutrients of turmeric (Curcuma longa L.) which is  widely used around the world as culinary spices, traditional medicine as well as a popular dietary supplement ingredient due to its wide range of health benefits including anti-inflammation, anti-cancer, cardiovascular regulation, respiratory, and immune system benefits. In addition, the suppression of multiple cytokines by curcumin suggested that it may be a useful approach in treating curcumin, and demothoxycurcumin exhibited high binding affinity on SARS-CoV-2 S- protein, PLpro, and RdRp. Binding of these proteins interfere with the viral entry, replication, and immune response evasion. Therefore, these compounds may have a great potential for inhibiting the virus.

Curcumin and Thymoquinone Combination Attenuates Breast Cancer Cell Lines’ Progression
Integrative Cancer Therapies | May 2022
Curcumin, the active ingredient of Curcuma longa, is the most studied compound described as a potential anticancer agent. Curcumin  targets multiple signaling/molecular pathways including, Rb, p53, mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and nuclear factor kappa B cells (NF-κB). Previous studies have demonstrated that curcumin can inhibit cancer cell proliferation. Recently, curcumin was reported to suppress breast cancer cell proliferation and migration through autophagy-dependent AKT degradation and increased natural killer cells activity. Curcumin, TQ, and their combination induced significant apoptosis of both cells and hindered their progression. Several reports have shown the anticancer effect of either curcumin  or TQ against MCF7 and MDA-MB-231 cell lines.  One interesting finding is curcumin , TQ, and their combination had synergistic effects. Curcumin  decreased proliferation and colony formation activities in MCF7 and MDA-MB-231 cell lines. This study supports evidence from previous observations of Effenberger-Neidnicht and Schobert,31 Attoub et al,32 Masuelli et al,33 Zhou et al,34 and El-Far et al16 who reported significant increases in caspase-3 expression, protein levels, or activities in either MCF7 or MDA-MB-231 cell lines treated with curcumin. These results suggest the promising anticancer benefit of the curcumin and TQ combination against breast cancer.

Curcumin Inhibits the Growth and Metastasis of Melanoma via miR-222-3p/SOX10/Notch Axis
Disease Markers | May 2022
Due to its antiinflammatory and antioxidant properties, curcumin has been also reported to have significant health benefits, including improved brain function and anticancer/anti-therosclerotic properties. A previous study has been indicated that curcumin could inhibit breast cancer cells proliferation and invasion via repressing the NF-κB inducing genes. It has been suggested that curcumin could influence the G0/G1 phase arrest by MTA1- (metastasis-associated protein 1-) induced inactivation of Wnt/β-catenin pathway in the lung cancer cell. In gastric cancer, curcumin could induce MMP proteins dissipation and cytochrome C into the cytosol in SGC-7901 cell lines, resulting in the downregulation of migration ability and apoptosis escaping. In colon cancer HCT116 and HT29 cells, curcumin could inhibit the level and activity of hexokinase II (HKII) by a concentration-dependent manner, inducing cell apoptosis. There is also an increasing number of studies showing that curcumin can also induce apoptosis and inhibit proliferation of melanoma cancer cells. In summary, these results indicated that curcumin was a key role in impeding the proliferation, migration, and invasion ability of melanoma cells. Curcumin could inhibit the proliferation, migration, and invasion of melanoma cells. Furthermore, curcumin repress the expression of SOX10, Notch1, and HES-1, and increase the expression of miR-222-3p. In addition, inhibition of miR-222-3p expression reversed the inhibitory effect of curcumin the growth of melanoma cells. Curcumin enhances the miR-222-3p level to reduce SOX10 expression, and ultimately inactivates the Notch pathway in repressing melanoma proliferation, migration, and invasion. According to the above, curcumin represents a potential therapeutic agent for the treatment of melanoma.

Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron
Computers in Biology and Medicine | May 2022
Curcumin, among seven phytochemicals, was found to have the most substantial inhibitory potential with Omicron S protein. Further, it was found that curcumin could disrupt the Omicron S-hACE2 complex. The molecular dynamic simulation demonstrated that Curcumin could form a stable structure with Omicron S in the physiological environment. Conclusion To conclude, Curcumin can be considered as a potential therapeutic agent against the highly infectious Omicron variant of SARS-CoV-2.

Curcumin supplementation may improve metabolic, inflammatory, and obesity markers in women with rheumatoid arthritis.
Clinical Edge Journal Scan | May 2022
Curcumin consumption for 8 weeks as a part of an integrated approach could help modulate metabolic factors, inflammation, and adiposity in women with rheumatoid arthritis. Major finding: After 8 weeks, insulin resistance, erythrocyte sedimentation rate, serum levels of high-sensitivity C-reactive protein, and triglycerides improved significantly in the curcumin supplementation vs. placebo group. Moreover, curcumin supplementation significantly decreased mean weight, body mass index, and waist circumference vs. no significant changes observed in placebo group.

Curcumin can improve Parkinson's disease via activating BDNF/PI3k/Akt signaling pathways
Food and Chemical Toxicology | May 2022
Curcumin, as one of the natural polyphenols, is significant in stimulating PI3k/Akt/glycogen synthase kinase 3 (GSK3) and BDNF/tyrosine kinase receptor B (TrkB)/PI3k/Akt signaling pathways, has great potential in neurodegenerative diseases and other different pathological settings. Curcumin can delay the progression of Parkinson's disease by protecting nerve cells.

The potential of curcumin for treating spinal cord injury: a meta-analysis study
Nutritional Neuroscience | May 2022
Curcumin had a strong significance in improving functional recovery after spinal cord injury. When curcumin was administered daily, it had a stronger effect than single-dose treatment or weekly administration. Curcumin also significantly reduced the expression of GFAP (Glial fibrillary acidic protein) marker compared to untreated groups.  These findings suggest that daily administration of curcumin can be an effective approach to improving functional recovery after spinal cord injury.

Therapeutic role of curcumin in adult neurogenesis for management of psychiatric and neurological disorders: a scientometric study to an in-depth review
Critical Reviews in Food Science and Nutrition | May 2022
Curcumin is a primary constituent of curcuminoid that exerts several positive pharmacological effects on aberrant neurogenesis. We explore the mechanisms by which curcumin regulates adult neurogenesis and in turn affects psychiatric diseases, i.e., depression and neurological disorders among them traumatic brain injury (TBI), stroke, Alzheimer’s disease (AD), Gulf War Illness (GWI) and Fragile X syndrome (FXS). This review aims to elucidate the therapeutic effects and mechanisms of curcumin on adult neurogenesis in various psychiatric and neurological disorders. Specifically, we discuss the regulatory role of curcumin in different activities of neural stem cells (NSCs), including proliferation, differentiation, and migration of NSCs. This is geared toward providing novel application prospects of curcumin in treating psychiatric and neurological disorders by regulating adult neurogenesis.

The Impact of Curcumin on the Inflammatory Profile of SW982 Cells in a Rheumatoid Arthritis Model
Journal of Immunology Research | May 2022
Curcumin, a natural polyphenol extracted from Curcuma longa, possesses plenty of proven properties, beneficial in ameliorating autoimmunological diseases, such as rheumatoid arthritis. Due to its structure, curcumin is a free radical scavenger, reducing redox-related inflammatory signaling. Profitable attributes of curcumin have been shown to lay a heavy impact on the functionality of rheumatoid arthritis by reducing their survivability and hence the number of overproliferating cells, decreasing expression of IL-1β, TNF-α, and COX-2 proteins and diminishing production of tissue destroying metalloproteinases. Presented anti-inflammatory properties, safety, and low cost of usage make curcumin a great candidate for potential therapies, which are already tested in trials conducted on patients with Rheumatoid arthritis. Aside from proving the overall anti-inflammatory properties of curcumin, results of conducted experiments showed some of the molecular basics of its action. Conducted investigations indicate the promising role of curcumin in decreasing the inflammation, enhancing its position as the potential compound in potential rreumatoid arthritis therapies.

Therapeutic Effects of Curcumin on Osteoarthritis and Its Protection of Chondrocytes
Alternative Therapies in Health and Medicine | May 2022
The curcumin  group show higher improvements in safety, joint mobility, and inhibition of inflammation. In-vitro experiments showed that curcumin  inhibited the apoptosis rate of chondrocytes and the levels of inflammatory factors, while the Wnt/β-catenin inhibitor did the opposite. Curcumin can effectively decrease the pathological results of OA, with a remarkable safety profile; its mechanism may be the activation of the Wnt/β-catenin signaling pathway to inhibit the inflammatory reaction and apoptosis in chondrocytes.

Curcumin treats endometriosis in mice by the HIF signaling pathway
American Journal of Translational Research | May 2022
Curcumin has become a hot topic in medical research because of its various pharmacological activities, such as anti-inflammatory and antioxidant. Curcumin has therapeutic effects on a variety of human diseases, including cancer, cardiovascular disease, diabetes, arthritis, neurologic disorders, Crohn’s disease, and cardiovascular disease. The modulation of curcumin for tumors has received the most attention from researchers; approximately 37% of curcumin studies are related to tumors. Curcumin can modulate multiple cellular signaling pathways simultaneously to alleviate or prevent different types of cancer, including multiple myeloma, colorectal, pancreatic, breast, prostate, and lung cancers, because it can modulate growth factors, enzymes, transcription factors, kinases, inflammatory cytokines, and apoptotic proteins. Previous studies focused on the antioxidant stress capacity of curcumin, which reduced ROS directly by enhancing the intracellular levels of reduced glutathione and counteracted antioxidants by increasing the activity of antioxidant enzymes and activating the Nrf2-Keap1 pathway. Our study demonstrated for the first time that curcumin can treat endometriosis and improve disease hypoxia through the HIF-1α pathway. Consistent with previous studies, curcumin exhibited therapeutic effect on endometriosis by inhibiting oxidative stress, thus alleviating inflammation. The real situation may be that curcumin inhibits oxidative stress on the one hand and improves hypoxia on the other hand. The number of lesions, volume, and degree of adhesions were significantly reduced in the curcumin group compared to the negative control group and the control group. Curcumin played a role in the treatment of endometriosis by modulating the HIF signaling pathway, improving the local hypoxia of the lesion, and reducing the inflammatory state of endometriosis.

Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases
Microbial Pathogenesis | May 2022
Curcumin exhibits anti-inflammatory, anti-carcinogenic, anti-oxidant properties and is widely used as a natural product-derived medicine or nutraceutical. Furthermore, curcumin has been reported to have anti-bacterial activity. Therefore, curcumin might be an effective herbal-based medicine for preventing, managing, or treating H. pylori infection. This review discusses the anti-inflammatory, anti-cancer, and anti-bacterial properties of curcumin as it pertains to gastric cancer and H. pylori-associated diseases.

Curcumin Selectively Induces Colon Cancer Cell Apoptosis and S Cell Cycle Arrest by Regulates Rb/E2F/p53 Pathway
Journal of Molecular Structure | May 2022
Curcumin has anti-inflammatory and anti-tumor activity.  Curcumin induces cells apoptosis through p53-mediated mechanism. Curcumin destabilizes cell cycle distributions by Rb/CDK/E2F signaling pathway. Curcumin inhibits tumor growth in vivo. Our data showed that curcumin preferentially and, in a dose, dependent way inhibited colon cancer cells proliferation, but was not toxic to normal colon mucosa epithelial cells. Curcumin induced apoptosis through a p53-mediated mechanism. Curcumin may be a potential strategy for the treatment of colon cancer.

The effect of curcumin on the risk of mortality in patients with COVID-19: A systematic review and meta-analysis of randomized trials
Phytotherapy Research | April 2022
Curcumin is a natural polyphenolic compound with multiple benefits, including antiviral, anti-inflammatory, anticoagulant, antiplatelet, and cytoprotective, which have been demonstrated to be advantageous in reducing the progression of several inflammatory illnesses (Rattis, Ramos, & Celes, 2021). The aforementioned effects have made curcumin one of the potential treatment options for patients with COVID-19. Since the pathophysiology of COVID-19 is known to involve life-threatening inflammatory reactions, cytokine storms, and coagulopathy, curcumin can be advantageous due to its anti-inflammatory effects via the inhibition of inflammasome formation (Yin et al., 2018). In addition, curcumin also demonstrates antiviral effects via its ability to bind to the viral primary protease (Mpro) enzyme of SARS-CoV-2, which is required for viral replication. Curcumin also prevents viral attachment and passage into the host cell with great potency (Dourado et al., 2021). The ability of curcumin in inhibiting the virus-receptor interaction is in two ways, according to modeling studies: it inhibits both the spike protein and the ACE2 receptor (Manoharan et al., 2020). Previously in this journal, the findings of the randomized trial reported by Hassaniazad et al. (2021) suggest that curcumin can accelerate the recovery of acute inflammatory phase in patients with COVID-19 by modulating inflammatory immune responses.

Curcumin as a Potential Therapeutic Agent in Certain Cancer Types
Cureus | April 2022
Curcumin has no noticeable toxicity and, in combination with existing chemotherapeutic agents, is a superior treatment option for certain cancer types. The potential applications of curcumin include the prevention and treatment of cancer, anti-inflammatory/antioxidant, and antiangiogenic activities. These beneficial effects of curcumin are exerted by modulating signaling molecules, including cytokines, chemokines, transcription factors, adhesion molecules, microRNAs, tumor suppressor genes, etc.. Several studies have shown the antitumor activity of curcumin on breast cancer, prostate cancer, brain cancer, lung cancer, and pancreatic cancer. Curcumin is a potent anti-oxidative, anti-inflammatory, and anti-tumor agent, and it is extracted from rhizomes of Curcuma species. Curcumin, as a cancer treatment agent, is recognized to affect multiple targets in different stages of cancer, including angiogenesis, proliferation, metastasis, and apoptosis. The molecular mechanism of action of curcumin has been studied comprehensively. It exerts this effect by interfering with several cell-signaling pathways as well as inducing and inhibiting the production of various growth factors, enzymes, or cytokines. Its therapeutic effects for the breast, lung, prostate, intestinal, liver, and hematological malignancies have been proven in the pre-clinical as well as in vivo studies.

Effects of Curcumin on Inflammatory Response During Exercise-Induced Muscle Damage
Biointerface Research in Applied Chemistry | April 2022
The results of this study explain that curcumin was able to provide anti- inflammatory effects by reducing pro-inflammatory cytokines such as IL-6, IL-8, TNF-α. Curcumin can also reduce muscle pain intensity, decrease CK activity, and increase ROM. The curcumin dose showed to reduce various inflammatory responses due to EIMD. Therefore, it is recommended that curcumin be used in individuals who carry out physical activities, leading to muscle damage and inflammation. Curcumin's anti-inflammatory benefits have been well known. Curcumin works by altering COX-2 pathway signaling, resulting in decreased pro-inflammatory cytokine and prostaglandin production. Curcumin is able to provide anti-inflammatory effects by reducing pro-inflammatory cytokines such as IL-6, IL-8, TNF-a. Curcumin can also reduce muscle pain intensity, decrease CK activity, and increase ROM. We recommend that curcumin be used in individuals who engage in physical activity that results in muscle damage and inflammation.

Specific Metabolic Response of Patient-derived Organoids to Curcumin of Colorectal Cancer
Journal of Chromatography | April 2022
Curcumin has been found to be effective in suppressing various phases of colorectal cancer development. Our research provided a reference for further revealing the role of curcumin in human-derived colorectal cancer-like solid tumors.

Quality of Evidence Supporting the Role of Curcuma Longa Extract/Curcumin for the Treatment of Osteoarthritis: An Overview of Systematic Reviews
Evidence-Based Complementary and Alternative Medicine | April 2022
Recently, curcuma longa extract, an anti-inflammatory and antioxidant preparation) has been used in traditional Chinese medicine and Ayurveda to treat arthritis and has thus become an attractive treatment option for improving the joint condition of OA patients. Often used as an alternative medicine or dietary supplement, turmeric is typically an extract that is standardized to 80–95% curcuminoids, among which curcumin is the most active ingredient in turmeric and is “generally regarded as safe” by the US FDA. In addition, the curcumin alone has anti-inflammatory properties similar to NSAIDs. Well known for its good anti-inflammatory effect, curcuma longa extract has a potential effect on osteoarthritis, and a large number of researchers have completed several systematic reviews/meta-analyses in this research area. According to the available published evidence, curcumin may be effective and safe for the treatment of osteoarthritis.

Curcumin for attention-deficit–hyperactivity disorder (ADHD) a systematic review and preliminary behavioral investigation
Naunyn-Schmiedeberg's Archives of Pharmacology | April 2022
Curcumin has protective actions in neuropsychiatric disorders, acting as a neuroprotective agent. As a first approach, the study aimed at a systematic review of the potential effects of curcumin on cognitive performance for attention-deficit–hyperactivity disorder (ADHD). The results of the Y-Maze Test demonstrated that curcumin improved spatial memory.

Protective Effects of Curcumin-Regulated Intestinal Epithelial Autophagy on Inflammatory Bowel Disease in Mice
Gastroenterology Research and Practice | April 2022
This study was aimed at exploring the ameliorating effect of curcumin on inflammatory bowel disease (IBD) in mice induced by 3% dextran sodium sulfate (DSS) by regulating intestinal epithelial cell autophagy. Compared with that of the DSS group, the diet of mice in the curcumin group was improved, the decline of body weight was slowed down, the hair glossiness was restored, the blood in the stool gradually decreased or occulted, the DAI score was decreased, the colon tissue was significantly improved, the expressions of LC3-II/LC3-I and Beclin1 were significantly increased, and the p62 was significantly decreased. Therefore, curcumin can increase the expression level of autophagy protein in IBD mice, which may be one of the molecular mechanisms for the treatment of IBD intestinal inflammation.

Anticancer Properties of Curcumin Against Colorectal Cancer: A Review
Frontiers in Oncology | April 2022
Several studies show that curcumin belongs to a class of plant-derived chemicals that can help prevent colorectal cancer. Several possible pathways have been proven in both in vitro and in vivo animal studies. Furthermore, treatment improvements in animals with inflammatory and hereditary colorectal cancer have been discovered. The Curcuma longa roots (dried) plant are used to produce curcumin. It has been discovered to have anti-carcinogenic properties. Curcumin has the ability to target colon cancer cells specifically, while allowing normal cells to remain alone; cancerous cells die as a result of an elevation in the expression of a protein known as GADD45a (Gene activated during DNA damage). Studies in humans have shown the ability of curcumin to tilt the ratio of pathogenic microbes and beneficial microbes. Curcumin, in fact, may lower intestinal inflammation via regulating gut flora. Curcumin was showed to reduce NF-κB activation in colonic epithelial cells and increase the growth of CD4+ Foxp3+ regulatory T cells in the colonic mucosa in an experimental DSS-colitis model. Another study revealed the effect of curcumin consumed in diet could cause an increase in the species of Clostridium, Enterobacter (have the potential to enhance mucosal Treg cells by producing butyrate) and reducing the levels of Blautia and Ruminococcus species (which has been linked with individuals that has colorectal cancer) that is present in abundance

The Curcumin Supplementation with Piperine Can Influence the Acute Elevation of Exercise-Induced Cytokines: Double-Blind Crossover Study
Biology | April 2022
The most important findings of this study were the administration of curcumin associated with piperine can inhibit the elevation of plasmatic levels of some cytokines such as IL-2, TNF-α, IFN, IL-6, and IL-10. This result shows the capacity of curcumin to modulate an inflammatory response acutely induced by exercise. Supplementation with 500 mg of curcumin associated with 20 mg of piperine for seven days was able to inhibit the inflammatory response after an experimental protocol of running on a treadmill until voluntary fatigue.

The Golden Spice Curcumin in Cancer: A Perspective on Finalized Clinical Trials During the Last 10 Years
Journal of Cancer Research and Therapeutics | April 2022
Curcumin is the main curcuminoid in turmeric and has been found to possess various beneficial properties, including anti-inflammatory, antioxidant, neuroprotective,, chemopreventive, and chemotherapeutic, activities, which make this phytocompound famous. Curcumin affects multiple signaling pathways involved in cell proliferation, survival, cell death, angiogenesis, invasion, migration, and metastasis. Cancer preventive and anticancer therapeutic actions of curcumin against different types of cancers, such as breast, liver, melanoma, lung, and endometrium, are available in the literature. Based on clinical trials in cancer patients, it was concluded that even 8 g of curcumin was safe and well tolerated. As a therapeutic agent, curcumin has been subjected to clinical trials for various diseases, such as psoriasis, multiple myeloma, chronic uveitis, pancreatitis, pancreatic, colorectal, and biliary tract cancers, familial adenomatous polyposis, inflammatory bowel disorder, Alzheimer's disease, and diabetes mellitus. Various clinical trials investigated curcumin's bioavailability, its effect on various cancer types, and the efficacy of turmeric and curcumin in mitigating the side effects of cancer chemotherapy and radiotherapy. We have presented 21 clinical trials, 16 of the 21 clinical trials were associated with the effectiveness of curcumin on various types of cancer, and the other 5  clinical trials were related to the evaluation of the curcumin's efficacy in relieving the side effects of cancer chemotherapy and radiotherapy. The emerging data from clinical trials confirm that curcumin has considerable potential to treat cancer patients. It is expected that findings from ongoing and future clinical trials may help the clinical application of curcumin in managing different types of cancer.

A Comprehensive Review on the Therapeutic Potential of Curcuma longa Linn. in Relation to its Major Active Constituent Curcumin
Frontiers in Pharmacology | April 2022
Curcumin has a variety of beneficial effects on humans, according to science. Curcumin’s efficacy, safety, and pharmacokinetics have all been examined extensively in clinical studies over the last 50 years (Gupta et al., 2013; Subramani et al., 2018). Cancer, CVD, arthritis, atherosclerosis, diabetes, gastric illness, IBD, psoriasis, acquired immunodeficiency syndrome, and other inflammatory disorders are all examples of pleiotropic activities. Several studies in this review discovered the anti-inflammatory effects of curcumin, including decreased white blood cell, neutrophil, and eosinophil numbers, as well as protective effects on serum levels of inflammatory mediators like phospholipase A2 and total protein in various inflammatory disorders. Curcumin has anticancer properties by interfering with many cellular systems and inhibiting/inducing the production of multiple cytokines, enzymes, or IκKβ, TNF-α, STAT3, COX-2, PKD1, NF-κB, epidermal growth factor, and MAPK, among others. Under oxidative stress conditions,  curcumin decreased MDA and NO levels while increasing thiol, SOD, and catalase levels. Curcumin also influenced the lifespan of organisms by regulating important signaling pathways such as the mTOR, PKA, and FOXO signaling pathways. In conditions where the immune system was disturbed, treatment with C. longa and curcumin enhanced IgE, IL-4, TGF-β, IL-17, IFN-γ, and the Th1/Th2 ratio. The pharmacological effects of curcumin on respiratory, allergy, and immunologic problems suggest that curcumin may have a possible therapeutic effect on these illnesses. Curcumin delay the onset of diabetes, improve β-cell functioning, prevent β-cell death, and reduce insulin resistance in animal models.Traditional medicine has exploited dried curcumin powder to treat illnesses in history. C. longa is said to have antitoxic, anticancer, antibacterial, anti-inflammatory, and antioxidant effects (Ghotaslou et al., 2017). Rhizome powder is supposed to flavor various cuisines and treat numerous disorders, including inflammation, flatulence, jaundice, menstrual troubles, hematuria, and hemorrhage. It is also a useful ointment to treat several skin disorders. Curcumin or diferuloylmethane and numerous volatile oils. C. longa of India is particularly popular when compared with those from other countries due to its high curcumin concentration, which is the most essential and active biological ingredient responsible for its therapeutic potential (Verma et al., 2018). Curcumin shows antioxidant features close to vitamins C and E in both aqueous and fat-soluble extracts.

Effects of turmeric (Curcuma longa) and its constituent (curcumin) on the metabolic syndrome: An updated review
Journal of Integrative Medicine | April 2022
Based on studies, turmeric and its bioactive component, curcumin, due to their anti-inflammatory and antioxidant properties, have antidiabetic effects through increasing insulin release, antihyperlipidemic effects by increasing fatty acid uptake, anti-obesity effects by decreasing lipogenesis, and antihypertensive effects by increasing nitric oxide. According to several in vivo, in vitro and human studies, it can be concluded that turmeric or curcumin has important values as a complementary therapy in Metabolic syndrome. In vitro and in vivo studies have proved that curcumin has anticancer, anti-inflammatory, antioxidant and anti-fat properties. Some studies have shown that curcumin has protective effects against many chronic diseases, for example, autoimmune disorders and pulmonary diseases. It has cardioprotective effects due to its lipid-lowering properties. In the last few years, much consideration has been paid to the benefits of curcumin. It can inhibit the development of atherosclerosis and also significantly reduce the serum levels of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C). Also, curcumin can increase insulin sensitivity through the inhibition of protein tyrosine phosphatase 1B. It has antioxidant effects in the artery and also can decrease the levels of reactive oxygen species (ROS) in the basilar artery wall. It remarkably delayed the onset of stroke. Curcumin in diabetic conditions decreased the levels of fast blood sugar, uric acid, serum urea and creatinine. Curcumin significantly alleviated the severity of liver fibrosis. Curcumin treatment lowered the increased blood pressure. It also plays a significant role in obesity and significantly decreases adiposity. One of curcumin and turmeric anti-diabetic mechanisms is decreasing the phosphorylation level of insulin and inhibiting the activation of the NF-κB. Curcumin and turmeric can treat hypertension by suppressing downregulation of eNOS.

Evaluation of the Anti-Cancer Effect of Curcumin on MCF-7 Cells in 3D Culture Conditions to Increase the Efficacy of Breast Cancer Treatment
Journal of Applied Biotechnology Reports | April 2022
Curcumin reduces the production of cellular NO and increases the production of catalase and glutathione, which confirms the results of the NO test. In addition, the release of cytochrome c from Mitochondria from cells treated with different concentrations of curcumin compared to control cells are significant. The evaluation of the toxicity effect of curcumin at concentrations of 20, 40, and 80 μM using comet assay showed that this substance induces apoptosis in MCF-7 cells in a dose-dependent manner. The findings of this study showed that the anti-cancer effect of curcumin on MCF-7 cells under 3D culture conditions could increase the effectiveness of treatment. The cancer cell survival rate actually depended on curcumin concentration.

Curcumin Alleviates DSS-Induced Anxiety-Like Behaviors via the Microbial-Brain-Gut Axis
Oxidative Medicine and Cellular Longevity | April 2022
Curcumin is a yellow polyphenol extracted from the rhizome of the ginger plant, which has been shown to have effects against both depression and anxiety. Research has indicated that curcumin affects the gut microbiome and exerts antianxiety and neuroprotective effects through the microbiota-gut-brain axis. The results suggested that curcumin can effectively relieve anxiety-like behaviors caused by DSS in mice. Further, curcumin treatment can alleviate disturbances in the gut microbiota and systemic disorders of lipid metabolism caused by DSS. Finally, through FMT, we verified that curcumin increased phosphatidylcholine in the prefrontal cortex of the mice and alleviated DSS-induced anxiety-like behaviors by modulating specific gut microbiota. We also revealed that Muribaculaceae may be a key part of the gut microbiota for curcumin to alleviate DSS-induced anxiety-like behaviors through the MGB axis. Curcumin is also believed to hold medicinal properties against many diseases, including gastrointestinal, cardiovascular, and mental diseases. High concentrations of curcumin have been detected in the gastrointestinal tract after oral administration. Supplementation of curcumin significantly enriched beneficial bacteria such as Butyricicoccus, a butyrate producing genus in the intestinal tract, and reduced Ruminococcus, and Mucispirillum, which were implicated in the development of obesity and diabetes. These findings were the basis to suggest that curcumin directly affects the gut microbiome despite its low systemic bioavailability. Curcumin can relieve inflammation and digestive tract symptoms caused by IBD.

Curcumin induces cortico-hippocampal neuronal reshaping and memory improvements in aged mice
Journal of Chemical Neuroanatomy | April 2022
Traditional medicine has long benefitted from naturally occurring molecules such as curcumin (diferuloymethane). Curcumin is extracted from the plant Curcuma longa and is known for its synaptic and antioxidant-related benefits. In this study, we tested the hypothesis that chronic curcumin treatment reduces cognitive and cellular effects of aging. Curcumin-treated mice showed improved learning and memory using the Morris Water Maze and novel object recognition task. In addition, using the Golgi-Cox stain, curcumin treatment increased spine density in all evaluated regions and increased dendritic arborization in the prefrontal cortex (PFC) layer 3 and CA3 subregion of the hippocampus. Moreover, chronic curcumin exposure increased synaptophysin and actin expression and reduced glial fibrillary acidic protein expression, a marker of astrocytes, in the hippocampus (CA1 and CA3 subregions), while simultaneously reducing the ROS-related molecule, metallothionein 3 expression in the PFC and hippocampus. Collectively, these novel findings suggest that curcumin reduces  cognitive, neuronal and astrocytic signs of aging in mice. Curcumin is the main metabolite found in Curcuma longa with potential benefits in aging. Curcumin-treated mice showed improved learning and memory in aged mice.  Curcumin treatment increased dendritic arborization in the PFC and hippocampus.  Curcumin exposure reduced astrocytic expression in the hippocampus.

Curcumin as a Potential Therapeutic Agent in Certain Cancer Types
Cureus Journal of Medical Science | March 2022
Several anticancer compounds have been extracted from plant sources such as Curcuma longa. Among these, curcumin (diferuloylmethane) has no noticeable toxicity and, in combination with existing chemotherapeutic agents, is a superior treatment option for certain cancer types. Curcumin is an important component of the curcuminoids family and is isolated from the rhizome of Curcuma longa L. (turmeric). The potential applications of curcumin include the prevention and treatment of cancer, anti-inflammatory/antioxidant, and antiangiogenic activities. These beneficial effects of curcumin are exerted by modulating signaling molecules, including cytokines, chemokines, transcription factors, adhesion molecules, microRNAs, tumor suppressor genes, etc. Several studies have shown the antitumor activity of curcumin on breast cancer, prostate cancer, brain cancer, lung cancer, and pancreatic cancer. Curcumin is a potent anti-oxidative, anti-inflammatory, and anti-tumor agent, and it is extracted from rhizomes of Curcuma species. Curcumin, as a cancer treatment agent, is recognized to affect multiple targets in different stages of cancer, including angiogenesis, proliferation, metastasis, and apoptosis. The molecular mechanism of action of curcumin has been studied comprehensively. It exerts this effect by interfering with several cell-signaling pathways as well as inducing and inhibiting the production of various growth factors, enzymes, or cytokines. Structural and chemical modifications have been tried to enhance the selectivity, bioavailability, and efficacy of curcumin for cancer. Its therapeutic effects for the breast, lung, prostate, intestinal, liver, and hematological malignancies have been proven in the pre-clinical as well as in vivo studies.

An Update on the Exploratory Use of Curcumin in Neuropsychiatric Disorders
Antioxidants | March 2022
Curcumin, the active compound of turmeric, is a polyphenol that has also been largely used as a remedy for different pathologies in Asia for several decades due to its healthy and biopharmacological properties, and its lack of adverse effects, even at high doses. Moreover, curcumin has been reported to have anti-inflammatory, antioxidant, neuroprotective, and even anti-aging and antineoplasic properties. Curcumin may exert its anti-inflammatory and antioxidant (anti-IOS) effects by influencing the synthesis of some IOS regulators, such as heme-oxygenase-1 (HO1), glutathione (GSH), catalase (CAT), and superoxide dismutase. These properties cause curcumin to have an impact on those diseases in which IOS regulation does not work correctly and are related to the disease appearance. Thus, curcumin may exert a beneficial effect on the immune system, reducing B lymphocyte proliferation by inhibiting B lymphocyte stimulator (BLYS). Curcumin can also reduce the neutrophil recruitment to areas affected by inflammation, and can also increase the phagocytic activity of macrophages. Furthermore, curcumin has proven to be an effective modulator of the endocrine system, enhancing the uptake or regulating some hormones, such as insulin. All these properties have boosted the interest of researchers in this compound in recent decades.  Recently, curcumin has also been used in different psychiatric disorders due to the likely involvement of IOS processes in their onset and evolution. In this sense, the above-described role of curcumin as an anti-IOS drug made this compound a good candidate to halt or palliate the course of these diseases. Anti-inflammatory, antioxidant, and neuroprotective properties of curcumin, along with many multi-target beneficial effects, such as the modulation of monoamine synthesis, have exponentially promoted the investigation of its properties during this last decade. Two-hundred and ninty-six articles containing research on curcumin were published in the PubMed database in 2005. In 2010, this number increased to 714 and, in 2020, to 2130. A total of 65 preclinical studies and 14 clinical trials were reported. Most of these studies were conducted on depression, approximately 88% were preclinical studies and 64% were clinical studies. In all disorders, curcumin was well tolerated, with no harmful side effects. This was not surprising, as curcumin has been used for the last centuries as an additive spice in East Asian cuisine. Moreover, curcumin was shown to be beneficial in palliating or reversing symptoms associated with psychiatry in all the studies analyzed and completed. In clinical trials, curcumin proved to be effective in alleviating both positive and negative symptoms of schizophrenia when administered together with regular antipsychotic medication. The clinical relevance of these results could be of great importance, due to the adverse events that can be caused by the extensive and chronic use of antipsychotics. In this sense, curcumin could exert its beneficial effect in schizophrenia through an inhibition of PLA2 enzyme. In depression, we found the vast majority of studies, in both preclinical and clinical domains, showed some beneficial effect of curcumin in reducing symptoms associated with depression. In addition to the recognized role of curcumin as an anti-inflammatory and antioxidant agent, positive improvement of depressive deficits could be exerted through modulation of the indolamine 2,3-dioxygenase (IDO) enzyme. Therefore, the overall effect of curcumin in this disorder seems to be mainly positive.  Overall, curcumin, due to its anti-inflammatory and antioxidant properties, has been shown to be effective in the vast majority of the studies presented.

Curcumin-Rich Curry Consumption and Neurocognitive Function from 4.5-Year Follow-Up of Community-Dwelling Older Adults
Nutrients | March 2022
Curcumin is a polyphenolic compound isolated from the roots of Curcuma longa, from which turmeric is prepared and used widely as a coloring agent, food additive and traditional Indian and Chinese medicine. For decades, curcumin and related bioactive curcuminoids (demethoxycurcumin and bisdemethoxycurcumin) have been the center of interest of scientific studies worldwide into their therapeutic potentials. Numerous laboratory studies have documented its antioxidant, anti-inflammatory, antimicrobial, antiviral, antineoplastic and antiaging activities. Curcumin is actively being investigated for its potential neuroprotective benefits. In vitro and in vivo studies show that curcumin crosses the blood–brain barrier and can bind to β amyloid (Aβ) and tau-inhibiting Aβ aggregation and modulate tau processing. Animal studies show that curcumin decreases Aβ deposition and plaque load in the brain of transgenic mouse models of AD. Experimental studies have also demonstrated that curcumin possesses beneficial antiplatelet, antidiabetic and cardioprotective activities ameliorating cardiac hypertrophy and chronic heart failure. On top of the known anti-inflammatory activities of curcumin attenuating neuroinflammation, this experimental evidence strongly suggests that curcumin has the potential to prevent accelerated cognitive decline in humans. Several animal studies have shown that curcumin improves cognitive function. Randomized controlled trials in humans are limited but suggest that curcumin could be safely and effectively used to slow cognitive decline. We found in this observational cohort study that the consumption of curcumin-rich curry in food was associated with the maintenance of higher levels of cognitive functioning over time among community-dwelling middle-aged and older Asian adults in Singapore. To our knowledge, this is the first longitudinal study demonstrating the cognitive benefits of curcumin from natural dietary food sources in humans. Curcumin exposure from dietary ingestion appears to offer neuroprotection especially through its beneficial metabolic, antiplatelet and cardioprotective properties.  There is evidence that the combination of piperine in black pepper with curcumin in turmeric increases the bioavailability of curcumin by 2000% and inhibits the intestinal and hepatic glucuronidation of curcumin. In this study, real-world observations of the potential cognitive benefits of curcumin in humans were provided in a large population-based cohort of community-dwelling older adults with follow-up over three to five years. The consumption of dietary curcumin was associated with the maintenance over time of higher functioning on attention, short-term working memory, visual spatial constructional ability, language and executive function among community-dwelling older adults. This suggests that, notwithstanding its known anti-amyloid, anti-tau, antioxidant and anti-inflammatory activities, curcumin exposure from dietary ingestion appears to offer neuroprotection especially through its beneficial metabolic, antiplatelet and cardioprotective properties. The results from the stratified analysis support this by showing that among participants with pre-existing metabolic and cardiovascular disease, curry consumption was associated with enhanced performance on attention, working memory and language executive function. In vitro and high-dose animal studies show that curcumin modulates molecular pathways that restore glucose homeostasis, lipid metabolism, endothelial function and insulin signaling and may thus offer potential cardiovascular protective effect. These observations suggest that population health in terms of healthy cognitive ageing and potential reduction of risks of dementia could be enhanced by increased consumption of curcumin in a turmeric-rich diet.  

Potential Role of Curcumin for the Treatment of Major Depressive Disorder
CNS Drugs | March 2022
Curcumin is the major biologically active polyphenolic constituent in the turmeric plant (Curcuma longa) that has been shown to have antioxidant, anti-inflammatory, neuroprotective, anticancer, antimicrobial, and cardioprotective effects. Interest in curcumin as a treatment for mental health conditions has increased and there is an expanding body of preclinical and clinical research examining its antidepressant and anxiolytic effects. Cell culture and animal studies have demonstrated that curcuminoids, and in particular curcumin, have extensive biological activity, including antioxidant, anti-inflammatory, neuroprotective, anticancer, antimicrobial, and cardioprotective effects. Turmeric has traditionally been used in Indian folk medicine to treat eye infections, skin wounds, respiratory conditions and digestive complaints, and to reduce general inflammation. More recently, interest in curcumin as a treatment for depression has increased and there is an expanding body of research confirming antidepressant and anxiolytic effects from its administration. There is an increasing body of research supporting the efficacy of curcumin as a treatment for depression.  Positive antidepressant effects were reported in six of seven trials, with the only non-significant finding identified by Bergman et al., where curcumin was used as an adjunct to pharmaceutical antidepressants and administered for the shortest treatment period of all the trials (5 weeks). Positive anxiolytic effects from curcumin administration were also identified in four trials. Interestingly, in this meta-analysis, an even larger treatment effect was identified when examining the effects of curcumin on anxiety symptoms (Hedge’s g = 2.62). In a meta-analysis conducted in 2016, it was concluded from subgroup analyses that curcumin had the highest antidepressant effects when administered to middle-aged adults, for longer treatment periods, and at higher doses.

 Investigation of the Effect of Curcumin on Protein Targets in NAFLD Using Bioinformatic Analysis
Nutrients | March 2022
Curcumin is a bioactive polyphenolic compound, isolated from Curcuma longa Linn, which is endowed with diverse pharmacological activities. Curcumin improves steatosis, inflammation, and fibrosis progression.  Curcumin may improve, or inhibit, progression of non-alcoholic fatty liver disease (NAFLD)through activation/inhibition of non-alcoholic fatty liver disease (NAFLD)-related genes. Numerous in-vitro and in-vivo investigations have indicated that curcumin exerts a positive effect at each stage of non-alcoholic fatty liver disease (NAFLD), improving both inflammation and the extent of fat deposition. Curcumin was also shown to inhibit the progression from non-alcoholic fatty liver disease (NAFLD) to fibrosis and decrease the risk of liver cancer. Emerging from these studies, therefore, are data supporting the significant clinical effect of curcumin on non-alcoholic fatty liver disease (NAFLD). Curcumin exerts its anti-diabetic, cardioprotective, hepatoprotective, neuroprotective, and antitumor effects via NFE2L2 signaling pathways. Curcumin activates NFE2L2 signaling pathways in four ways. In a high-fat and high-fructose diet (HFHFr) mouse model, NFE2L2 was downregulated, while curcumin administration could reverse the abnormal serum biochemical parameters of hepatic steatosis. Another animal study using carbon tetrachloride (CCL4) induced liver damage showed that curcumin’s protective role in reducing inflammation and oxidative stress was mediated through NFE2L2/HO-1 pathways. An in-vitro study showed that curcumin, through activation of NFE2L2, can promote lipocyte activation in stellate cells (HSCs) and repress hepatic fibrosis. In this study, we identified 14 genes in non-alcoholic fatty liver disease (NAFLD) that are likely to be the target of curcumin and observed that curcumin induces or inhibits them. According to our results, this activity of curcumin was in line with improving non-alcoholic fatty liver disease (NAFLD) based on literature. We believe that the ongoing clinical trials investigating the effect of curcumin on fatty liver could yield positive results in the future, enhancing the therapeutic status of curcumin in this metabolic disorder.

 Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer
Nutrition and Cancer | March 2022
Curcumin is a natural product found in the rhizome extract of Curcuma longa and has been extensively used over the last decades for its unique biological and medicinal properties, which include: having antioxidant, analgesic, anti-inflammation, and anti-tumor activities. Curcumin exerts its anticancer properties against ovarian cancer via multiple mechanisms: interfering with cellular interactions necessary for metastasis and recurrence of OC cells, increasing pro-apoptotic proteins as well as inducing or suppressing generation of different molecules such as cytokines, transcription factors, enzymes, protein kinases, and growth factors. Moreover, curcumin down-regulates various signaling pathways such as PI3K/Akt, Wnt/β-catenin, JAK/STAT3, and MEK/ERK1/2 axes, which at least in part have a role in inhibiting further tumor proliferation, growth, and angiogenesis. In this review, we overview the potential of incorporating curcumin into the treatment of ovarian cancer.

Curcumin in Combination with Aerobic Exercise Improves Follicular Dysfunction
Oxidative Medicine and Cellular Longevity | March 2022
Curcumin is a natural medicine containing phenol and quinone groups extracted from turmeric in the ginger family. It is well known as a safe dietary supplement worldwide. In several randomized, double-blinded, clinical trial, patients with PCOS received curcumin (in doses of 500-1500 mg 3 times daily for 1-3 months) or placebo. It is suggested that curcumin can effectively improve blood glucose, insulin resistance, and hyperandrogenemia in PCOS. Moreover, curcumin reportedly exerts numerous biological effects to manage human diseases, including cancer and neurodegenerative and metabolic disorders. Both curcumin gavage and aerobic exercise improved ovarian function.  Curcumin and aerobic exercise (irisin) can alleviate hyperandrogenism-induced ER stress and suppress the IRE1α-XBP1 pathway, which prevented ovarian GC apoptosis in PCOS-like rats, leading to the improvement in the ovarian microenvironment and promotion of follicular development.

Curcumin Suppresses Lead-Induced Inflammation and Memory Loss in Mouse Model and In Silico Molecular Docking
Foods | March 2022
Curcumin is a polyphenol primarily extracted from turmeric, and has drawn much attention in the field of natural drug discovery due to its excellent therapeutic effects, such as its antioxidant, anti-inflammation, anti-microbial, anti-arthritic, and anti-depressant activities. In addition, curcumin can modulate cognitive dysfunction and astrocyte proliferation. Research revealed that curcumin can suppress memory impairment and can attenuate cognitive deficits. In mercury chloride-treated offspring mice, curcumin treatment improved memory and learning activity, antioxidant profile, and increased AChE, serotonin, and dopamine. Curcumin also downregulated the AChE gene expressions.  Curcumin is known to have a potent antioxidant activity due to its capacity for chain-breaking, as well as the hydrogen-donating phenolic groups in its structure. Much research has also revealed the neuroprotective effects of curcumin, which operate via exerting antioxidant effects and reducing oxidative damage. Curcumin exhibits great promise as a therapeutic agent for a variety of cancers, as well as for psoriasis, and Alzheimer’s disease. It has been reported that curcumin suppresses aluminum- and Pb-induced oxidative neurotoxicity, alterations in NMDA receptors that lead to decreased antioxidant enzyme activity, and AChE dysfunctions. Thus, the present study has indicated that curcumin, a potent antioxidant compound, ameliorated lipid peroxidation and oxidative stress parameters in mice exposed to Pb, along with protecting against cholinergic dysfunction. Curcumin co-treatment effectively suppresses Pb-induced brain inflammation. Thus, Curcumin may completely bind with AchE to increase enzymatic activity, which is predicted to have dose-dependent neuroprotective effects, at least in part via exerting antioxidant and anti-inflammatory effects, and reversing the Pb-induced alterations in transmitters and enzymes.

Cardioprotective effects of exercise and curcumin supplementation against myocardial ischemia–reperfusion injury
Sport Sciences for Health | March 2022
Exercise and curcumin individually provided cardioprotective effects against ischemia–reperfusion-induced injury which appears to be associated with an attenuation in mRNA expression of β-amyloid peptide precursor in addition to processing enzymes and an increase in mRNA expression of neprilysin.

Curcumin Inhibits Papillary Thyroid Cancer Cell Proliferation
Analytical Cellular Pathology | March 2022
Curcumin is a polyphenolic compound and a member of the Zingiberaceae (ginger) family derived from turmeric plants. It has been extensively used in Chinese medicine to treat various diseases, including inflammation and cancer. Curcumin was found to participate in the process of pancreatic cancer, colorectal cancer, and hepatocellular cancer by regulating specific lncRNAs and miRNAs. In addition, curcumin can suppress PTC cell metastasis. Curcumin was shown to enhance the anticancer activity of cisplatin in PTC cells and cancer stem-like cells by regulating the JAK/STAT3 signaling. In conclusion, the present study provides evidence that curcumin promotes apoptosis and inhibits proliferation and the Warburg effect by inhibiting LINC00691 in B-CPAP cells. Moreover, the specific molecular mechanism might be mediated through the Akt signaling pathway. This study provides a theoretical basis for the treatment of PTC with curcumin.

Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer
International Journal of Molecular Sciences | February 2022
Collectively, curcumin in combination with chemotherapy drugs may improve their clinical application in breast cancer therapy, and it is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer.  Curcumin is an ideal chemopreventive and chemotherapy agent owning to its multitargeting function on various regulatory molecules, key signaling pathways, and pharmacological safety. This review aimed to elucidate the potential role of curcumin in enhancing the efficacy of doxorubicin, paclitaxel, 5-fluorouracil, and cisplatin via combinational therapy. Additionally, the molecular mechanisms underlying the chemosensitizing activity of these combinations have been addressed. Overall, based on the promising therapeutic potential of curcumin in combination with conventional chemotherapy drugs, curcumin is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer.

Effects of curcumin supplementation on metabolic parameters, inflammatory factors and obesity values in women with rheumatoid arthritis: A randomized, double-blind, placebo-controlled clinical trial
Phytotherapy Research | February 2022
Curcumin supplementation significantly decreased homeostatic model assessment for insulin resistance (HOMA-IR), erythrocyte sedimentation rate, serum levels of high-sensitivity C-reactive protein and triglycerides, weight, body mass index, and waist circumference of patients compared with the placebo at the end of the study (p < .05 for all). HOMA-IR and triglyceride levels significantly increased within the placebo group.

Curcumin induces autophagic cell death in human thyroid cancer cells
Toxicology in Vitro | February 2022
Curcumin acts as an autophagy inducer on many cancer cells. In the present study, curcumin significantly inhibited the growth of thyroid cancer cells. Autophagy was markedly induced by curcumin treatment as evidenced by an increase in LC3-II conversion, beclin-1 accumulation, p62 degradation as well as the increased formation of acidic vesicular organelles (AVOs). 3-MA, an autophagy inhibitor, partially rescued thyroid cancer cells from curcumin-induced cell death. Additionally, curcumin was found to exert selective cytotoxicity on thyroid cancer cells but not normal epithelial cells and acted as an autophagy inducer through activation of MAPK while inhibition of mTOR pathways.

Effect of Curcumin in Experimental Pulmonary Tuberculosis: Antimycobacterial Activity in the Lungs and Anti-Inflammatory Effect in the Brain
International Journal of Molecular Sciences | February 2022
Curcumin is a natural product with antioxidant, anti-inflammatory and antibacterial activities. Curcumin is a polyphenolic compound obtained from the rhizomes of Curcuma longa, a rhizomatous native plant from South and Southeast Asia that belongs to the family Zingiberaceae. Research has revealed that curcumin has pleiotropic properties, including anti-inflammatory, antioxidant, chemopreventive, chemotherapeutic activity, neuroprotective properties, and antibacterial activity. The pleiotropic actions of curcumin are derived from its complex chemistry and its ability to influence multiple signaling pathways. Curcumin controls the inflammatory response by downregulating the activity of the enzymes cyclooxygenase-2 (COX-2), lipoxygenase, and inducible nitric oxide synthase (iNOS). In addition, curcumin suppresses the activation of nuclear factor kappa B (NF-κB) activation; inhibits the production of the inflammatory cytokines TNF-α, interleukin (IL)-1, -2, -6, -8, and -12, monocyte chemoattractant protein (MCP) and migration inhibitory protein; and down-regulates mitogen-activated and Janus kinases. In addition, curcumin protects the brain from damage through the upregulated expression of the transcription factor, the nuclear factor erythroid 2-related to factor 2 (Nrf2) expression, and the hippocampal levels of brain-derived neurotrophic factor (BDNF). Indeed, there is evidence that curcumin has a beneficial effect on humans suffering from depression and anxiety, linked to curcumin anti-inflammatory effects, dopamine release, antioxidant activity, and neurotrophic factor regulation. Curcumin also resulted in a dose-dependent increase in hippocampal BDNF in a model of depression. These data coincide with our results, where we observed a significant increase in BDNF levels in the hippocampus of animals with TB treated with curcumin,  related to the beneficial effect of curcumin on memory and the decrease in depression-like behavior in this model. Curcumin protected from injury in a model of an ischemic brain through the Akt/Nrf2 pathway. Curcumin has a neuroprotective effect in a model of traumatic brain injury (TBI) associated with activating the Nrf2 pathway. These data suggest that treatment with curcumin has a beneficial effect on various neuroinflammatory and neurodegenerative diseases, including those related to pulmonary TB. This investigation revealed the efficacy of curcumin administration as a novel treatment for controlling neuroinflammation in chronic infectious diseases such as pulmonary TB. In addition, it is worth noting that curcumin had a therapeutic effect on lung disease, indicating that curcumin might be used as a coadjuvant treatment in TB chemotherapy.

Curcumin Ameliorates Cardiac Fibrosis
Frontiers in Pharmacology | February 2022
The therapeutic potential of curcumin has been widely investigated, including its utilization in various of cardiovascular diseases. Curcumin’s health benefits has been well-established, including anti-tumor, anti-viral, anti-oxidative stress, anti-inflammatory, anti-microbial, hypoglycemic etc. Therapeutically, curcumin exhibits promising potential in preclinical as well as clinical studies and is currently in human trials for a variety of conditions, including metabolic syndrome, nonalcoholic fatty liver disease, atherosclerosis, liver cirrhosis, depression, psoriasis, and Alzheimer’s disease (Kocaadam and Şanlier, 2017). The immunomodulatory functions of curcumin arise due to its interactions with cellular and molecular components during inflammatory reactions. Dietary exposure to 40 mg/kg curcumin for 5 weeks showed enhanced IgG levels in rats, suggesting an improvement in immune function after curcumin intervention (South et al., 1997). Curcumin has also been shown to regulate macrophage polarization by increasing the M2 phenotype marker CD163 together with the anti-inflammatory cytokine IL-10 and decreasing the M1 phenotype marker CD86 along with the pro-inflammatory cytokines TNF-α and IL-6 (Li et al., 2017). Curcumin significantly ameliorated the inflammation process subsequent to myocardial infarction, reflected by decreased expression of CD68+ and CD3+ cells, accompanied by dramatically improved cardiac function compared with the placebo group. In addition, cardiac fibrosis is inhibited by curcumin administration. Mechanistically, we discovered that curcumin significantly downregulated pro-inflammatory cytokines in macrophages. Curcumin improves cardiac function and reduces cardiac fibrosis after myocardial infarction. Curcumin has roles in various cardiovascular diseases, including ischemic heart, pressure overload heart, and metabolic disorder-related cardiac diseases. It is well-established that curcumin can directly exerts cardio-protective effect by targeting cardiomyocyte through various of signaling pathway, like disrupts the p300/GATA4 complex and represses agonist-and p300-induced hypertrophic responses in cardiomyocytes (Morimoto et al., 2008)or activates the autophagy by upregulating AMPK and JNK1 to alleviate the apoptosis of cardiomyocytes under ischemic stimulation (Yao et al., 2018).  In summary, our study revealed that the administration of curcumin significantly ameliorated inflammation in the acute phase, as reflected by the promotion of macrophage apoptosis, accompanied by decreased pro-inflammatory cytokine secretion, including IL-6, IL1b, and TNF-α.  These findings suggest that curcumin has potential as a potent therapeutic target in treating adverse remodeling in ischemic heart disease.

Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota
Cancer Chemotherapy and Pharmacology | February 2022
Curcumin is a natural phenolic compound extracted from curcuma longa, which exerts a wide range of biological effects, such as anti-tumor, anti-inflammatory, anti-oxidation and anti-fibrosis. Moreover, Curcumin was also reported to affect energy metabolism to increase energy expenditure as well as improve insulin sensitivity in obese mice]. Energy metabolism also plays crucial roles in response to chemotherapy. Several studies have reported that targeting energy metabolism could sensitize resistant cells to chemotherapy, such as oxidative phosphorylation inhibitor redirected metabolism toward glycolysis to sensitize resistant cells to cytarabine (Ara-C) in AML.  Curcumin could affect intestinal microbiota to prevent renal failure. Conversely, intestinal microbiota could also enhance the effect of Curcumin in ameliorating HFD-induced obesity by enhancing Ucp1-dependent thermogenesis through regulating bile acids metabolism, suggesting the interaction between intestinal microbiota and Curcumin in curing diseases. Curcumin resulted in strengthening intestinal intact, leading to reduced transfer of bacteria (or their metabolites) to the blood, causing SQLE inhibition. In conclusion, we demonstrated that Curcumin sensitizes response to Ara-C by regulating microbiota and strengthening intestinal intact is promising in chemoresistant therapy.

Curcumin supplementation in the rhesus monkey: effects on cognitive decline and neuroinflammation
Boston University Theses & Dissertations | February 2022
Curcumin, the active ingredient in turmeric, is a polyphenol nutraceutical with potent anti-inflammatory and antioxidative effects. Several ongoing research studies are underway to explore this potential anti-aging compound. Curcumin treatment improved performance on object reversal testing, with treated monkeys making fewer perseverative type errors. We demonstrated that curcumin treatment did affect morphological features of microglia specifically within the while matter. Within the white matter, curcumin treatment was associated with a significant increase in microglial ramification, evidenced by greater process length, number of nodes and convex-hull area and volume. Increased microglial ramification suggests greater likelihood of microglial surveillance within the white matter associated with curcumin treatment. While our findings show the benefit of curcumin supplementation on cognitive performance and its effects on microglial morphology, further study is needed to understand the precise changes that curcumin supplementation may have on inflammation.

Protective Effects of Curcumin in Cardiovascular Diseases—Impact on Oxidative Stress and Mitochondria
Cells | February 2022
In this review, we will highlight the impact of curcumin on age-related cardiovascular dysfunction, adipose tissue, and obesity, as well as its protective effects in atherosclerosis and myocardial infarction. Curcumin can positively affect different risk factors for CVDs and the outcome in the diseases themselves which has been shown in a number of animal models. More importantly, it is effective against cardiovascular diseases and has shown a promising impact on cardiovascular diseases in clinical studies. Already more than 20 years ago, it was shown that piperine, an alkaloid responsible for the pungency of black pepper, dramatically increases the serum levels of curcumin in rats and humans.

A New Perspective on the Treatment of Alzheimer’s Disease and Sleep Deprivation-Related Consequences: Can Curcumin Help?
Oxidative Medicine and Cellular Longevity | February 2022
Curcumin, a natural compound isolated from C. longa, has multiple applications in treatment of various diseases such as cardiovascular diseases, liver disease, obesity, cancer, inflammatory diseases, and aging. Besides these applications and activities, curcumin has been reported to be effective in many neurodegenerative diseases. Studies have shown that curcumin can lead to many improvements in the pathological process of Alzheimer’s disease. Its mechanisms of action can be classified as (I) sustaining homeostasis of the inflammatory system, (II) increasing the clearance of toxic substances from the brain, (III) scavenging free radicals and inducing antioxidant elements, and (IV) binding and limiting aggregation of misfolded proteins. In addition to the effects of curcumin on neurodegenerative diseases, especially Alzheimer’s disease, it has been reported that curcumin can be beneficial in the management of sleep deprivation (SD) and SD-induced neurological consequences as well. The effects of curcumin on the medial prefrontal cortex (mPFC), the protective potential on the dendritic trees from shortening and shedding induced by chronic SD, and the effects of SD-induced memory impairments have been demonstrated by in vivo studies.

Curcumin protects rats against gentamicin-induced nephrotoxicity by amelioration of oxidative stress, endoplasmic reticulum stress and apoptosis
Pharmaceutical Biology | February 2022
Curcumin is a major yellow phenolic pigment of turmeric that is extracted from rhizome of Curcuma longa L. (Zingiberaceae), a spice widely cultivated in tropical countries in south and southeast Asia, such as China, India and Thailand (Wanninger et al. 2015). Numerous studies have shown that curcumin has excellent antioxidant and anti-inflammatory properties. It has the ability to inhibit free radical generation, scavenge ROS and induce an antioxidant response. Moreover, curcumin has also exerted renoprotective effects in several experimental models, including diabetic nephropathy, chronic renal failure, ischaemia and reperfusion; it also combats nephrotoxicity protecting against renal injury from oxidative stress (Trujillo et al. 2013). Interestingly, curcumin  treatment helps protect against acute myocarditis by inhibition of cardiac oxidative and ER stress-mediated apoptosis (Mito et al. 2011).  Curcumin eliminates the hydroxyl radical, superoxide radical, singlet oxygen, nitrogen dioxide and NO (Ruby et al. 1995; Sreejayan and Rao 1997) and has been shown to inhibit hydrogen peroxide induced oxidative injury in a renal cell line (Farombi and Ekor 2006) and prevented reduced activity of antioxidant enzymes including glutathione peroxidase and SOD in rat remnant kidney (Tapia et al. 2012). These results demonstrated that curcumin inhibited oxidative stress and restoration of the antioxidant enzymes leading to improved renal function and rescued kidney damage in GM-induced nephrotoxicity.  These results were in line with the previous report demonstrating that curcumin ameliorated high glucose-induced neural tube defects by suppressing ER stress, caspase activation and apoptosis (Afrin et al. 2015). Moreover, curcumin treatment also prevented cell death induced by H2O2 (Wang et al. 2016). It might be suggested that curcumin attenuated ER stress-induced apoptosis in GM-induced nephrotoxicity, probably associated with the antioxidative activity. The GM-induced nephrotoxicity was contributed by the increasing of oxidative stress, ER stress activation which eventually resulted in the apoptosis cell death. These events were restored by the pre-treatment of curcumin based on its activities to reverse several hallmarks of nephrotoxicity. These findings emphasized the potential therapeutic use of curcumin to be developed as an alternative treatment for nephrotoxicity.

Neuroprotective effects of curcumin on the cerebellum in a rotenone-induced Parkinson’s Disease Model
CNS Neuroscience & Therapeutics | February 2022
Curcumin has a lipophilic property, can pass through cell membranes, and exerts intracellular effects. Curcumin crosses the blood brain barrier  and is also detected in cerebrospinal fluid. The strong antioxidant properties of curcumin scavenge reactive oxygen species and inhibit lipid peroxidation. In one study, administration of curcumin improved behavioral alterations, oxidative damage, and mitochondrial enzyme dysfunction induced by the administration of rotenone in mice. Curcumin also restored electrical activity in the hippocampus altered by rotenone. Curcumin is a strong antioxidant that minimizes oxidative stress in vivo and in vitro. Curcumin exerts various beneficial effects in treating and preventing neurodegenerative diseases, such as stroke and Alzheimer's disease. Additionally, several studies demonstrated curcumin's ability to inhibit key Parkinson's disease-associated features, including ROS formation, apoptosis, cytokine production, oxidative damage, and cognitive impairment in cell lines and experimental animals.  Moreover, Khuwaja et al. demonstrated that curcumin helps stop Parkinsonism and has therapeutic potential. Based on the results of this study, rotenone causes Purkinje cell death and astrogliosis by increasing oxidative stress in the cerebellar cortex. Administration of curcumin prevented these effects. Furthermore, cholinergic neurotransmission alterations induced by rotenone were suppressed by curcumin, thus confirming the behavioral and histological findings. This shows that curcumin attenuated the neurotoxic effects and degenerative histological changes in the cerebellar cortex and alleviated oxidative stress in a Parkinson's disease  rat model. Thus, curcumin could have a role in therapeutic strategies for cerebellar affection related to Parkinson's disease.

Supplements immunologist takes every day to strengthen immune system
CNBC | February 2022
Curcumin is the main active ingredient in turmeric root and has been shown to bestow multiple health benefits. In fact, there are more than 120 human clinical trials showing the effectiveness of curcumin in treating diseases ranging from autoimmunity to Alzheimer’s disease. The magic of curcumin is how it decreases inflammation at multiple levels in the body, not only helping with symptom relief from pain and arthritis but also blocking inflammatory cytokines driving autoimmune disease, heart disease and diabetes. It also improves the health of our gut bacteria, which adds to our overall immune health. Because curcumin is not absorbed well and one would have to eat copious amounts of turmeric root to have significant benefits, I recommend supplementing with 1,000 milligrams per day with food.

Curcumin alleviates hepatic steatosis by improving mitochondrial function in postnatal overfed rats and fatty L02 cells through the SIRT3 pathway
Food & Function | February 2022
It was concluded that postnatal overfeeding damaged mitochondrial biogenesis and antioxidant response, and increased hepatic lipids and the severity of high-fat-induced NAFLD, while curcumin alleviated hepatic steatosis, at least partially, by enhancing mitochondrial function through SIRT3.

Therapeutic Applications of Curcumin in Diabetes: A Review and Perspective
BioMed Research International | February 2022
The curcumin molecule exhibits a multitargeting ability in various pathological conditions, which allows translation into a therapeutic or nutraceutical agent. Curcumin can support balance for oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia. Curcumin has antioxidant, antiamyloid, antimicrobial, antineoplastic, immune-modulating, and neuroprotective effect. Curcumin also showed antidepressant activity through modulating the release of serotonin and dopamine. Diabetics are not able to metabolize well glucose due to defects in insulin secretion and/or action, and curcumin is capable to exert a therapeutic effect playing a critical role on β-cell functions. Several studies have been shown the high therapeutic properties of curcumin in hyperglycemia, diabetic wound healing, diabetic neuropathy, diabetic cardiomyopathy, and diabetic retinopathy and cataract.

Curcumin supplementation in pediatric patients: A systematic review of current clinical evidence
UWA Medical School | February 2022
This systematic review was designed to determine the clinical efficacy and safety of curcumin supplementation for pediatric patients based on clinical trials in children. We systematically searched electronic databases including PubMed, EMBASE, Web of Science, and Scopus for all studies that investigated curcumin administration in the pediatric population without any time frame limitation. Finally, we identified 16 studies for this review. Clinical efficacy and safety of curcumin were assessed in children with inflammatory and immune disorders (including asthma, inflammatory bowel disease (IBD), and juvenile idiopathic arthritis (JIA)), metabolic disorders, autosomal dominant polycystic kidney disease (ADPKD), cystic fibrosis (CF), tetralogy of Fallot (TOF), and infectious diseases. Curcumin was administered in a wide range of doses (45 mg-4,000 mg daily) and durations (2-48 weeks). Overall, curcumin was well tolerated in all studies and improved the severity of inflammatory and immune disorders and metabolic diseases. However, more studies are needed to clarify the role of curcumin supplementation among children with ADPKD, CF, TOF, and infectious diseases.

Effect of curcumin on body mass index and glycemic indices in females with PCOS: a systematic review and meta-analysis of randomized controlled trial
Nutrition & Food Science | February 2022
Random-effects meta-analysis showed significant effects of curcumin on fasting blood sugar (FBS) (−3.62 mg/dl, 95% CI [−5.65, −1.58], p-value < 0.001, I2 = 0.0%), insulin level (−1.67 µU/mL, 95% CI [−3.06, −0.28], p-value = 0.018, I2 = 0.0%) and homeostasis model of assessment insulin resistance (HOMA-IR) (−0.42, 95% CI [−0.76, −0.09], p-value < 0.01, I2 = 0.0%).

A Plethora of Actions of Curcumin - A Magical Agent for Treatment of Wide Range of Diseases Varying from Neuroinflammatory Disease (Alzheimer's disease, Parkinson's disease) IBD to DM and CVD, NAFLD, NASH Along with Various Cancers
Acta Scientific | February 2022
Curcumin has been evaluated for its biological actions: Neuroinflammation; Alzheimer’s disease (AD); parkinson’s disease (PD); antioxidant actions; other anti-inflammatory actions; cardio protection; hepatoprotection in liver fibrosia; non alcoholic fatty liver disease (NAFLD); non alcoholic steatohepatitis (NASH); Anti cancer actions. We observed a total of over 3000 articles and  selected 53 articles for this review with the journals constraints of up to 50 references.  Here we have reviewed in detail the mechanism of action of Curcumin in various above mentioned diseases along with transcription factors involved. Recently even in COVID its use has got documented. In case of cancers, usually it is a good coagent with other chemotherapeutic drugs, might hamper human papilloma virus (HPV) infection as well as avoid cancer cervix generation. In case of NASH, or liver cirrhosis its use with beta blockers might aid in conversion back towards normalcy. Curcumin's pleiotropic actions include inflammatory diseases like cancer, CVD, arthritis, atherosclerosis, DM, gastric disease, inflammatory bowel disease (IBD), psoriasis, HIV etc.  Curcumin is accepted to be a molecule having the capacity to avoid/slowdown the pathological events resulting in age – associated dementia, cognitive decrease, or depression. Additionally, various evaluations have pointed that Curcumin is a potential anticancer treatment in case of human papilloma virus (HPV) infection, in addition to primary as well as malignant squamous cell cancer.

Curcumin Alleviates Dextran Sulfate Sodium-induced Colitis in Mice Through Regulating Gut Microbiota
Molecular Nutrition & Food Research | February 2022
Results showed that oral administration with curcumin relieved macroscopic pathological manifestations, e.g. colon length and histological change. Moreover, it enhanced intestinal barrier via increasing expression of tight junction proteins, e.g. occludin, ZO-1, claudin-3; alleviated DSS-induced intestinal apoptosis via suppressing caspase-3 pathway; mitigated intestinal inflammation via inhibiting the MAPK/NFκB/STAT3 pathway. We also noticed that curcumin is beneficial for modulating abundance of some specific bacteria, including Akkermansia, Coprococcus, Roseburia, and Turicibacter, as well as families such as F16, Enterococcaceae, and Aerococcaceae. Most of the altered bacteria by curcumin are highly correlated with colitis-associated parameters. Curcumin shows therapeutic potential against colitis. It may be served as alternative medicine or adjuvant therapy in the treatment of colitis.

Effectiveness of Curcumin on Outcomes of Hospitalized COVID-19 Patients: A Systematic Review of Clinical Trials
Nutrients | January 2022
The natural spice curcumin has received recent attention in treating diseases involving perturbations of the immune system and inflammation responses, such as COVID-19. Curcumin and other curcuminoids are the main bioactive ingredients of turmeric (Curcuma longa). They have been used for millennia in the traditional medicines of multiple cultures due to their anti-inflammatory, antioxidant, antibacterial, antiviral, antidiabetic, and neuroprotective properties. Curcuminoids have received approval from the USA Food and Drug Administration (FDA), and these compounds have good tolerability and safety. Furthermore, they have already been tested with some successes in clinical trials targeting various diseases. Curcumin treatment—as an adjunct therapy—helps restore the balance between the pro-inflammatory and anti-inflammatory pathways and, at the same time, reduces the persistence of common COVID-19 symptoms and decreases mortality. Together, these findings support curcumin formulations as adjunctive therapy to reduce the hyper-inflammatory effect in COVID-19 patients and improve patient outcomes. Curcumin treatment led to the amelioration of cytokine storm manifestation by reducing pro-inflammatory factors and stimulating anti-inflammatory pathways. Thus, these findings suggest that curcumin treatment may alleviate COVID-19 symptoms by restoration of the pro-inflammatory and anti-inflammatory balance. Furthermore, the study by Pawar et al. showed that curcumin-piperine supplementation led to fewer thromboembolic episodes following recovery from COVID-19 infections.

Cancer Chemoprevention: A Strategic Approach Using Phytochemicals
Frontiers in Pharmacology | January 2022
Curcumin (diferuloylmethane), a polyphenol isolated from Curcuma longa is the most studied phytochemical as a chemopreventive. Curcumin displays a wide variety of pharmacological functions such as anti-inflammatory agent, anti-mutagenic agent, antineoplastic agent, hepatoprotective agent, nutraceutical, anti-microbial agent, anti-oxidant agent, and immunomodulator. It has been shown to have significant roles in prevention, treatment and chemo sensitization of cancer cells (Pavan et al., 2016). Studies have established the anti-proliferative, anti-angiogenic, anti-metastatic, and pro-apoptotic properties of curcumin (Anto et al., 2002; Puliyappadamba et al., 2010; Bava et al., 2011; Vinod et al., 2013). We have reported that curcumin exhibits potential chemopreventive effect against nicotine-induced survival signalling in lung cancer cells. We found that it down-regulates multiple survival signals induced by nicotine in lung cancer cells irrespective of their p53 status (Puliyappadamba et al., 2010). Another study conducted in our laboratory revealed its chemopreventive efficacy against the lung carcinogenesis induced by B (a)P, a potential environmental carcinogen found in cigarette smoke and deep-fried food, in Swiss albino mice (Puliyappadamba et al., 2015). Curcumin treatment has a significant impact on improving the general health of colorectal cancer patients by enhancing expression of p53 molecules in tumour cells and also by promoting the apoptosis of tumour cells (He et al., 2011; Pricci et al., 2020). Curcumin intake causes the down-regulation of NF-kB, COX-2 and phosphorylated STAT3 in peripheral blood mononuclear cells from patients with pancreatic cancer (Dhillon et al., 2008). It has been reported that, daily curcumin intake leads to a significant and dose-dependent reduction in spontaneous ovarian cancer incidence and tumor growth in Hen ovarian cancer model indicating a significant role of curcumin as a chemopreventive strategy for ovarian cancer (Sahin et al., 2018). The administration of curcumin to paediatric patients with relapsed brain tumours undergoing chemotherapy increased their response compared with the controls (Wolff et al., 2012).

Inflammaging and Brain: Curcumin and Its Beneficial Potential as Regulator of Microglia Activation
Molecules | January 2022
Curcumin is a natural compound with a polyphenolic structure. This turmeric extract derives from the rhizome of the Curcuma longa, a member of Zingiberaceae, and shows a wide range of biological and pharmacological activities including antioxidant, anti-inflammatory, antimicrobial, immunomodulatory, and anti-tumor activity. Curcumin is a widely studied polyphenol isolated from Curcuma longa with a variety of pharmacologic properties. It is well-known for its healing properties and has been extensively used in Asian medicine to treat a variety of illness conditions. The number of studies that suggest beneficial effects of curcumin on brain pathologies and age-related diseases is increasing. Curcumin is able to inhibit the formation of reactive-oxygen species and other pro-inflammatory mediators that are believed to play a pivotal role in many age-related diseases. Curcumin has been recently proposed as a potential useful remedy against neurodegenerative disorders and brain ageing. In light of this, our current review aims to discuss the potential positive effects of Curcumin on the possibility to control inflammaging emphasizing the possible modulation of inflammaging processes in neurodegenerative diseases. Curcumin as dietary phenolic compound should be considered as a pharmacological support for longevity, especially in neurodegenerative and neuroinflammatory diseases, due to its activity via declining oxidative stress, modulating signal transduction and gene expression. Curcumin, in fact, is effective as an immune enhancer in modulating systemic inflammation and brain pathologies through multiple communication mechanisms and, for this reason, is hopefully a particularly promising natural agent in counteracting the damages of aging and neurodegenerative diseases. In this respect, the possible interventions by curcumin on microglia suggest the possibility of this natural product to mediate regulation of microglia phenotypes and its functions and also to control redox imbalance and neuroinflammation, thus suggesting a possible use of curcumin as therapeutic agent in preventing and managing major chronic inflammatory disorders typical of the inflammaging process, including brain diseases such as Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. Hence, once again, attention is paid to the modulatory potential of curcumin in its ability to mediate the anti-inflammatory effects and consequently to positively influence immunity and brain aging. Therefore, the use of curcumin as an anti-inflammatory agent with inhibitory effects on microglial transformation could be a valid and promising approach for the treatment of neurodegenerative disorders. Multiple lines of evidence show that the involvement of microglial cells in brain neuroinflammation process typical of aging may be a target for pharmacological interventions. The anti-inflammatory activity of curcumin in microglia is ascribable to the ability of this molecule to inhibit many pro-inflammatory mediators by impeding inflammatory cascades and heightening endogenous anti-inflammatory mediators where curcumin may act as an immunomodulator. In line with what emerges from this review, there is evidence that the combination of standard protocols or new therapies with the use of curcumin-based formulations could be a desirable approach in the containment and treatment of the inflammaging process, including that related to the brain.

The Multifaceted Actions of Curcumin in Obesity
Natural Products and Human Diseases | January 2022
Crcumin, the active ingredient in turmeric, has attracted considerable research interest in tracking down the possible effects in protection against obesity and obesity-related comorbidities. According to the existing literature, curcumin may regulate lipid metabolism and suppress chronic inflammation interacting with white adipose tissue, which plays a central role in the complications associated with obesity. Curcumin also inhibits the differentiation of adipocyte and improves antioxidant properties. In the present review, we sought to deliberate the possible effects of curcumin in downregulating obesity and curtailing the adverse health effects of obesity.

Curcumin and Weight Loss: Does It Work?
International Journal of Molecular Sciences | January 2022
Curcumin is a polyphenolic compound that represents the most important curcuminoid isolated from the rhizome of the plants. It is believed that curcumin possess subtle effects through multiple mechanisms and biochemical targets, collectively leading to substantial health benefits. This indicates that this compound has potential for preventing (and, in the future, treating) obesity. Curcumin has many properties, including antioxidant. The role of antioxidants during the occurrence of oxidative stress is important, which in turn may contribute to the prevention or delay of the development of many diseases (including civilizational) and their possible complications. Therefore, naturally derived antioxidants such as curcumin are of high clinical value. The anti-inflammatory effect of curcumin is equally significant. Curcumin inhibits and regulates tissue production and secretions of pro-inflammatory cytokine, such as interleukins or tumor necrosis factor alpha (TNF-α). Curcumin is a potential anti-cancer agent because of its multidirectional properties with regard to the signaling/molecular pathways. Curcumin possesses the ability to modulate the core pathways involved in cancer cell proliferation, apoptosis, cell cycle arrest, paraptosis, autophagy, oxidative stress and tumor cell motility. Curcumin and Curcuma longa extract inhibit the growth of microorganisms, both G(+) and G(-) bacteria, which often cause human infectious diseases. Curcumin is known to have an antiviral effect; it also has been suggested as a potential treatment option for patients with COVID-19. Curcumin has an anti-diabetic effect through, for example, enhancing glucose uptake and improving pancreatic beta cell function. In addition, curcumin contributes to the reduction of the gluconeogenesis process and to the increase of glucokinase activity. Curcumin was able to restore oxidative stress and DNA methyltransferase functions against diabetic retinopathy. Moreover, curcumin has shown anti-lipidemic effects. There are animal model studies on the use of curcumin in pregnancy. Due to the anti-inflammatory activity of this compound, the possibility of using this compound in the treatment of complications of pregnancy has been suggested, including Gestational Diabetes Mellitus, PreTerm Birth, Preeclampsia and exposure to toxic agents and pathogens. Other activities of curcumin worth mentioning include immune modulation, cardiovascular protection, anti-pulmonary fibrosis, anti-chronic obstructive pulmonary disease and anti-dementia activity. There is a growing scientific interest in curcumin’s therapeutic potential. Indeed, more and more clinical trials based on curcumin administration have been published or are underway. Curcumin is a promising natural bioactive compound which possesses numerous pharmacological activities. It shows multiple mechanism of action and can affect cellular biochemical and physiological regulation. In pharmacies, there are more and more preparations containing curcumin recommended for the prevention of obesity.

Curcumin alleviates restraint stress-induced learning and memory deficit and activity
Behavioral Neuroscience | January 2022
Several investigations have reported that curcumin has a protective effect against stress disturbance. The present study is designed to investigate the effects of curcumin on learning and memory, activity, biochemical, morphology changes, and apoptosis in the hippocampus and prefrontal cortex of restraint stress rats. Curcumin inhibited and reversed the changes of stress induced in the prefrontal cortex and hippocampus of the rats. These findings provided evidence for the protective effect of curcumin therapy on biochemical, morphology, and behavioral changes induced by restraint stress.

Curcumin improves atherosclerosis by inhibiting the epigenetic repression of lncRNA MIAT to miR-124
Vascular | January 2022
Curcumin has protective effect on atherosclerosis. Curcumin suppressed inflammation in atherosclerosis mouse model and ox-LDL-induced cell model. Curcumin relieved ox-LDL-induced cell inflammation. MIAT/miR-124 axis mediated the effect of curcumin on atherosclerosis and altered cell apoptosis and proliferation, both in vivo and in vitro. These data further support the application of curcumin in control of atherosclerosis advancement.

Effect of curcumin supplementation on muscle damage, antioxidant status and inflammatory factors after successive simulated taekwondo competitions
Science & Sports | January 2022
Creatine kinase (CK), lactate dehydrogenase (LDH) and Malondialdehyde (MDA) increased significantly after the competition in placebo group compared to Curcumin supplemented group. Total antioxidant capacity (TAC), significantly increased in Curcumin supplemented compared to placebo group after the competition. Based on the results of this study, Curcumin supplementation has positive effects on reducing muscle damage and oxidative stress.

Curcumin Induces Immunogenic Cell Death In Murine Colorectal Carcinoma
Pharmacological Research | January 2022
Curcumin, a compound found in the rhizome of Curcuma longa, is known to impair the function in cancer cells. This event triggers apoptosis in curcumin-treated cells and can be an important mechanism of the pharmacological effects attributed to curcumin. The present work suggests that curcumin is an inducer of  immunogenic cell death. This observation brings more insights into the mechanism of action of curcumin. It has already been shown that the efficacy of certain cancer therapies, such as anthracycline-based chemotherapy, photodynamic therapy, and radiotherapy, also rely on their ability to reinstate cancer immunosurveillance. Circumventing the immune evasion strategies deployed by cancers and reeducating the host immune system to detect and clear tumor cells can be used as strategies to treat cancer. Thus, the use of curcumin not only to directly kill cancer cells, but also to help inducing an immune response against tumor antigens is an alternative that can be explored in future studies.

Dietary curcumin restores insulin homeostasis in diet-induced obese aged mice
Aging | January 2022
Curcumin is a bioactive polyphenolic compound extracted from the herb Curcuma longa.  Curcumin treatment maintains insulin homeostasis during aging and dietary challenge that is mediated by hepatic IDE. It has antioxidant, anti-inflammatory, and anti-diabetic properties which should mitigate age-associated diseases.  Curcumin supplementation suppresses body weight gain and fat accumulation in aged mice. Its basic mechanism of action as an anti-diabetic therapeutic agent was largely unknown however we previously demonstrated that curcumin supplementation increases insulin sensitivity in hepatocytes by upregulating hepatic IDE expression and preserved islet integrity in a diet-induced obese (DIO) mouse model. Curcumin changes hepatic gene expression profiling and supplementation preserves pancreatic islet integrity in aged mice. Furthermore, we enumerated various cellular and molecular events in the insulin signaling pathway regulated by curcumin.  Dietary curcumin alters gene expression associated with insulin signaling and senescence pathways in the aged mice. In this study, we sought to determine if curcumin supplementation during a nutrient stressor known to cause insulin resistance in aged mice might be beneficial to preserving hepatocytes in an insulin-sensitive phenotype while protecting β -cells from the need to compensate for insulin resistance. In summary, our study illustrates that curcumin supplementation in aged individuals is likely to play a role in mitigating reduced hepatic insulin sensitivity due to aging per se and dietary challenges. It seems convincing that curcumin positively regulates insulin sensitivity in hepatocytes because of the upregulation of IDE that is reflected in reduced demand for increased insulin secretion and synthesis. Thus, curcumin is a potent, natural therapeutic agent which acts in a multifaceted manner to protect aging-induced metabolic disorders.

Nrf2-Related Therapeutic Effects of Curcumin in Different Disorders
Biomolecules | January 2022
Curcumin is a natural polyphenol with antioxidant, antibacterial, anti-cancer, and anti-inflammation effects. This substance has been shown to affect the activity of Nrf2 signaling, a pathway that is activated in response to stress and decreases levels of reactive oxygen species and electrophilic substances. Nrf2-related effects of curcumin have been investigated in different contexts, including gastrointestinal disorders, ischemia-reperfusion injury, diabetes mellitus, nervous system diseases, renal diseases, pulmonary diseases, cardiovascular diseases as well as cancers. In the current review, we discuss the Nrf2-mediated therapeutic effects of curcumin in these conditions. The data reviewed in the current manuscript indicates curcumin as a potential activator of Nrf2 and a therapeutic substance for the protection of cells in several pathological conditions.

Curcumin alters distinct molecular pathways in breast cancer subtypes
Cancer Reports | January 2022
Curcumin is well known for its anticancer properties. Its cytotoxic activity has been documented in several cancer cell lines, including breast cancer. The pleiotropic activity of curcumin as an antioxidant, an antiangiogenic, antiproliferative, and pro-apoptotic, is due to its diverse targets, such as signaling pathways, protein/enzyme, or noncoding gene. Curcumin, a polyphenol extracted from turmeric, is well known for its multifaceted properties like anti-inflammatory, antioxidant, anti-bacterial, anti-malarial, and anticancer. Clinical and preclinical studies have validated the role of curcumin in varied human chronic diseases, including cancer. The therapeutic potential of curcumin can be attributed to its capability to regulate both epigenome and transcriptome. In conclusion, curcumin regulates miRNA and mRNA in a cell type specific manner. Curcumin altered different pathways in breast cancer cell lines such as cell cycle, migration, invasion, and so forth. The integrative analysis led to the detection of miRNAs and mRNAs pairs, which can be used as biomarkers, associated with carcinogenesis, diagnosis and treatment response in breast cancer.

Curcumin exerts a protective effect against obesity and liver injury induced by an atherogenic diet
Functional Foods in Health and Disease | January 2022
Background: Curcumin is a natural yellow polyphenol extracted from the turmeric rhizome (Curcuma longa). Curcumin is known for its potential therapeutic properties as an analgesic, anti-inflammatory, antioxidant, antimicrobial, hepatoprotective, and anti-mutagenic, although some of these biological activities remain unproven. Epidemiological studies have shown a positive relationship between high-fat diets and diet-related chronic diseases. We hypothesized that some adverse effects of consuming atherogenic or high-fat diets can be ameliorated by curcumin supplementation. This study provides supporting evidence to confirm the beneficial effects of curcumin from the point of view of functional food science.

Age-related alterations to working memory and to pyramidal neurons in the prefrontal cortex of rhesus monkeys begin in early middle-age and are partially ameliorated by dietary curcumin.
Neurobiology of Aging | January 2022
Curcumin-treated subjects exhibit better working memory ability and less neuronal excitability. Middle-aged subjects given curcumin exhibited better workng memory performance and less neuronal excitability compared to control subjects. These findings suggest that the appropriate time frame for intervention for age-related cognitive changes is early middle age, and points to the efficacy of curcumin in delaying working memory decline.

Curcumin inhibits the invasion and metastasis of triple negative breast cancer
Journal of Ethnopharmacology | January 2022
Modern pharmacological studies have found that curcumin has many kinds of pharmacological activities of anti-inflammatory, anti-tumor, anti-angiogenesis, anti-metastasis and anti-multidrug resistance. Curcumin has good anti-inflammatory (Lei et al., 2014), anti-oxidation (Santosh et al., 2007), and reducing the levels of ROS(Sethi et al., 2008). It can also inhibit the activation of multiple pathways such as NF-κB (Cho et al., 2007) and IL-1α, IL-6 and other gene expression (Momeni and Eskandari, 2017). A recent study showed that curcumin inhibited the expression of HIF-1 by degrading ARNT in cancer stem-like cells, thereby improving the hypoxia environment and promoting the early apoptosis of breast cancer cells (Sarighieh et al.,2020). Curcumin could significantly reduce cancer proliferation and the expression level of PLAC8 in MCF-7/TAM cells through proteasome and PLAC8/MAPK signaling pathways which showed that curcumin might be a potential adjuvant therapeutic agent for the treatment of tamoxifen-resistant patients (Mao et al.,2021). Moreover, curcumin, as the main ingredient of curry, has no obvious toxic and side effects according to toxicological studies, so it has great potential in the treatment of breast cancer (Lewis and Veltmaat, 2004). Our previous study found that curcumin inhibited the proliferation of breast cancer cells MDA-MB-231 and MCF-7 in vitro and growth of xenograft in vivo. In this study, we found that Gli1 overexpression in MDA-MB-231 adherent cells could promote cell proliferation, invasion and migration, which were inhibited after curcumin and GANT61 treatment. Moreover, curcumin inhibited the formation of mammospheres, and down-regulated the expression of PTCH1,Gli1, Gli2 in Hh pathway in adherent cells, and the expression of E-cadherin, vimentin of EMT genes and Gli1,Gli2, SMO of Hh pathway in MDA-MB-231 mammospheres. In addition, further studies demonstrated that curcumin could inhibit the entry of Gli1 into the nucleus. These data suggested curcumin may inhibit invasion and metastasis of TN breast cancer cells by targeting Gli1. Curcumin can inhibit the proliferation and metastasis of TN breast cancercells, EMT and characteristics of breast cancer stem cells.

Protective Effects of Curcumin in the Reproductive System
Natural Products and Human Diseases | January 2022
The well-known antioxidant natural product curcumin may have properties which could diminish toxic effects. Curcumin has also shown some promise in the cryoprotection of sperm samples through its antioxidant potential.

Curcumin supplementation in pediatric patients: A systematic review of current clinical evidence
Phytotherapy Research | January 2022
Clinical efficacy and safety of curcumin were assessed in children with inflammatory and immune disorders (including asthma, inflammatory bowel disease (IBD), and juvenile idiopathic arthritis (JIA)), metabolic disorders, autosomal dominant polycystic kidney disease (ADPKD), cystic fibrosis (CF), tetralogy of Fallot (TOF), and infectious diseases. Curcumin was administered in a wide range of doses (45 mg–4,000 mg daily) and durations (2–48 weeks). Overall, curcumin was well tolerated in all studies and improved the severity of inflammatory and immune disorders and metabolic diseases. However, more studies are needed to clarify the role of curcumin supplementation among children with ADPKD, CF, TOF, and infectious diseases.

Curcumin Relieves Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior
Behavioral Neurology | January 2022
Curcumin, the major active component extracted from the Chinese medicine Curcuma longa, has been reported to possess neuroprotective effects. Ccurcumin’s potential antidepressant-like effects have been highlighted in many preclinical trials conducted on rats and mice models of depression. Curcumin might be effective as adjunctive treatment in depressive disorders, indicating the promising efficacy of curcumin depression. More and more studies have discussed the potential mechanism of curcumin's antidepressant-like effects. Our previous study found that curcumin could restore changes in proinflammatory cytokines and the indolamine-2, 3-dioxygenase- (IDO-) kynurenine pathway in the hippocampus of CUMS rats, which might ultimately contribute to its antidepressant-like effect. Another study conducted by our teammates Liao et al. suggested that the possible antidepressant-like effects of curcumin are associated with oxidative stress and with changes in the activation of erythroid-2-related factor 2 (Nrf2) in the brain. Moreover, Liao et al. found that curcumin could reverse the decreased expression of BDNF. Other studies have also indicated curcumin’s ability to increase BDNF levels. These studies point strongly to an association between the antidepressant-like effects of curcumin and the regulation of BDNF levels. Curcumin successfully attenuated the abnormal behaviors induced by CUMS and effectively prevented CUMS-induced reduction of PGC-1α, ERRα, FNDC5, and BDNF expressions. Curcumin also enhanced PGC-1α and ERRα translocation from cytoplasm to nucleus. Furthermore, we found that curcumin supplementation effectively promoted neurocyte proliferation and suppressed neuronal apoptosis induced by CUMS. Of note, the PGC-1α inhibitor SR18292 remarkably reversed the beneficial effects of curcumin on depressed rats, indicating an important role of PGC-1α in the antidepressant-like effects of curcumin. Collectively, our data evaluating the neuroprotective action of curcumin in the CUMS rats highlights the involvement of the PGC-1α/FNDC5/BDNF pathway in the antidepressant-like effects of curcumin.

Role of Curcumin in Retinal Diseases—A review
Clinical and Experimental Ophthalmology  | January 2022
Curcumin showed its pleiotropic effects in retinal diseases like diabetic retinopathy by increasing anti-oxidant enzymes, upregulating HO-1, nrf2 and reducing or inhibiting inflammatory mediators, growth factors and by inhibiting proliferation and migration of retinal endothelial cells in a dose-dependent manner in HRPC, HREC and ARPE-19 cells. In age-related macular degeneration, curcumin acts by reducing ROS and inhibiting apoptosis inducing proteins and cellular inflammatory genes and upregulating HO-1, thioredoxin and NQO1. In retinitis pigmentosa, curcumin has been shown to delay structural defects of P23H gene in P23H-rhodopsin transgenic rats. In proliferative vitreoretinopathy, curcumin inhibited the action of EGF in a dose- and time-dependent manner. In retinal ischemia reperfusion injury, curcumin downregulates IL-17, IL-23, NFKB, STAT-3, MCP-1 and JNK. In retinoblastoma, curcumin inhibits proliferation, migration and apoptosis of RBY79 and SO-RB50. Curcumin has already proven its efficacy in inhibiting viral replication, coagulation and cytokine storm in COVID era. Curcumin is a curcuminoid obtained from turmeric (curcuma longa) that belongs to the Zingiberaceae family. They belong to the group of phytocompounds that are biologically active molecules obtained from plants with positive effects on health. Curcumin is a bis-α,β-unsaturated β-diketone with the chemical name 1,7-bis-(4-hydroxy-3-methoxyphenyl)1,6-heptadiene-3,5-dione and commonly called diferuloylmethane, E100 (European code of food additives) or Natural Yellow 3. Its chemical formula is C21H20O6 and molecular weight is 368.38 gm/mol. It has two aromatic ring systems containing o-methoxy phenolic groups that are linked with a seven-carbon linker consisting of α, β-unsaturated β-diketone moiety. It also exists in two tautomeric forms, keto-enol and diketo tautomers. It is present in keto-enol form in polar organic solvents, which is the predominant form of tautomer. Cheng et al. studied the pharmacokinetics, toxicology and biologically effective dose of curcumin in humans with high risk or premalignant lesions. An initial dose of 500 mg once a day in empty stomach in 25 patients and the dose was increased to 1000, 2000, 4000, 8000 and 12,000 if there was no toxicity ≥ grade 2 in at least 3 successive patients. No toxicity was seen in doses up to 8000 mg. Curcumin showed no toxicity up to 8000 mg when taken for 3 months. 

The Effect of Curcumin Differs on Individual Cognitive Domains across Different Patient Populations: A Systematic Review and Meta-Analysis
Pharmaceuticals | December 2021
Curcumin is a polyphenol with strong antioxidant and anti-inflammatory activity. It is also the primary active component of the Indian spice turmeric (Curcuma longa)and curry powders. Animal studies have also confirmed that curcumin has protective effects against cognitive decline, both in aging rhesus monkeys and in a streptozotocin-induced dementia rat model. Specifically, curcumin has been found to exhibit various selective effects, including preventing atrophic change and cell loss in the prefrontal cortex compared to the hippocampus, decreasing neuroinflammation compared to promoting neurogenesis, and more positive effects on working memory than on recognition. Following at least 8 weeks of nutritional supplementation, curcumin was found to improve working memory more than a placebo regimen. The results in the cognitive domain of processing speed were notable, with a borderline p-value, which may be significant if further trials are included. The protective effect of curcumin in the prefrontal cortex has also been demonstrated in animal models. Noorafshan et al. used three different neural damage rat models, including stress-induced, sulfite-induced, and sleep deprivation, and found that curcumin could prevent structural deterioration in neurons and glial cells, and could also counteract behavioral changes. This showed that curcumin had a direct protective effect on the prefrontal cortex and may explain why curcumin was able to effectively improve working memory, as observed in our meta-analysis.

Turmeric Root and Its Bioactive Ingredient Curcumin Effectively Neutralize SARS-CoV-2 In Vitro
Viruses | December 2021
Turmeric root, also known as Curcuma longa, is broadly used as a spice widely cultivated in Southeast Asia. The rhizome of Curcuma longa contains several structurally related curcuminoids. Sixty to 75% of the curcuminoid content consists of curcumin, also known as diferuloylmethane. The remaining fraction is a combination of demethoxycurcumin (20–25%) and bisdemethoxycurcumin (5–15%). Turmeric root has been used for thousands of years as medicine for the complementary treatment of a wide variety of diseases. As early as 1815, the bioactive ingredient curcumin was first isolated from turmeric root by Vogel and Pelletier. Curcumin reveals a broad spectrum of bioactivities such as antioxidant, anti-inflammatory, antibacterial, antiviral, antitumor, and hepatoprotective activities.  In addition to the antiviral activity, curcumin also exhibits anti-inflammatory effects. Randomized controlled trials indicated a significant downregulation of the human tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) through curcumin supplementation. A meta-analysis showed that 8–12 weeks of treatment with 1 g curcumin per day can reduce symptoms of rheumatoid arthritis such as pain and symptoms related with inflammation. We and others have demonstrated the antiviral activities of curcumin against various viruses, including Dengue Virus, Human Immunodeficiency Virus (HIV), Kaposi Sarcoma-associated Herpesvirus, Enterovirus, Zika Virus, Chikungunya Virus, Vesicular Stomatitis Virus, the Human Respiratory Syncytial Virus, Viral Hemorrhagic Septicemia Virus, Influenza A Virus, Herpes Simplex Type 2, Norovirus, and Hepatitis C Virus. Furthermore, curcumin is known for its pharmacological abilities especially as an anti-inflammatory and antiviral agent. Moreover, curcumin was discussed as a potential candidate in the therapeutic regimen of COVID-19. Curcumin acts as an antiviral agent against a variety of viruses, including HIV, HCV, Influenza A, and Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1). Furthermore, curcumin inhibits SARS-CoV-1 and also inhibits SARS-CoV-2. Curcumin treatment significantly reduced SARS-CoV-2 RNA levels in cell culture supernatants of Vero E6 cells with an EC50 of ≈14 µg/mL (≈38 µM). We demonstrated that curcumin efficiently inhibited SARS-CoV-2 infection in both cell lines, Vero E6, and human Calu-3 lung cells, thereby indicating a genuine antiviral effect of curcumin against SARS-CoV-2.

Curcumin Ameliorates the Cd-Induced Anxiety-like Behavior in Mice by Regulating Oxidative Stress and Neuro-Inflammatory Proteins in the Prefrontal Cortex Region of the Brain
Antioxidants | February 20
Curcumin is an active component of turmeric (Curcuma longa) which is widely used as a food additive in Indian cuisines and Ayurvedic medicines. Previously, researchers have reported the neuroprotective effect of curcumin in various neurodegenerative diseases. In our study on dim light-induced neurodegeneration, we have shown the antioxidant effects of curcumin. Other researchers have also highlighted the anti-inflammatory and antioxidant effects of curcumin. Curcumin plays an effective role as a natural therapeutic drug to combat Cd-induced behavioral impairment by regulating oxidative stress and modulating inflammatory markers. Curcumin was found to improve the behavior of mice through reduction of prefrontal cortex oxidative stress and neuroinflammation as well as promotion of hippocampal neurogenesis. Therefore, curcumin supplementation in food and diet could reduce the deleterious effect of heavy metal exposure.

Curcumin mediates presenilin-1 activity to reduce β-amyloid production in a model of Alzheimer’s disease
Pharmacological Reports | December 2021
Curcumin has been reported to inhibit the generation of Aβ. Aβ is thought to play an important role in the pathogenesis of Alzheimer’s disease. Curcumin treatment was found to markedly reduce the production of Aβ40/42. Treatment with curcumin also decreased both PS1 and GSK-3β mRNA and protein levels in a dose- and time-dependent manner. Furthermore, curcumin increased the inhibitory phosphorylation of GSK-3β protein at Ser9. Therefore, we propose that curcumin decreases Aβ production by inhibiting GSK-3β-mediated PS1 activation.

Antiviral Therapeutic Potential of Curcumin
Molecules | December 2021
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), also called diferuloylmethane, is the best example of a plant derivative with an enormous number of therapeutic properties, such as anti-oxidant, anti-carcinogenic, anti-diabetic, anti-microbial, and antiviral activity. In traditional Indian Ayurvedic medicine, curcumin was widely applied in many therapeutic remedies. This compound is a natural polyphenolic substance and an active form of the traditional herb that is found in the rhizome of Curcuma longa (turmeric). Curcumin is the main molecule of the curcuminoids; the curcuminoids are comprised of curcumin (77%) as well as includes bisdemethoxycurcumin (BDMC) (17%) and demethoxycurcumin (DMC) (6%). The first suggestion that curcumin had antiviral properties came in the 1990s, with the discovery that curcumin and curcumin boron complexes could inhibit the human immunodeficiency virus (HIV). Since then, numerous studies have found that curcumin has antiviral activity against a diverse set of viruses, including both RNA and DNA viruses, both enveloped and non-enveloped. Multiple selected studies were on different types of human viruses, including human immunodeficiency virus (nine studies), hepatitis C virus (five studies), human cytomegalovirus (three studies), hepatitis B virus (four studies), herpes simplex viruses (four studies), dengue virus (four studies), enterovirus 71 (two studies), human T lymphocyte virus (two studies), vesicular stomatitis virus (two studies), and respiratory syncytial virus (two studies). There was one study for viruses including zika and chikungunya, coronavirus, Rift Valley fever virus, human norovirus, coxsackievirus B3, Japanese encephalitis virus, and viral hemorrhagic septicemia virus.  27 studies showed that curcumin reduced the production of infectious particles in various infected cells in a dose-dependent manner.

Curcumin supplementation improves biomarkers of oxidative stress and inflammation in conditions of obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD)
Food & Function | December 2021
A systematic search, through prominent online databases such as MEDLINE, Scopus, and Google Scholar was done focusing on randomized controlled trials (RCTs) reporting on the impact of curcumin supplementation in individuals with diverse metabolic complications, including obesity, type 2 diabetes and nonalcoholic fatty liver disease. Summarized findings suggest that curcumin supplementation can significantly reduce blood glucose and triglycerides levels, including markers of liver function like alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in patients with type 2 diabetes and nonalcoholic fatty liver disease. Importantly, this effect was consistent with the reduction of predominant markers of oxidative stress and inflammation, such as the levels of malonaldehyde (MDA), tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP) and monocyte chemoattractant protein-1 (MCP-1) in these patients. RCTs suggest that curcumin is beneficial in ameliorating some metabolic complications.

Curcumin as a Possible Treatment for COVID-19-Induced Anosmia and Ageusia
Cureus | December 2021
Curcumin, the main component of the spice turmeric, is derived from the rhizome of the plant Curcuma longa. Beneficial effects of curcumin have been reported over centuries in the treatment of various ailments, from oncological to autoimmune disorders. Curcumin has been observed to block pro-inflammatory regulators and signaling pathways, including inhibiting nuclear factor (NF)-kappa B activation and suppressing tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), monocyte chemotactic protein-1 (MCP-1), prostaglandin E2, and cyclooxygenase-II, among others. Curcumin has been shown to bind and block the active site of Mpro, the main protease utilized by COVID-19 to produce proteins required for viral replication from viral genomic RNA. Curcumin may also hinder the formation of the COVID-19 spike protein-ACE2 complex, preventing viral entry into cells. The anti-inflammatory action of curcumin may reduce nasal mucosal swelling.

Antioxidant effects of curcumin and neuroaging
Genetics, Neurology, Behavior, and Diet | December 2021
Curcumin, a plant-based polyphenol, is known to scavenge free radicals and promote antioxidant activity. This chapter gives an overview of the molecular evidence that curcumin prevents oxidative stress, cellular senescence, and death. In addition, curcumin’s role in protection against memory impairment as evidenced by brain imaging studies is reviewed. There is preliminary evidence for curcumin improving memory and decreasing amyloid-β plaque accumulation. Consequently, curcumin has potential as a therapy in aging and aging-related disorders.

Curcumin in Metabolic Health and Disease
Nutrients  | December 2021
In recent years, epidemiological studies have suggested that metabolic disorders are nutritionally dependent. A healthy diet that is rich in polyphenols may be beneficial in the treatment of metabolic diseases such as polycystic ovary syndrome, metabolic syndrome, non-alcoholic fatty liver disease, cardiovascular disease, and, in particular, atherosclerosis. Curcumin is a polyphenol found in turmeric and has been reported to have antioxidant, anti-inflammatory, hepatoprotective, anti-atherosclerotic, and antidiabetic properties, among others.

Targets of Curcumin against Colorectal Cancer and the Correlation with Tumor-Infiltrating Immune Cells
Evidence-Based Complementary and Alternative Medicine | December 2021
In recent years, more and more studies have shown that curcumin has great potential in the treatment of colorectal cancer. Curcuma longa L., commonly known as turmeric, is a rhizomatous herb of the ginger (Zingiberaceae) family. Curcumin is a lipophilic polyphenol compound extracted from the Zingiberaceae family, which lowers blood glucose and has anticancer, anti-inflammation, and antiaging effects. Howells et al. confirmed that curcumin is a safe and well-tolerated adjuvant chemotherapy drug for folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) chemotherapy of metastatic colorectal cancer. In a clinical trial, curcumin has been proved to promote the transformation of Treg cells to Th1 cells and enhance the production of interferon-γ, supporting the antitumor effect of curcumin in colorectal cancer. The clinical efficacy of curcumin in the treatment of colorectal cancer has been recognized. Subsequent in vivo experiments confirmed that curcumin can reduce inflammation and colorectal cancer formation in mouse models. These research results showed that curcumin has many potential effects and has definite therapeutic effects on colorectal cancer . In conclusion, in this study, we identified the key targets of curcumin in colorectal cancer inhibition through the combination of network pharmacology, molecular docking, and tumor immune microenvironment analysis. The mechanism of action of curcumin is binding to AKT1, STAT3, and EGFR by hydrogen bond, hydrophobic effect, and π-cation bond.

The Functional Roles of Curcumin on Astrocytes in Neurodegenerative Diseases
Neuroimmunomodulation | December 2021
Curcumin is the main component of a yellow pigment, commonly called diferuloylmethane, and is an active ingredient in the rhizome of the herb Curcuma longa that represents various biomedical applications. Curcumin has also been traditionally used for its medicinal benefits and wound healing for centuries. However, it was first applied as a drug to treat biliary disease in 1937. Curcumin is a lipophilic polyphenol that is relatively stable in the acidic pH but decomposes in neutral-basic conditions. Curcumin contains approximately 77% diferuloylmethane, 17% dimethoxycurcumin, and 6% bisdemethoxycurcumin. Nowadays, curcumin (C21H20O6) has important roles in the attenuation of progression of some NDs because of its anti-amyloid and anti-inflammatory agents. In addition, curcumin also has several benefits, such as being safe, inexpensive, and readily available polyphenol that can cross the blood brain barrier, thus attracting researchers to use it for treating neurodegenerative diseases.  Curcumin is an NF-κB inhibitor by interrupting ZO-1 expression and localization, MLC phosphorylation, and ROS generation inhibition, which constrains disruption of the BBB by Th17 cells. Furthermore, curcumin, through its NF-κB inhibitory effect, causes intestine dendritic cell differentiation into tolerogenic phenotypes, as well as naive T cells to differentiate into FoxP3+ regulatory T cells (intestine protective, Treg). Thus, curcumin can prevent colitis, due to its anti-inflammatory function. Curcumin has a critical role in transcription factor regulation. Furthermore, curcumin can regulate cytokines, adhesion molecules, protein kinases, redox status, and inflammation-associated enzymes. The pharmacological activities of curcumin are antimicrobial, anti-inflammatory, antioxidant, and anticarcinogenic. It also exhibits potent immunoregulatory activities that can modulate the T cells, B cells, neutrophils, natural killer cells, and macrophage activation and function. Curcumin has been shown to be protective for several cells, including astrocytes, neurons, microglia, and different part of the CNS such as hippocampal, mesencephalic, cortical, and spinal cord. A multiple sclerosis study showed that curcumin regulates T-cell responses to IL-12 by blocking IL-12 production, and IL-12 signaling, through inhibiting JAK-STAT signaling activation. Thus, it has been suggested that curcumin could be used for treating multiple sclerosis and other Th1-cell-mediated inflammatory diseases. Furthermore, curcumin at high doses can directly induce T-cell apoptosis and inhibit T-cell proliferation through blocking of the IL-2 signaling pathway, high-affinity IL-2R, and interfering with IL-2R signaling. These data indicate that curcumin has immunosuppressive effects on many pathways. Thus, curcumin, through its proinflammatory cytokines, decreases TNF-α/β, IL-1, IL-6, and IL-8, and COX-2 provides a therapeutic effect by reducing inflammatory conditions. Curcumin can cross blood brain barrier and, by inhibiting proinflammatory cytokines, can regulate homeostasis of the CNS. The blood brain barrier has a crucial role in controlling the homeostasis of the brain microenvironment. Thus, because autoreactive T-cell penetration plays a key role in MS lesion development, the role of curcumin to protect the blood brain barrier could reduce the severity of MS. Curcumin also decreases the severity of chronic inflammatory diseases, such as rheumatoid arthritis, asthma, AD, and cancer. In phase II clinical trial, curcumin was used orally in a mouse model of colorectal cancer. It has been demonstrated that curcumin can prevent carcinogenesis through different mechanisms such as reduction of cyclooxygenases 1 and 2, 5-lipoxygenase, prostaglandin E2 (PGE2), and 5-hydroxyeicosatetraenoic acid production inhibition. Fortunately, curcumin via inhibition of NF-κB signaling pathways can improve the effects of some chemotherapy drugs. For example, in the mouse model of human breast cancer, curcumin, in conjunction with paclitaxel, can slow breast cancer progression and metastasis to the lung. According to Alavez et al., curcumin, through its involvement in the regulation of protein homeostasis, can increase life span in several species. Curcumin, as a natural cost-effective product with proven pharmacological safety, has strong antioxidant and anti-inflammatory effects through modulating many cellular signaling pathways, affects numerous molecular targets in astrocytes, and is a promising candidate for the prevention and treatment of various neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, multiple scleroses, and Huntington’s disease.

Effect of curcumin supplement or placebo in delayed onset muscle soreness: a systematic review and meta-analysis
Bulletin of the National Research Centre | December 2021
Curcumin is a natural polyphenolic substance extracted from turmeric. It has various physiological effects, such as membrane protective effects, as well as anti‐inflammatory and antioxidant responses. These mechanisms have been reported to suppress the activity of NF‐κB, thereby suppressing the expression of IL-6 and tumor necrotic factor TNF-α. This review suggested that persons who took curcumin supplement before exercise have pain score of about 1 score lower than those who took placebo in and post-exercise at 1, 2, 3 and 4 days. For indirect markers of muscle damage, the persons who took curcumin supplement before exercise have lower CK, TNF and IL score than those who took placebo. From a review of previous meta-analysis (Fang and Nasir 2021), curcumin has efficacy in reducing CK serum levels and muscle soreness index among adults. Therefore, curcumin may be known as a priority EIMD recovery agent in interventions.  To conclude, curcumin supplement has reduced muscle soreness and CK after exercise after 1, 2, 3, and 4 days when compared to placebo.

Curcumin and Its Potential Impact on Microbiota
Nutrients | December 2021
Curcumin is a polyphenol substance isolated from the rhizome of Zingiberaceae and Araceae plants. It is a major active constituent of turmeric, a common Asian spice used as a dietary spice, food-coloring, as a herbal remedy, and in the beverage industries. Its bioactive components have been investigated recently [1,2]. Diferuloylmethane (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), which is commonly referred to as curcumin, has been shown to have activity at the cellular level, by signaling multiple molecules. In addition it exerts antioxidant and anti-inflammatory properties. It may have many therapeutic effects, having exhibited antitumor, chemosensitizing, hepatoprotective, lipid-modifying, and neuroprotective effects. Piperine is a natural alkaloid that is found in black pepper (Piper nigrum), which is capable of increasing the bioavailability of curcumin by inhibition of biotransformation—especially glucuronidation—in the liver and small intestine. As Hewlings and Kalman emphasized in their work, piperine has been associated with an increase in the bioavailability of curcumin by 2000%. Polyphenols, such as curcuminoids, are naturally occurring bioactive compounds that, due to their antioxidant abilities, play important roles in human nutrition. A substantial amount of promising evidence has indicated that curcumin may be capable of preventing and combating several metabolic syndromes, cancer, and obesity, and may even play a neuroprotective role. The metabolism of curcumin, which occurs in the intestine, enhances its biological activity and, as a consequence, biotransforms it into active metabolites, which may promote beneficial effects in the gut microbiota.

Curcumin as a great contributor for the treatment and mitigation of colorectal cancer
Experimental Gerontology | December 2021
This review mainly brings out the correlation between the curcumin and its use for the mitigation of colorectal cancer, the use of curcumin as a chemotherapeutic agent, chemosensitizer, and in a combination and synergistic approach. The pharmacokinetics and pharmacodynamics properties of curcumin and its formulation approach helps in giving an idea to develop new approaches for the treatment of colorectal cancer using curcumin.

Protective effect of the association of curcumin with piperine on prostatic lesions
Food and Chemical Toxicology | December 2021
Curcumin plus piperine reduce malignant effects of BPA in prostate.  Inflammation provoked to BPA in the prostate was minimized by curcumin and piperine. Curcumin and piperine helped to minimize carcinogenesis. Thus, these phytochemicals minimize the deleterious action of BPA in prostatic lobes, especially when administered in association. The protective action of curcumin and piperine consumption is associated with weight loss, anti-inflammatory potential, and control of prostate epithelial cell homeostasis.

The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer
Phytomedicine | December 2021
This study evaluated the immune-modulating effects of Curcumin, which has well-established anti-cancer and chemopreventive properties, and its long-term safety as a phytochemical drug. We found that Curcumin decreased the expression of IC ligands such as PD-L1, PD-L2, and Galectin-9 in HNSCC, leading to regulation of epithelial-to-mesenchymal transition-associated tumor invasion. Curcumin also effectively restored the ability of CD8+ cytotoxic T cells to lyse cancer cells. To evaluate the effect of Curcumin on the TME further, the 4-NQO oral cancer model was used. Curcumin increased T-cell proliferation, tumor-infiltrating lymphocytes (TILs), and effector cytokines, and decreased the expression of PD-1, TIM-3, suppressive IC receptors and their ligands (PD-L1, PD-L2, and Galectin-9) in the TME, implying reinvigoration of the exhausted CD8+ T cells. In addition, Curcumin inhibited expression of CD4+CD25+FoxP3+ Treg cells as well as PD-1 and TIM-3. These results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multi-level (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC.

The efficacy of high and low dose curcumin in knee osteoarthritis: A systematic review and meta-analysis
Complementary Therapies in Medicine | December 2021
Curcuminoids have been shown to possess multiple pharmacological effects, such as anti-inflammatory, anti-oxidative, anti-hyperlipidaemic, and anti-platelet effects, and also to relieve pain and reduce swelling. These properties can be attributed to curcumin acting as an inhibitor of the nuclear factor-kappa β (NF-κβ) pathway and a scavenger of reactive oxygen and nitrogen species. Curcuminoids are employed as adjunctive treatment for rheumatoid arthritis, degenerative neural disease, some cancers, and polycystic ovary disease. Recent randomized controlled trials) have revealed that curcumin has similar effects on pain relief and fewer gastrointestinal AEs than NSAIDs, such as diclofenac and ibuprofen. Moreover, Ali Mobasheri et al. reported that “curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of the NSAID in OA-derived synovial adherent cells”, suggesting that combination treatment with curcumin and an NSAID may lower the NSAID dosage needed and reduce its side effects. Additionally, a recent study by Shep et al. reported less rescue medication use and fewer AEs in patients taking combined curcuminoid and diclofenac than in those taking diclofenac alone. Previous meta-analyses have shown that curcuminoids have beneficial effects on knee OA. Low- and high-dose curcuminoids have similar pain relief effects and adverse events in knee OA.  Curcuminoids are associated with better pain relief than non-steroid anti-inflammatory drugs.

Effects of curcumin supplementation on inflammatory biomarkers in patients with Rheumatoid Arthritis and Ulcerative colitis: A systematic review and meta-analysis
Complementary Therapies in Medicine | December 2021
Curcumin is the active ingredient of turmeric which its anti‐inflammatory and antioxidant properties have been studied in patients with cardiovascular diseases and cancers.22, 23, 24 Some studies indicated that curcumin decreased inflammatory markers, such as (Erythrocyte Sedimentation Rate) ESR and C-Reactive Protein (CRP), in patients with ADs,25,26 but other studies failed to find such associations.27 Inconsistent findings were also reported for the effects of curcumin supplementation on serum levels of interleukins and tumor necrosis factor-α.28,29 For instance, curcumin supplementation in doses of 2000 mg/day over 12 weeks was associated with a significant reduction in serum IL-22 concentrations in comparison with placebo administration but had no significant influence on IL-17 concentrations in a randomized clinical trial (RCT).28 In addition, in another study, curcumin caused a significant reduction in hs-CRP and ESR levels but had no significant influence on TNF-α levels.29 In 2014, a meta‐analysis of 19 RCTs found that turmeric and curcumin/curcuminoids supplementation had no significant effect on serum levels of inflammatory markers in patients with chronic inflammatory diseases.30 However, it should be noted that the combined effect of curcumin with turmeric was investigated in that meta-analysis and the exclusive influence of curcumin on outcomes of interest was unclear. Curcumin supplements in doses of 250−1500 mg/day over 8–12 weeks was associated with decreases in ESR in adult patients with rheumatoid arthritis and ulcerative colitis in comparison with the control group. Curcumin supplements in doses of 250−1500 mg/day over 8–12 weeks was associated with decreases in CRP in adult patients with rheumatoid arthritis and ulcerative colitis in comparison with the control group. All subgroup analyses showed significant changes in ESR and CRP although curcumin supplements in doses of 250−1500 mg/day over 8–12 weeks was more associated with decreases in ESR and CRP in younger patients (≤40 years) with rheumatoid arthritis and ulcerative colitis in comparison with the control group. Furthermore, more duration (> 8 weeks) and more dosage of curcumin (more than 500 mg) is more related to reduction in ESR and CRP in adult patients with rheumatoid arthritis and ulcerative colitis in comparison with the control group.

Curcumin prevents arsenic-induced carcinogenesis
Chinese Medical Journal | December 2021
Curcumin, an acidic polyphenol compound has anti-inflammatory and anti-tumor effects. This natural chemopreventive agent, derived from rhizomes of curcuma species, provides antioxidant, anti-tumor, and anti-proliferative efficacy. Curcumin blocks cancer development by modulating multiple signaling pathways. Researchers have previously provided novel perceptions about the mechanisms of curcumin action in gastric cancer cell growth inhibition and its therapeutic strategies for gastric cancer control. Therefore, curcumin could be considered a novel therapeutic strategy to control gastric cancer cell growth. Some studies have emphasized the importance of curcumin in lung cancer treatment and the potential utility of curcumin as a method for improving therapeutic outcome. Curcumin suppressed gemcitabine-resistant non-small cell lung cancer cell proliferation and induced apoptosis. Curcumin upregulated the expression of lncRNA-MEG3 and PTEN. Previous studies have also showed that curcumin has potential clinical application in gemcitabine-resistant non-small cell lung cancer treatment for its anti-tumor activity. Furthermore, curcumin also showed anti-inflammatory activity in the kidney. Another study identified curcumin as a common inhibitor of NLRP3 inflammasome activation and revealed that curcumin repressed inflammation. In view of the various advantages and characteristics of curcumin, its anti-tumor effect has attracted the attention of researchers, and has good application prospect in the prevention and treatment of lung cancer. Curcumin, a major yellow pigment and spice in turmeric and curry, is a powerful anti-cancer agent. The anti-tumor activities of curcumin include inhibition of tumor proliferation, angiogenesis, invasion, and metastasis, induction of tumor apoptosis, increase in chemotherapeutic sensitivity, and regulation of cell cycle and cancer stem cells, indicating that curcumin has strong therapeutic potential in modulating the progression of various cancers. Numerous studies have provided evidence that curcumin protects against neurotoxicity, genotoxicity, and DNA damage in vivo and in vitro. To date, more than 100 clinical trials have been completed with curcumin, all of which have demonstrated its safety, tolerability, and effectiveness against various chronic diseases, including various cancers, diabetes, obesity, and cardiovascular, pulmonary, neurological, and autoimmune diseases in humans. Curcumin may represent a useful supplement to improve chronic inflammation and prevent carcinogenic changes in patients. These studies have indicated that curcumin is a promising molecule for the prevention and treatment of cancer. In summary, in the first stage of As3+-induced carcinogenesis, curcumin activates Nrf2, decreases ROS, and induces autophagy in normal cells to prevent As3+-induced cell transformation. In the second stage, curcumin inhibits constitutive expression of Nrf2 and promotion of ROS, apoptosis, and inhibition of angiogenesis in AsT cells to prevent tumorigenesis. Our results suggest that antioxidant natural compounds such as curcumin should be evaluated further as potential candidates for complementary therapy for As3+-induced carcinogenesis.

Improvement of intestinal barrier function, gut microbiota, and metabolic endotoxemia in type 2 diabetes rats by curcumin
Bioengineered | November 2021
Curcumin is a natural polyphenol compound extracted from Curcuma tuber and Curcuma rhizome. It is believed to possess the ability of anti-tumor, anti-inflammatory, antioxidant and anti-fibrosis effects. Studies have shown that curcumin could inhibit nuclear factor-κB (NF-κB) mediated interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) release in db/db diabetic mice, and further reduce the inflammatory reaction of mouse liver. In obese rats fed with high fat diet and obese mice with leptin gene deficiency,  curcumin can inhibit the secretion of TNF and monocyte chemoattractant protein-1 (MCP-1), improve inflammatory response, and reduce the levels of blood glucose and glycosylated hemoglobin. Clinical trials indicated that oral curcumin can improve the function of islet B cells in prediabetic patients, reduce insulin resistance, prevent progression to type 2 diabetes. Therefore, curcumin has good clinical application prospects. In this study, we demonstrated that curcumin could improve the intestinal integrity in the type 2 diabetes animal model, and promoted the expression of ZO-1 and occludin. In addition, the hyperglycemia and insulin resistance of type 2 diabetes rats were relieved by curcumin. The suppressive effect of curcumin on TLR4/NF-κB was also observed. Curcumin also improve the gut microbiota dysbiosis in type 2 diabetes Some studies have indicated the protective role of curcumin in intestinal barrier of diabetes. Their conclusions that curcumin could improve the intestinal barrier function are in line with our study. In this study, we found that the significant increase of LPS caused by HFD could be remarkably reduced by curcumin. We demonstrated that curcumin could improve the intestinal barrier function, gut microbiota, and metabolic endotoxemia in type 2 diabetes rats. Therefore, curcumin might be a potential therapeutic agent for the treatment of type 2 diabetes.

Neuroprotective Effects of Curcumin in Methamphetamine-Induced Toxicity
Molecules | November  2021
Curcumin, a natural polyphenol extracted from rhizome of the Curcuma longa L, has received great attention for its multiple potential health benefits as well as disease prevention. For instance, curcumin protects against toxic agents acting on the human body, including the nervous system. In detail, curcumin possesses, among others, strong effects as an autophagy activator. The present data provide evidence that curcumin counteracts the neurotoxic effects induced by methamphetamine by promoting autophagy.  In recent years, curcumin has received great attention for its multiple potential health benefits as well as disease prevention. Curcumin has been explored for its multiple biological activities mostly focusing on autophagy activation, which is considered to be relevant to counteract various toxicants and disease conditions.

Curcumin Inhibits In Vitro SARS-CoV-2 Infection In Vero E6 Cells through Multiple Antiviral Mechanisms
Molecules | November 2021
Curcumin, the main polyphenolic compound of turmeric, has attracted significant attention owing to its biological effects, such as anti- tumor, anti-inflammatory, immunomodulating, antioxidant, antimicrobial, and antiviral activities; therefore, it has been proposed that curcumin may be a potential treatment against COVID-19. Notably, it has been observed that the consumption of curcuminoids leads to a significant reduction in circulating levels of C-reactive protein and decreases the expression of proinflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α, demonstrating its anti-inflammatory capacity; it is important to highlight that this cytokines has been correlated with severe illness. Moreover, in macrophages, it has been observed that curcumin inhibits NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, which plays a significant role in the development of inflammatory diseases. Additionally, curcumin exhibits its inhibitory activity against the replication of diverse viruses, such as dengue virus, hepatitis B virus, zika virus, influenza A virus, and chikungunya virus. Curcumin can exert antiviral effects directly on the viral particle or at different stages of the replicative cycle by interacting with viral proteins or by modulating cellular processes or pathways crucial for viral replication. Specifically for SARS-CoV-2, studies in silico (computer modeling) have reported that curcumin exhibits favorable binding affinities with the spike protein of the virus, as well as with its main cellular receptor, ACE2. These results suggest that curcumin has the ability to interfere with the entry of the virus into the cell. Furthermore, it has been reported that curcumin can affect the expression of other key molecules in the entry and decay of the virus, such as TMPRS22, Cat B, and L. The cumulative evidence suggests that curcumin could be an effective treatment strategy to complement the COVID-19 clinical management. Further, it has been persistently reported that curcumin has anti-inflammatory effects on in vivo models, such as atherosclerosis, multiple sclerosis, Alzheimer’s, or arthritis. These studies demonstrated that curcumin blocks inflammation in parts by preventing the activation of macrophages and lymphocytes and inhibiting the production of pro-inflammatory cytokines and chemokines. In this sense, it has been shown that despite the low bioavailability of curcumin, in two models of chronic disease, this compound has anti-inflammatory effects at low doses, via IL-10 production. Moreover, the ability of curcumin to alter the inflammatory state through the modulation of its regulatory elements can prevent the onset of the cytokine storm.  Evidence presented in this article suggests that curcumin represents a promising compound for developing therapy against SARS-CoV2. In this study, curcumin showed high cytotoxicity at 20 µg/mL in Vero E6 cells. In conclusion, curcumin showed in vitro antiviral activity against SARS-CoV-2, with different treatment strategies, which suggest the inhibition at different stages of the replicative cycle; furthermore, these effects seem to be independent of the virus strain/variant. This antiviral effect, together with the observed immunomodulatory properties, suggests that curcumin could be a promising compound for the treatment of COVID-19 patients.

Effects of Curcumin on Aging: Molecular Mechanisms and Experimental Evidence
BioMed Research International | November 2021
Several lines of evidence highlighted a pleiotropic potential of curcumin towards several human diseases, such as malignancies, skin and immune-related disorders, cardiovascular diseases, pulmonary and renal fibrosis, nonalcoholic fatty liver disease (NAFLD), fatigue, neuropathic pain, bone and muscle loss, neurodegenerative disease, ocular diseases, leprosy, osteoporosis, leishmaniosis, and HIV infection. Curcumin supplementation in human melanoma cells induces growth arrest and then apoptosis. Other studies also reported that curcumin may target oncogene expression, angiogenesis, invasion, and metastatic dissemination. Alongside with antitumorigenic activity, curcumin was also shown to induce antimicrobial, antioxidant, antiglycemic, antiseptic, and analgesic effects. With regard to inflammation, curcumin stimulates a xenobiotic response with upregulation of defense genes and suppression of proinflammatory transcription factors and cytokines. Moreover, several studies indicated that curcumin and may be used as senolytic and anti-inflammatory agents for senescent cells.  As reported by Banji et al., curcumin(40 mg/kg) and piperine (12 mg/kg), especially when combined, counteract D-gal-induced senescence in male Wistar rats by targeting OS and lipofuscin deposition, finally leading to higher hippocampal volume and function with improved spatial memory
. Aging and senescence are complex processes leading to organ dysfunction. Despite being permanent, delaying the occurrence of these processes is a reliable target, and curcumin might be a promising candidate for this purpose. Nevertheless, evidence from clinical studies on the long-term effects of curcumin on age-related pathological events remains largely understudied. While several strategies to enhance the systemic bioavailability of curcumin have been suggested, the effects of long-term therapy with such bioavailability-boosted curcumin preparations is not fully known, and increased concentrations may even lead to opposite results. Pleiotropic benefits of curcumin supplementation involve the control of aging genes, OS, and inflammation in both the vascular system and the central nervous system. Further studies are warranted to clarify the mechanisms of curcumin function for potential clinical application.

Therapeutic Potential of Curcumin on the Cognitive Decline in Alzheimer’s Disease
Research Square | November 2021
Curcumin, a polyphenol derived from the herb turmeric, has emerged as a promising potential therapy in the management of Alzheimer’s disease (AD). A meta-analysis of 29 publications showed that curcumin exerts significantly positive effects on cognitive performance. Our findings suggested that curcumin may reduce cognitive deficits in AD through multi-target and multi-pathway mechanism, providing a scientific basis for further experimental and clinical application.

Is Curcumin the Answer to Future Chemotherapy Cocktail?
Molecules | November 2021
Curcumin, also regarded as diferuloylmethane, is a yellow polyphenol extracted from the rhizome of the Curcuma longa (turmeric) plant, belonging to the Zingiberaceae family. Indigenous in south-eastern and southern tropical Asia, curcumin is traditionally applied for pain-relieving and wound healing effects. Commercial curcumin products contain approximately 77 % curcumin, 18 % demethoxycurcumin and 5 % bisdemethoxycurcumin. Out of those curcuminoids, curcumin exhibits the most potent medicinal properties as compared to demethoxycurcumin and bisdemethoxycurcumin. A growing body of evidence has demonstrated the benefits of curcumin in treating various diseases, including metabolic syndromes, hyperlipidaemia, inflammatory skin conditions, neurodegeneration and rheumatoid arthritis. These clinical benefits are attributed to the anti-inflammatory, anti-oxidant, and wound healing activities of curcumin. Moreover, curcumin can impede pathogenic infections by exerting a broad spectrum of anti-bacterial, anti-fungal and anti-viral activities. Alongside profound medicinal properties, curcumin is listed as a “generally recognized as safe (GRAS)” compound by the Food and Drug Administration (FDA), supporting its safety and tolerability when consumed by patients. Enormous attention has given to the exploration of anticancer properties in curcumin. To date, curcumin has shown its anticancer benefits in numerous cancers such as breast cancer, colorectal cancer, lung cancer, pancreatic cancer and prostate cancer. In fact, these anticancer effects depicted by curcumin are highly associated with the modulation of several oncogenic signalling pathways, which are essential in cancer development. Curcumin constrains these oncogenic signalling pathways and further limits the downstream pro-tumorigenic activities. In vitro studies illustrated that curcumin treatment limited the proliferation and caused cell cycle arrest in HT-29 colon cancer cells and PLC/PRF/5 liver cancer cells via the inhibition of cyclin D1, with the downregulation of NF-κB and cyclooxygenase-2 (COX-2) signalling. Concurrent with the upregulation of tumor suppressor gene p53, curcumin repressed the proliferative potential of cancer cells via the downregulation of PI3K/Akt/mTOR signalling. Furthermore, it also impedes cancer cells’ survival and suppresses their metastatic ability through the downregulation of EGFR pathways and inhibition of MMP activities. Apart from limiting the expression of IAP family proteins, curcumin promotes the apoptosis of cancer cells by increasing the expression of Bax while downregulating the expression of Bcl-2 in various cancer cells. It has also been shown to be able to abrogate angiogenesis elicited by breast tumors via the suppression of VEGF. Lately, curcumin has gained a great deal of interest, attributed to its broad range of medicinal properties. Intriguingly, curcumin exhibited countless anticancer properties, such as limiting cancer cell proliferation, promoting tumor cell death and preventing metastasis. Besides, curcumin supplementation greatly relieves the patients from experiencing adverse effects caused by conventional therapies. Hence, these properties pose great advantages to the development of curcumin combination therapy for cancer treatment. This review focuses on the use of curcumin in combination therapy in various cancers. The evasive mechanisms developed by cancer cells in response to cancer therapy are discussed. Curcumin combination therapies used are reviewed in depth in each type of cancer in both preclinical and clinical studies. We also addressed how curcumin modulates a variety of molecular targets in cancer cells in the combination treatment, to provide an insight into the multitargeting effects of such treatment cocktails.

Curcumin inhibits ovarian cancer progression
Journal of Ovarian Research | November 2021
Curcumin is the active component of turmeric which has an anti-cancerous property in multiple cancers, including ovarian cancer. It can exhibit the anti-cancer role in ovarian cancer by decreasing tumorigenesis and increasing the efficiency of radio-chemotherapy. Curcumin suppressed ovarian cancer cell proliferation and promoted apoptosis. Circ-PLEKHM3 was downregulated in ovarian cancer, and its expression could be promoted by curcumin treatment. Circ-PLEKHM3 overexpression exacerbated the effect of curcumin on ovarian cancer cell proliferation and apoptosis, as well as anti-tumor effect. MiR-320a was targeted by circ-PLEKHM3. The inhibition effect of circ-PLEKHM3 overexpression on cell proliferation and the enhancing effect on cell apoptosis could be reversed by miR-320a mimic. SMG1 was targeted by miR-320a, and its knockdown also reversed the regulation of miR-320a inhibitor on the proliferation and apoptosis of ovarian cancer cells. In addition, circ-PLEKHM3 could upregulate SMG1 expression via sponging miR-320a.

Anti-Inflammatory Effects of Curcumin in the Inflammatory Diseases
Drug Design, Development and Therapy | November 2021
Curcumin is a natural compound with great potential for disease treatment. A large number of studies have proved that curcumin has a variety of biological activities, among which anti-inflammatory effect is a significant feature of it. The anti-inflammatory effect of curcumin can effectively improve the symptoms of these diseases and is expected to be a candidate drug for the treatment of related diseases.  Curcumin has anti-inflammatory, anti-oxidant, anti-tumor and other biological activities. The anti-inflammatory properties of curcumin are considered to be the basis of its various biological activities and play an important role in the treatment of diseases. Curcumin is mainly derived from the root tuber of Curcuma aromatica Salisb and the rhizome of C. longa L. (Turmeric) of Zingiberaceae. Turmeric is a common spice in India and has been described in Ayurveda, as a treatment for inflammatory diseases. In western herbalism, turmeric is primarily used as an anti-inflammatory agent.3 Curcumin and curcuminoids, the active components of turmeric, are found as effective therapies over the years. Curcumin, demethoxycurcumin and bisdemethoxycurcumin, these three compounds are called curcuminoids. In addition, curcumin-containing dietary supplements are extremely popular, and there are many anti-oxidant and anti-inflammatory curcumin dietary supplements on the market. The significant anti-inflammatory activity of curcumin has attracted a lot of researchers’ interests and is considered to be one of the natural compounds with the greatest potential in the treatment of diseases. Current evidences suggest that curcumin is effective in reducing levels of inflammatory mediators, and that curcumin’s anti-inflammatory properties may have a beneficial effect on these diseases. In conclusion, curcumin has good anti-inflammatory properties, and curcumin regulates NF-κB, MAPK, AP-1, JAK/STAT and other signaling pathways, and inhibiting the production of inflammatory mediators. Curcumin in the treatment of IBD, arthritis, psoriasis, depression and atherosclerosis and other diseases, can reduce inflammatory response, effectively improve symptoms, play a role in the treatment of diseases. Now, the pharmacokinetics and anti-inflammatory effects of curcumin have been improved to some extent by the structural modification and modification of curcumin, preparation research and drug combination therapy. Among them, curcumin dietary supplement or adjuvant drug has significant therapeutic effect, which is the most feasible way for curcumin application at present.

Oral Curcumin With Piperine as Adjuvant Therapy for the Treatment of COVID-19
Frontiers in Pharmacology | November 2021
Patients with mild, moderate, and severe symptoms who received curcumin/piperine treatment showed early symptomatic recovery (fever, cough, sore throat, and breathlessness), less deterioration, fewer red flag signs, better ability to maintain oxygen saturation above 94% on room air, and better clinical outcomes compared to patients of the control group. Patients received curcumin-piperine capsules (three capsules/day; each capsules containing 500 mg curcumin plus 5 mg piperine; in total 1500 mg curcumin and 15 mg piperine/daily). Furthermore, curcumin/piperine treatment appeared to reduce the duration of hospitalization in patients with moderate to severe symptoms, and fewer deaths were observed in the curcumin/piperine treatment group.  Administration of oral curcumin with piperine as an adjuvant symptomatic therapy in COVID-19 treatment could substantially reduce morbidity and mortality, and ease the logistical and supply-related burdens on the healthcare system. Curcumin could be a safe and natural therapeutic option to prevent Post-Covid thromboembolic events. Orally administered curcumin with piperine could play a multifaceted role in the treatment of COVID-19. The anti-inflammatory and anti-thrombotic properties of curcumin could expedite the recovery of COVID-19 patients, and its antiviral, antibacterial, and antifungal properties could prevent superadded or secondary infections. Our results suggest that the use of orally administered curcumin with piperine as adjuvant therapy in COVID-19 treatment could substantially reduce morbidity and mortality, reduces treatment costs, and decrease logistical burden healthcare systems. Dose-escalating studies have indicated the safety of curcumin over 3 months. Hence, Curcumin can be a safe and natural therapeutic option to prevent Post-Covid thromboembolic events.

Curcumin induces apoptosis through caspase dependent pathway in human colon carcinoma cells
Molecular Biology Reports | November 2021
We investigated the apoptotic effects of curcumin in the colon carcinoma cell line SW480.  The proportion of BrdU-stained cells in the control groups were 58%, 57% and 61% and 28%, 27%, and 30% in the curcumin treatment groups at 24, 48, and 72 h, respectively. The proportion of apoptotic cells was 28%, 29%, and 28% in the control groups and 59%, 61%, and 60% in the curcumin treatment groups at 24, 48, and 72 h, respectively. As expected, caspase-3 staining also revealed a higher number of apoptotic cells in curcumin treatment groups at 24, 48, and 72 h compared to controls. These results suggest that curcumin may be a potential protective or treatment agent against colon cancer.

The emerging role of curcumin for improving vascular dysfunction
 Critical Reviews in Food Science and Nutrition | November 2021
Clinical intervention studies with curcumin have demonstrated significant improvements in endothelial function, arterial compliance, arterial stiffness, and other measures of vascular hemodynamics in young, middle-aged, old, post-menopausal, healthy, diabetic, and obese individuals. Mechanistically, curcumin is believed to improve vascular function through its effects on inflammation, oxidative stress, nitric oxide bioavailability, and structural proteins of the artery. Current data give support for curcumin to be administered for improvements in vascular health to individuals that may or may not be at risk for cardiovascular disease. This review briefly summarizes the techniques used for the establishment of vascular health and overviews the literature investigating the role of curcumin in the improvement of vascular health.

Curcumin enhances drug sensitivity of gemcitabine-resistant lung cancer cells and inhibits metastasis
Pharmazie International Journal of Pharmaceutical Sciences | November 2021
This study aimed to investigate the effects of curcumin on the proliferation, migration, and invasion of gemcitabine (GEM) resistant lung cancer A549 cells (A549/GEM), and the potential mechanism.  Curcumin and GEM can improve the sensitivity of A549/GEM to the GEM. Compared with the GEM, GEM plus curcumin significantly decreased the migration and invasion of A549/GEM cells. The expression levels of MMP9 , Vimentin, and N-cadherin were significantly decreased, while the E-cadherin expression was increased. In vivo experiments showed a better therapeutic effect of GEM combined with curcumin than that of GEM alone, and the combination therapy did not cause more toxicity to animals. In summary, curcumin reversed GEM resistance and inhibited the EMT process in A549/GEM cells. GEM, combined with curcumin, is safe and more effective in the treatment of non-small cell lung cancer.

Anti‑inflammatory role of curcumin in retinal disorders
Experimental and Therapeutic Medicine | November 2021
Curcumin belongs to the group of phytocompounds, which can be defined as biologically active molecules produced by plants with positive effects on health. In 1815, more than 140 years ago, Vogel isolated it from the Curcuma longa rhizomes, a traditional perennial plant belonging to the Zingiberaceae family. Later, in 1913, Lampe synthesized this molecule. Owing to its anti-inflammatory, antioxidant, antimicrobial, anti-angiogenesis, antimutagenic and neuroprotection properties, curcumin is considered to be a nutraceutical substance for the treatment of several chronic diseases such as diabetes, atherosclerosis, rheumatism, infectious and oncological diseases (brain, lung, breast and colon cancer). The most promising feature of curcumin is its anti-inflammatory and antioxidant activity. Curcumin's anti-inflammatory and antioxidant properties are mainly related to its hydroxyl and methoxy groups. Curcumin leads to deregulation of TNF-α and proinflammatory interleukins owing to its ability to down regulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Bioavailability enhancers have been considered encouraging: This definition refers to compounds which improve substance availability. In the case of curcumin, there has been a great interest in piperine owing to its ability to decrease curcumin hepatic and intestinal glucuronidation with consequent augmentation of curcumin bioavailability. This pharmacological effect was demonstrated by comparing serum curcumin concentration when given alone versus administration together with piperine. In this last case, curcumin blood levels presented a significant increase. Curcumin, the main polyphenolic compound of the food flavoring turmeric, has gained significant interest due to its biological anti-tumoral, antioxidant, immune-modulating, anti-inflammatory, antiparasitic and antiviral properties. For this reason, it has been extensively studied in different fields of medicine, in general, and particularly, in ophthalmology, where inflammatory cytokines are involved in the development of many ocular diseases, such as conjunctivitis, keratitis, uveitis, glaucoma, age-related macular degeneration and diabetic retinopathy. Since a wide range of beneficial properties have been identified at different levels, it is important to emphasize that curcumin is included in the food and drug category ‘generally regarded as safe’. In the light of this, curcumin can be also considered a promising and alternative option in several retinal diseases.

Effects of Curcumin Supplementation on Inflammatory Markers, Muscle Damage, and Sports Performance during Acute Physical Exercise in Sedentary Individuals
Oxidative Medicine and Cellular Longevity | November 2021
Nutritional supplements with antioxidant and anti-inflammatory properties have represented an alternative for such purposes. Among the alternatives, curcumin stands out, being the main polyphenol of Curcuma longa L. The Food and Drug Administration (FDA) of the United States has listed curcumin as “Generally Recognized as Safe” (GRAS), and supplements containing curcumin have been approved for human consumption. A recent review has shown that curcumin has various biological activities, thanks to its antioxidant and anti-inflammatory properties, which could be cardioprotective, immune-regulating, antineoplastic, and hepatoprotective effects, in addition to positive effects on diabetes and the nervous system. Moreover, it has shown positive effects on exercise practitioners and athletes. A clinical trial with individuals of both sexes has shown that, after eccentric exercise, supplementation with curcumin (500 mg) significantly reduced EIMD and CK concentrations, leading to better recovery after exercise. Another study has also shown that curcumin significantly decreased CK levels and muscle pain in men undergoing muscle damage protocol. The study by Sahin et al.] showed that curcumin prevented muscle damage and improved performance in animals by regulating the pathways of NF-κB and nuclear factor derived from erythroid 2-like 2. Curcumin supplementation has been shown to improve sports performance, providing less EIMD and reducing fatigue by decreasing CK activity. In addition, curcumin exerts an anti-inflammatory effect by modulating proinflammatory cytokines. Curcumin supplementation is safe and probably represents beneficial sport potential, demonstrating effectiveness before and/or after acute physical exercise in sedentary individuals.

Curcumin: A Possible Treatment for Coronavirus Infection
International Academic & Research Journal of Pharmacy | November 2021
Curcumin is recognized as medicinal herb in Chinese and Indian medicine traditionally, where it is used to treat different diseased condition like depression, liver disorders, dermatological ailments, skin disorders. The use of curcumin does not have any toxic effect and the FDA recognized it as “Generally Recognized As Safe.” An antiviral activity of curcumin was detected against several different viruses like hepatitis viruses, influenza viruses and Zika virus (ZIKV) or chikungunya virus (CHIKV). Moreover, it has also been demonstrated that curcumin inhibits human immunodeficiency virus (HIV), herpes simplex virus 2 (HSV-2) and human papillomavirus (HPV) also. Curcumin is used to treat vomiting from ancient times in Asian countries. Curcumin with the dose of 20 mg/kg, intragastric, 3 days improved appetite of rats in chemotherapy induced by fluorouracil (5‐FU). Therefore, it may be effective to treat certain symptoms in COVID‐19 patient. Anti‐inflammatory effects of curcumin in animal and human studies were reported previous. Also, in an in vitro study, curcumin with dose of 100 mg/kg, i.p. has an antipyretic effect in rats. Curcumin can be used to mitigate headache and other related symptoms in Covid-19 patients. Curcumin is reported to have antioxidant properties. Curcumin with dose of 1 mg/kg, 5 mg/kg increased the antioxidant enzyme profiling. Curcumin with administration of 200 mg/kg reduced oxidative stress. The use of curcumin might be effective to treat COVID‐19.

Curcumin and Piperine in COVID-19: A Promising Duo to the Rescue?
Biomarkers, New Treatments, and Vaccines for COVID-19 | October 2021
The combination of curcumin and piperine is a potential option for the management of COVID-19 based on several mechanisms including antiviral, anti-inflammatory, immunomodulatory, antifibrotic, and antioxidant effects. Here, we describe the probable mechanism of curcumin-piperine against COVID-19. Administration of curcumin-piperine combination appears as a potential strategy to counterbalance the pathophysiological features of COVID-19 including inflammation.

Curcumin for Parkinson's disease
Cellular and Molecular Biology | October 2021
Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders worldwide. Curcumin represents a promising bioactive compound with high therapeutic potential. Diverse studies in cellular and animal models have suggested that curcumin could be employed for the treatment of PD.

Current clinical developments in curcumin-based therapeutics for cancer and chronic diseases
Phytotherapy Research | October 2021
Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems.

Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells
Frontiers in Oncology | October 2021
Along with direct anticancer activity, curcumin hinders the onset of chemoresistance. Among many, high glucose condition is a key driving factor for chemoresistance. Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production. Modulated molecular regulators are suggested to play a crucial role as curcumin pretreatment also prevented the onset of chemoresistance by high glucose. Curcumin alleviated the suppression of drug retention and nuclear condensation along with hindering the high glucose-induced alterations in transcription factors and signal transducers. Curcumin inhibited the elevated expression of these enzymes, transporters, and receptors in cancer cells. Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition. Taken together, the findings of the present investigation first time demonstrate the ability of curcumin against high glucose-induced chemoresistance, along with its molecular mechanism. This will have implication in therapeutic management of malignancies in diabetic conditions.

The effects of curcumin supplementation on muscle damage, oxidative stress, and inflammatory markers in healthy females
International Journal of Preventive Medicine | October 2021
Given the reports of positive effects attributed to curcumin, many studies have investigated the antioxidant and antiinflammatory properties of curcumin. A previous report by Sahin et al. declared that curcumin administration can decrease muscle damage by regulating the nuclear factor-kappa B (NF-κB) in male Wister rats. In addition, the results of another study that performed on 90 rats with poly cystic ovarian syndrome (PCOS) showed a significant reduction in C-reactive protein (CRP) levels in the curcumin-treated rats. In healthy young adult women, 8 weeks of curcumin supplementation yielded significant improvements in CRP, LDH, MDA, and VO2 max. In the present study, we found that 8 weeks of curcumin administration attenuates MDA in females with moderate activity. In agreement with these findings, a previous study revealed that curcumin (1000 mg/day co-administered with piperine 10 mg/day) supplementation for 8 weeks led to a significant decrease in serum MDA and increase TAC in subjects with type 2 diabetes mellitus. Concordantly, 6-week supplementation of 1500 mg/day curcumin elicited significant improvements in antioxidant status and a significant decrease in MDA concentrations in patients with knee osteoarthritis. Curcumin, as an antioxidant agent, can increase superoxide dismutase level via inhibiting ROS-generating enzymes. In addition, it can increase serum activities of antioxidants. Another positive action of curcumin is related to scavenging properties to decrease oxidative damage.

Curcumin as a great contributor for the treatment and mitigation of colorectal cancer
Experimental Gerontology | October 2021
This review mainly brings out the correlation between the curcumin and its use for the mitigation of colorectal cancer, the use of curcumin as a chemotherapeutic agent, chemosensitizer, and in a combination and synergistic approach. The pharmacokinetics and pharmacodynamics properties of curcumin and its formulation approach helps in giving an idea to develop new approaches for the treatment of colorectal cancer using curcumin.

Curcumin induces apoptosis and autophagy in human renal carcinoma cells
Bioengineered | October 2021
Curcumin is a traditional Chinese herb that has been used for the treatment of various diseases. The compound has been particularly confirmed to have anti-inflammatory, anti-cancer, anti-virus, and anti-oxidant activities. Curcumin shows less side effects, hence appropriate as a novel anticancer drug. Previous studies have shown that curcumin administration inhibited the growth, formation, invasion, and proliferation of prostate cancer. Curcumin induces apoptosis of RCC through AKT/mTOR pathway inhibition, suppresses the TNF-a, IL6 and IL-8 pro-inflammatory cytokines. Further, curcumin down-regulates Akt/mTOR through upregulation of autophagy and finally, curcumin inhibits tumor weight and volume in vivo. Use of curcumin to target AKT/mTOR pathway could be an effective treatment alternative for renal cell carcinoma.

Curcumin attenuates spatial memory impairment by anti-oxidative, anti-apoptosis, and anti-inflammatory mechanism
NeuroToxicology | October 2021
Curcumin treatment improves spatial memory impairment after methamphetamine neurotoxicity. Curcumin treatment has an antioxidant activity in methamphetamine neurotoxicity. Curcumin treatment reduced caspase-3 activation after methamphetamine neurotoxicity. Curcumin treatment has an anti-inflammatory activity in methamphetamine neurotoxicity via reducing of TNFα. Curcumin treatment reduced astrogliosis after methamphetamine neurotoxicity.

Curcumin supplementation in the treatment of patients with cancer: a systematic review
Brazilian Journal of Pharmaceutical Sciences | October 2021
Curcumin is a long-used phytochemical with a large number of biological targets, for which anti-inflammatory, antioxidant, anti-tumor, immunoregulatory, hepatoprotective, anti-ischemic, anti-dyspeptic, anti-depressant, and analgesic effects have been determined (Amalraj et al., 2017). Preclinical studies have reported curcumin as a potent epigenetic regulator, acting in the inhibition of deoxyribonucleic acid (DNA), DNA methyltransferases (DNMTs), regulation of modifications of histone acetyltransferases (HATs) and deacetylases (HDACs) and in regulation of micro ribonucleic acids (miRNA) (Boyanapalli et al., 2015; Remely et al., 2015). Studies conducted in vitro show that curcumin prevents the degradation of nuclear factor erythroid 2-related factor 2 (Nrf2), leading to an increase in antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). In addition, it balances the level of these enzymes and recovers reactive oxygen species (Rezaee et al., 2017; Sahebkar, 2013). It was also shown to have an anti-inflammatory effect through negative regulation of several cytokines, such as tumor necrosis factor alpha (TNF-α), interleukins (IL-1, IL-6, IL-8, IL-12), monocyte chemoattractant protein-1, cyclooxygenase-2 activity (COX-2), lipoxygenase enzyme and inducible nitric oxide synthase (iNOS) (Aggarwal et al., 2007; Gupta et al., 2013). In vitro and in vivo investigations have also shown that curcumin reduces the inflammatory process by means of inflammatory transcription factors such as nuclear factor kappa (NF-kB), activator protein-1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) (Panda et al., 2017; Imran et al., 2016). NF-ĸB and AP-1 also act as transcription factors that regulate the expression of different genes which affect cellular processes, such as proliferation and apoptosis. Curcumin also inhibited the expression of urokinase plasminogen (uPA), focal adhesion kinase activity (FAK), suppressed expression of matrix metalloproteinases (MMPs), inhibited epidermal growth factor receptor (EGFR) activity, regulating tumor cell invasion and metastasis (Durgaprasad et al., 2005; Vadhan-Raj et al., 2007; Kim et al., 2011; Belcaro et al., 2010; Shokes et al., 2005; Adhvaryu et al., 2008; Biswas et al., 2010). Due to these therapeutic properties, curcumin exhibited activities against various types of cancer (Gupta et al., 2013; Dhillon et al., 2008; Golombick et al., 2009; Ide et al., 2010).  The results of this study are based on those obtained in the literature on the effect of curcumin on the anti-inflammatory profile, on reducing dermatitis, on PSA alteration and on anti-oxidant profile for a total of 450 individuals, comprising 259 in the intervention group and 191 in the control group. Some studies have reported improvement in biochemical and clinical indicators, with limited adverse effects and good tolerance.

The clinical use of curcumin on neurological disorders: An updated systematic review of clinical trials
Phytotherapy Research | October 2021
Neuroprotective effects of curcumin have been shown in previous studies. This updated systematic review of clinical trials aimed to investigate the effect of curcumin on neurological disorders. Databases including PubMed, Scopus, Web of Science, and Google Scholar were systematically searched to identify clinical trials investigating the effects of curcumin/turmeric supplements alone, or in combination with other ingredients, on neurological diseases. Nineteen studies comprising 1,130 patients met the inclusion criteria. Generally, intervention and study outcomes were heterogeneous. In most of the studies, curcumin had a favorable effect on oxidative stress and inflammation. However, with the exception of AD, curcumin supplementation either alone, or in combination with other ingredients, had beneficial effects on clinical outcomes for the other aforementioned neurodegenerative diseases. For example, the frequency, severity, and duration of migraine attacks, scores on the revised ALS functional rating scale, and the occurrence of motor complications in PD were all significantly improved with curcumin supplementation either alone or in combination with other ingredients.

Curcumin exhibited better potential inhibition than Hydroxy-Chloroquine against COVID-19
Biological and Medicinal Chemistry | October 2021
According to present research results, Quercetin, Hispidulin, Cirsimaritin, Sulfasalazine, Artemisin and Curcumin exhibited better potential inhibition than Hydroxy-Chloroquine against COVID-19 main protease active site and ACE2.

Targeting of cancer cell death mechanisms by curcumin: Implications to cancer therapy
Basic & Clinical Pharmacology & Toxicology | October 2021
Curcumin (which originates from turmeric) is a hydrophobic polyphenol. It is one of the most famous anticancer and anti-inflammatory herbal agents. Traditionally, curcumin was used for some diseases such as acne and some inflammation-related diseases like arthritis.  Today, we know that curcumin has antioxidant and anti-inflammatory effects, which cause beneficial effects on the cardiac and neural systems and also has pharmacological effects on some diseases such as diabetes, Alzheimer, atherosclerosis, some immune system diseases and cancer. Curcumin has shown anticancer properties for several types of malignancies in both in vitro and in vivo studies. Gastrointestinal system malignancies, lung cancer, brain cancer cells, leukaemia, melanoma and renal, breast, prostate and pancreas cancers are some examples of inhibition of cancers by curcumin. Curcumin has also been shown to amplify the anticancer effects of chemotherapy drugs and radiotherapy. Although several agents may increase the therapeutic response of cancer cells to therapy, curcumin has shown interesting results for the protection of normal cells/tissues, a property that can reduce side effects of cancer therapy. Curcumin has been shown to protect several organs such as the lung, gastrointestinal system, heart, liver, testis, bone marrow and skin against the toxic effects of radiotherapy and chemotherapy. Curcumin as a natural agent has shown interesting anticancer properties. It can prevent genomic instability in normal cells to prevent the development of cancer. Furthermore, it can suppress tumour growth at different stages through induction of cell death, suppression of cancer cells' migration, angiogenesis, and others. In this review, we focused on the mechanisms of cell death induction in tumours using curcumin.  Curcumin is one of the most common herbal agents that has shown several anticancer properties. It can regulate immune system responses against cancer. Furthermore, curcumin has been shown to potentiate cell death signalling pathways and attenuate survival signalling pathways in cancer cells. The knowledge of how curcumin induces cell death in cancers can improve therapeutic efficiency. In this review, the regulatory effects of curcumin on different cell death mechanisms and their signalling pathways will be discussed. Furthermore, we explain how curcumin may potentiate the anticancer effects of other drugs or radiotherapy through modulation of apoptosis, mitotic catastrophe, senescence, autophagy and ferroptosis.

The Functional Roles of Curcumin on Astrocytes in Neurodegenerative Diseases
Neuroimmunomodulation | October 2021
Curcumin is the main component of a yellow pigment, commonly called diferuloylmethane, and is an active ingredient in the rhizome of the herb Curcuma longa that represents various biomedical applications. Curcumin has also been traditionally used for its medicinal benefits and wound healing for centuries. It was first applied as a drug to treat biliary disease in 1937. Curcumin is a lipophilic polyphenol that is relatively stable in the acidic pH but decomposes in neutral-basic conditions. Curcumin contains approximately 77% diferuloylmethane, 17% dimethoxycurcumin, and 6% bisdemethoxycurcumin. Nowadays, curcumin (C21H20O6) has important roles in the attenuation of progression of some neurodegenerative diseases because of its anti-amyloid and anti-inflammatory agents. In addition, curcumin also has several benefits, such as being safe, inexpensive, and readily available polyphenol that can cross the blood-brain barrier, thus attracting researchers to use it for treating neurodegenerative diseases. Curcumin is an NF-κB inhibitor by interrupting ZO-1 expression and localization, MLC phosphorylation, and ROS generation inhibition, which constrains disruption of the blood-brain barrierby Th17 cells. Furthermore, curcumin, through its NF-κB inhibitory effect, causes intestine dendritic cell differentiation into tolerogenic phenotypes, as well as naive T cells to differentiate into FoxP3+ regulatory T cells (intestine protective, Treg). Thus, curcumin can prevent colitis, due to its anti-inflammatory function.  The pharmacological activities of curcumin are antimicrobial, anti-inflammatory, antioxidant, and anticarcinogenic. It also exhibits potent immunoregulatory activities that can modulate the T cells, B cells, neutrophils, natural killer cells, and macrophage activation and function. Curcumin has been shown to be protective for several cells, including astrocytes, neurons, microglia, and different part of the CNS such as hippocampal, mesencephalic, cortical, and spinal cord. An MS animal study showed that curcumin regulates T-cell responses to IL-12 by blocking IL-12 production, and IL-12 signaling, through inhibiting JAK-STAT signaling activation. Thus, it has been suggested that curcumin could be used for treating MS and other Th1-cell-mediated inflammatory diseases. Furthermore, curcumin at high doses can directly induce T-cell apoptosis and inhibit T-cell proliferation through blocking of the IL-2 signaling pathway, high-affinity IL-2R, and interfering with IL-2R signaling. These data indicate that curcumin has immunosuppressive effects on many pathways. Thus, curcumin, through its proinflammatory cytokines, decreases TNF-α/β, IL-1, IL-6, and IL-8, and COX-2 provides a therapeutic effect by reducing inflammatory conditions. Curcumin can cross blood-brain barrier and, by inhibiting proinflammatory cytokines, can regulate homeostasis of the CNS. The blood-brain barrier has a crucial role in controlling the homeostasis of the brain microenvironment. Thus, because autoreactive T-cell penetration plays a key role in MS lesion development, the role of curcumin to protect the blood-brain barrier could reduce the severity of MS. Curcumin also decreases the severity of chronic inflammatory diseases, such as rheumatoid arthritis, asthma, AD, and cancer. In phase II clinical trial, curcumin was used orally in a mouse model of colorectal cancer. It has been demonstrated that curcumin can prevent carcinogenesis through different mechanisms such as reduction of cyclooxygenases 1 and 2, 5-lipoxygenase, prostaglandin E2 (PGE2), and 5-hydroxyeicosatetraenoic acid production inhibition. Fortunately, curcumin via inhibition of NF-κB signaling pathways can improve the effects of some chemotherapy drugs. For example, in the mouse model of human breast cancer, curcumin, in conjunction with paclitaxel, can slow breast cancer progression and metastasis to the lung. Unfortunately, curcumin has several disadvantages in cancer treatment, including inhibition of some chemotherapy drug activities. For example, curcumin decreased camptothecin-induced death in cultured breast cancer cells and inhibited breast tumor regression in mice. Furthermore, curcumin can also interfere with colon cancer treatment through the change in irinotecan absorption and efficacy. Curcumin is a valuable ingredient present in turmeric spice and has several essential roles, including those which are anticarcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, anti-inflammatory, antioxidant, chemopreventive, chemotherapeutic, and anti-infectious. Furthermore, curcumin can suppress inflammation; promote angiogenesis; and treat diabetes, pulmonary problems, and neurological dysfunction. Here, we review the effects of curcumin on astrocytes in NDs, with a focus on Alzheimer’s disease, Parkinson’s disease, multiple scleroses, Huntington’s disease, and amyotrophic lateral sclerosis.

Pharmacological properties and underlying mechanisms of curcumin and prospects in medicinal potential
Biomedicine & Pharmacotherapy | October 2021
The chemical structure of curcumin known as diferuloylmethane has been elucidated in 1910, the first study on its biological activity as an antibacterial agent according to the PubMed database has been published in 1949 Nature journal and the first clinical trial has been reported in 1937 Lancet journal. Until now, there are numerous in vitro, in vivo, and clinical studies that show it contained antioxidant, anti-inflammatory, anti-cancer, anti-diabetic, and anti-viral infection. The major constituents of curcuminoids contain Dihydrocurcumin, Tetrahydrocurcumin, Curcumin, Bis-demethoxycurcumin, and Demethoxycurcumin from turmeric (C. longa L.) rhizome. The beneficial health properties and medicinal values of curcumin include its effect on immune modulation, cardiovascular protection, and neuroprotection.  Previous report, the potential of turmeric as an antimicrobial, insecticidal, larvicidal, antimutagenic, radioprotector, and anticancer agent have validated in cell-based studies. Numerous animal studies have found the latent of turmeric against proinflammatory diseases, obesity, diabetes, atherosclerosis, cancer, depression, and neurodegenerative diseases. Moreover, turmeric has shown efficacy against numerous human disorders including lupus nephritis, irritable bowel syndrome, acne, fibrosis, diabetes, and cancer in clinical trial. Of note, curcumin, major component of turmeric, is widely studied at the preclinical level in various chronic illnesses that have been extensively reviewed in many papers including mechanistic insights . Of note curcumin is an important active ingredient in turmeric that exerts pharmacological effects. Current research has demonstrated that the pharmacological effects of curcumin include: anti-lipidemics, anti-diabetics, anti-tumor, anti-inflammatory, anti-fibrosis, anti-virus, anti-oxidation, and serve as free radical scavengers.

Curcumin suppresses the progression of gastric cancer
Open Life Sciences | October 2021
Curcumin is a natural polyphenolic compound isolated from turmeric, which has lipid-lowering, anti-tumor, anti-inflammation, and anti-oxidation effects. Recently, studies have shown that curcumin can reduce the malignancy of several cancers, such as pancreatic cancer, retinoblastoma, osteosarcoma, and bladder cancer. Moreover, curcumin has also been reported to have an anti-tumor effect on gastric cancer. Nonetheless, the role and underlying mechanism of curcumin in gastric cancer have not been well recognized.  We discovered that curcumin was able to inhibit gastric cancer cell growth and motility and induce apoptosis by suppressing circ_0056618 and elevating miR-194-5p. Previous research have verified that curcumin exerts the anti-tumor effect mainly by repressing tumor cell proliferation and motility and facilitating apoptosis. For example, curcumin treatment restrained Rb cell proliferation, invasion, and migration and accelerated apoptosis. Curcumin suppressed the growth and cell cycle process and facilitated the apoptosis of gastric cancer cells. In line with these reports, we demonstrated that curcumin treatment restrained cell colony formation, migration, and invasion and accelerated cell cycle arrest and apoptosis in gastric cancer cells in vitro and blocked tumorigenesis of gastric cancer in vivo, indicating that curcumin might be a candidate agent for gastric cancer therapy.  In summary, curcumin treatment could repress gastric cancer cell growth and metastasis and promote apoptosis partly by regulation of circ_0056618/miR-194-5p axis. The findings facilitated our understanding on the mechanism of curcumin in gastric cancer therapy and indicated that curcumin might be a potential therapeutic drug for gastric cancer . In addition, accumulating evidence showed that curcumin might prevent gastric cancer through regulation of oncogenic pathways.

The Therapeutic Effects of Curcumin in Early Septic Acute Kidney Injury: An Experimental Study
Drug Design, Development and Therapy | October 2021
Curcumin, the major active component of Curcuma longa, was first isolated in 1870 and widely used as spice, flavor, and colorant in daily life.12 Several studies have evidenced the antioxidant, anti-inflammatory, anticarcinogenic, cardioprotective and nephroprotective effects of curcumin. The protective effects of curcumin on AKI are generally associated with its bifunctional antioxidant activity and anti-inflammatory activity Curcumin could ameliorate kidney disease with either acute or chronic nephritis, and reduce activation of the NF-κB, MAPK, AKT and pBAD pathways either systemically, or within the inflamed kidneys. In addition, previous research found that curcumin could improve renal function during ischemia-reperfusion induced acute kidney injury, which protected the tubular epithelium from injury by modulating inflammatory processes, oxidative stress, and apoptosis. In our study, we show that curcumin represents a new and promising effective treatment in S-AKI rat models. Treatment with curcumin ameliorates renal functions, improves both renal macro- and microcirculatory flow, reduces inflammatory response and prevents pathological changes in kidney.  Curcumin may be a potential novel therapeutic agent for the prevention or reduction of S-AKI.

Curcumin Reduces Adipose Tissue Inflammation and Alters Gut Microbiota in Diet-Induced Obese Male Mice
Molecuar Nutrtion and Food Research | October 2021
Curcumin exerts protective metabolic effects in dietary obesity, in part through downregulation of adipose tissue inflammation, which may be mediated by alterations in composition of gut microbiota, and metabolism of curcumin into curcumin-o- glucuronide.

New insights of structural activity relationship of curcumin and correlating their efficacy in anticancer studies
American Journal of Cancer Research | October 2021
During the process of carcinogenesis at multiple stages, curcumin is involved in several mechanisms including (a) the inhibition of tumor initiation (cytotoxic studies) (b) suppression of cellular proliferation (antiproliferation studies) (c) the induction of apoptosis (d) the inhibition of angionesis and metastasis (e) the inhibition of tumor induced immunosuppression. Analyzing the cytotoxic results, curcumin has shown its potency towards most of the cancer cell lines like Hela (Cervical cancer), HepG2 (Liver cancer), A549 (Adenocarcinoma human alveolar), MCF-7 and MDA-MB-231 (Breast cancer), PC-3, RWEP-1 and DU145 (Prostate cancer), SkoV3 (Ovarian cancer), A-431 (Epidermoid carcinoma), U-251, T98, U87, U87 MG and U87 GBM (Glioblastoma), Panc-1 and BxPC3 (Pancreatic cancer), HT-29 and HCT116 (Colon cancer), H1299 and H460 (Lung cancer), AGS (Gastric cancer), HCT-15 (Colorectal adenocarcinoma), K562 (Chronic myelogenous). Demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are naturally occurring compounds, which shows enhance potency against cancer cell lines in vitro and differ from curcumin in the position and number of hydroxyl and methoxy substitution pattern. The presence of methoxy and hydroxyl group in curcumin plays a vital role in deciding various biological activities as reported by various research groups. Curcumin is a naturally occurring compound which appears to be significant clinical for applications in vitro as well as in vivo studies. Many of the research groups have been paying attention towards natural products for the development of anticancer drugs. Curcumin, Rosmarinic acid and Chalcone are the naturally occurring compounds, which are chemopreventive and chemotherapeutic.

The effects of curcumin as dietary supplement for patients with polycystic ovary syndrome
Phytotherapy Research | October 2021
Compared with the control group, curcumin was associated with a statistically significant improvement in the glycemic control including fasting blood glucose, insulin level, homeostasis model assessment of insulin resistance, and quantitative insulin sensitivity check index. The mean difference in total cholesterol was also statistically significant. This review concluded that among patients with PCOS, the use of curcumin demonstrated a significant difference from the control group for glycemic control. Those findings suggest that curcumin confers clinical benefits in patients with PCOS. 

Curcumin as an Adjuvant to Cancer Immunotherapy
Frontiers in Oncology | September 2021
Turmeric, a common spice obtained from Curcuma longa of the Zingiberacea (Ginger) plant family, is the natural source of curcuminoids, a mixture of three different components, i.e., curcumin, demethoxycurcumin, and bisdemethoxycurcumin. A major fraction of this compound mixture is curcumin or diferuloylmethane with 368.38 molecular weight. The crystalline orange-yellow powder is an active polyphenolic phytochemical and has been widely used in medicinal purposes for centuries in India and South Asia, due to its nontoxic but miraculous properties such as anti-oxidant, analgesic, antiseptic, anti-inflammatory, and anti-cancer activity.  Over time, curcumin has been considered as a potential anti-cancer molecule. Its potentialities have been recorded against the standard hallmarks of cancer such as continuous proliferation, escaping apoptosis, continuous angiogenesis, insensitivity to growth inhibitors, tissue invasion, and metastasis. Hence, the diversity of curcumin functioning has already been established and exploration of its application with immunotherapies might open up a new avenue for scientists and clinicians. In this review, we briefly discuss the tumor’s way of immune escaping, followed by various modern immunotherapies that have been used to encounter the escaping paths and their minute flaws. Finally, the conclusion has been drawn with the application of curcumin as a potential immune-adjuvant, which fearlessly could be used with immunotherapies for best outcomes. Hence, it is considered very interesting to envision the role of curcumin concerning cancer immunotherapies as an immunomodulator.

Curcumin improves memory deficits by inhibiting HMGB1-RAGE/TLR4-NF-κB signalling pathway
Journal of Cellular and Molecular Medicine | September 2021
Curcumin, extracted from turmeric rhizomes, is a Food and Drug Administration-approved food additive in the curry spice turmeric. It possesses potent anti-inflammatory and antioxidant properties and is widely used to treat chronic inflammatory diseases, such as heart disease, cancer, metabolic syndrome and various other degenerative diseases.It has therapeutic potential in AD models, both in vitro and in vivo. Curcumin is a natural polyphenolic product derived from the rhizome of Curcuma longa and has various beneficial properties, such as anti-inflammatory, antioxidant and antitumor properties. Here, we found that curcumin treatment effectively improved the cognitive performance of transgenic mice in the MWM and Y-maze, and our results were consistent with those of previous studies. In conclusion, this study demonstrated that curcumin treatment significantly ameliorates cognitive impairment in aged APP/PS1 transgenic mice. The possible underlying mechanism might be associated with the accumulation of amyloid plaques, activation of the HMGB1-RAGE/TLR4-NF-κB signalling pathway, and astrocytes activated during neuroinflammation in APP/PS1 transgenic mice. These results suggest that curcumin treatment, as a food additive for long-term oral administration, is an effective therapeutic strategy for AD
.

Antimetastatic Effects of Curcumin in Oral and Gastrointestinal Cancers
Frontiers in Pharmacology | September 2021
For centuries, curcumin has been widely used as a dietary spice, and contemporary research studies have confirmed its efficacy in cancer therapy. Anticancer effects are the most pivotal properties of curcumin, which affect the different stages of cancer progression, including cancer cell formation, proliferation, and tumor invasion. According to extensive research, curcumin can suppress metastasis in GI cancers via regulating various signaling pathways. Curcumin has a crucial function in metastasis prevention by several mechanisms, including preventing transcription factors as well as their signaling pathways (e.g., NF-κB, STAT3, AP-1), multiple proteases (e.g., MMPs, uPA), inflammatory cytokines (e.g., CXCL1, IL-6, CXCL2, IL-8), modulation of miRNAs (e.g., miR181b, miR21), multiple protein kinases (e.g., FAK, MAPKs), and heat shock proteins (HLJ1). According to research, curcumin treatment leads to significant elevation in metastatic tumor cross-sectional volume (70%) and zone (46%). Curcumin may enhance LLC's metastatic growth in mice by elevating the concentration of VEGF, angiogenic factors, monocyte chemotactic protein-1 (MCP-1), and IL-1β. In addition to the possible pharmaceutical effects of curcumin, the safety and relevant therapeutic dose should also be established, given reports on the side effects of curcumin in cancer therapy. Curcumin a polyphenolic extraction of Curcuma longa species, which is often termed as turmeric (Shafabakhsh et al., 2019; Ashrafizadeh et al., 2020). Curcumin had been used as a traditional Ayurvedic medicine due to its significant anti-inflammatory (Satoskar et al., 1986), antioxidant (Masuda et al., 2001), and antimicrobial (Negi et al., 1999) properties. Currently, curcumin is associated with powerful anticancer properties. Different animal studies have shown that curcumin has important roles in inhibiting primary tumorigenesis in numerous organs as metastatic sites, such as mammary glands (Inano et al., 1999) and gastrointestinal tract (Huang et al., 1994). Some investigations showed that curcumin has potential regulatory effects on the expression of proangiogenic growth factors (6–8). Curcumin inhibits angiogenic activities caused by fibroblast growth factor (bFGF) in rabbit and mouse models (Mohan et al., 2000). It also diminished the vascular endothelial growth factor (VEGF) serum levels in mice models of hepatocellular carcinoma (Yoysungnoen et al., 2006).

Curcumin suppresses inflammatory signaling in brain microglia
The Journal of Immunology | September 2021
Curcumin is a major component of tumeric. It has been used as an Indian medicine for centuries, and is currently commonly used as a spice for flavor and to impart a yellow color. Curcumin has recently received much attention for its anti-inflammatory, antioxidant, and antitumor activities. The anti-inflammatory actions of curcumin seem to be closely related to the suppression of proinflammatory cytokines and mediators of their release such as TNF-γ, IL-1β, and NOs. There are reports that curcumin inhibits cytokine-mediated NF-κB activation by blocking a signal leading to I-κB kinase activity in intestinal epithelial and mouse fibroblast cells, and also suppresses phorbol ester-induced c-Jun/AP-1 activation. However, the mechanisms underlying interactions of curcumin with these signaling pathways are poorly understood. Recently, we have shown that JAK-STAT inflammatory signaling modulates glial activation. Thus, we examined whether curcumin inhibits the JAK-STAT pathways in activated microglia. Curcumin inhibits the phosphorylation of JAK1 and JAK2 via the increased phosphorylation of SHP-2 and its association with JAK1/2, thus attenuating inflammatory response. Our results show that curcumin acts via a novel anti-inflammatory mechanism and is also a negative regulator of the JAK-STAT pathway by the activation of SHP-2. Taken together, these data suggest curcumin suppresses JAK-STAT signaling via activation of SHP-2, thus attenuating inflammatory response of brain microglial cells.

Curcumin as Prospective Anti-Aging Natural Compound: Focus on Brain
Molecules | September 2021
Curcumin is a natural dietary polyphenol extracted from Curcuma longa Linn with different biological and pharmacological properties including antioxidant, immunomodulatory, anti-inflammatory, anti-microbial, cardio-protective, nephro-protective, hepato-protective, anti-neoplastic, anti-rheumatic, and anti-aging. The chemical name of curcumin is 1,7-bis(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione with a chemical formula of C12H20O6; it is formed by two aromatic rings with a methaxy phenolic group, kinked with a linear carbon chain, with an α,β-unsatured β-diketone moiety. Curcumin, like other polyphenols, has pleiotropic activity. Indeed, due to its capacity to interact with many proteins, curcumin can induce cellular response to external stimuli. Moreover, curcumin up- and downregulates different miRNA and takes part in epigenetic changes in cell.  In our view, curcumin is one of the best candidates to achieve this goal with its antiviral, antinociceptive, anti-inflammatory, antipyretic, and antifatigue proprieties. It is important to highlight that Curcumin is devoid of any significant toxicity in most of the preclinical as well as clinical investigations, and few investigations have reported negative effects of curcumin. In addition, natural products may be a safe, secure, and dependable source to find drugs responsible for controlling the current pandemic, and even if the beneficial effects of curcumin against SARS-CoV-2 have not yet been reported, curcumin has some useful clinical effects that could be effective to manage the symptoms of the infected patient with COVID-19. Curcumin in fact can modulate the events of SARS-CoV-2 cellular entry, their replication, and molecular cascade manifesting pathophysiological consequences of COVID-19. Due to its important and healthy proprieties, we think that dietary supplementation with curcumin could be a suitable approach to prevent a large panel of diseases and improve the quality of life. In this review, we have described the anti-aging potential of curcumin with particular regard to prevention and treatment of brain diseases, in different ways: (1) by acting on different target proteins, (2) by inducing antioxidant and anti-inflammatory events, (3) by modulating microglia neuroprotection, and (4) by acting on telomerases to arrest cancer progression.

Curcumin Reduces Colorectal Cancer Cell Proliferation and Migration and Slows In Vivo Growth of Liver Metastases in Rats
Biomedicines | September 2021
Curcumin has shown an anti-tumor effect against liver implants from colorectal cancer, both in vitro and in vivo, in this experimental model. Curcumin is a well-known plant-derived polyphenol with a wide range of activities, such as antibacterial, anti-inflammatory, and hepatoprotective properties. In vitro studies with several cancer cell lines have proven curcumin to inhibit proliferation, such as on MCF-7 human breast tumor cells. It has also been observed that curcumin can improve the efficacy of other therapies, such as Paclitaxel on rat glioma C6 cells, and of 5-FU and/or oxaliplatin in BGC-823 human gastric cancer cell line or in HCT116 human colon cancer cells. In this cell line, it has been found that curcumin inhibits the cell cycle, activates p53 (only in p53+/+ cells) and p21, and triggers cellular senescence (irreversible growth arrest of proliferating cells) through the activation of the lysosomal enzyme senescence-associated-β-galactosidase (SA-β-gal) and the upregulation of the p21 protein. Other studies have also shown that curcumin-induced apoptosis is related to oxidative stress caused by the production of superoxide anion, which contributes to p53-independent cellular cytotoxicity. These findings were further corroborated in other cell lines (COLO-205), showing that curcumin induces cytotoxicity and apoptosis in a dose-dependent manner. In addition, curcumin promotes the production of reactive oxygen species and Ca2+, and induces the caspase-3 activity. In in vivo animal studies using cancer cells implants (most of them in animals lacking immune system), curcumin reduces the growth of the implants and the appearance of metastases. It has also been demonstrated that curcumin reduces tumor invasion and metastatic growth by, for example, reducing the activity of matrix metalloproteinases (MMPs) 2 and 9, or blocking nuclear translocation of nuclear factor kappa B (NFκB) by inhibiting the inhibitor of kappaB kinase. This molecular pathway is also involved in the prevention of liver damage after exposure to radiotherapy by regulating oxidative stress damage and reducing the accumulation of reactive oxygen species, which are well known to contribute to tumor progression by promoting cell transformation, proliferation, and the survival of tumor cells.

Phenolic compounds like curcumin disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions
PLOS ONE | September 2021
Among 56 tested polyphenols, including plant extracts, brazilin, theaflavin-3,3’-digallate, and curcumin displayed the highest binding with the receptor-binding domain of spike protein, inhibiting viral attachment to the human angiotensin-converting enzyme 2 receptor, and thus cellular entry of pseudo-typed SARS-CoV-2 virions. Both, theaflavin-3,3’-digallate at 25 μg/ml and curcumin above 10 μg/ml concentration, showed binding with the angiotensin-converting enzyme 2 receptor reducing at the same time its activity in both cell-free and cell-based assays. Our study also demonstrates that brazilin and theaflavin-3,3’-digallate, and to a still greater extent, curcumin, decrease the activity of transmembrane serine protease 2 both in cell-free and cell-based assays. Similar pattern was observed with cathepsin L, although only theaflavin-3,3’-digallate showed a modest diminution of cathepsin L expression at protein level. Finally, each of these three compounds moderately increased endosomal/lysosomal pH. ccording to Patel et al., curcumin and its derivatives showed high binding affinity to the RBD of SARS-CoV-2, with ΔG (i.e., binding energy) between -10.01 to -5.33 kcal/mol. Based on a binding energy that resembles that of synthetic drugs, and also pharmacokinetic parameters, these researchers identified curcumin as a candidate for SARS-CoV-2 spike protein inhibition. Moreover, Jena et al. reported on catechin and curcumin, which have dual binding affinity, i.e., they bind to viral spike protein as well as to hACE2, although catechin’s binding affinity is greater (i.e., cathechin: -7.9 kcal/mol and -7.8 kcal/mol; curcumin: -10.5 kcal/mol and -8.9 kcal/mol, respectively). While these theoretical and molecular modelling approaches could identify potential applications of various molecules, the experimental proofs of their efficacy remain sparse. Here, we provide in vitro evidence that among 56 tested phenolic compounds and plant extracts, brazilin, TF-3, and curcumin exhibited the highest binding to RBD-spike protein of SARS-CoV-2. In conclusion, this study demonstrates pleiotropic anti-SARS-CoV-2 efficacy of specific polyphenols and their prospects for further scientific and clinical investigations.

Behavioral and morphological effects of resveratrol and curcumin in rats submitted to doxorubicin-induced cognitive impairment
Research in Veterinary Science | September 2021
Curcumin prevented short and long-term memory deficits caused by doxorubicin.

The Influence of Turmeric and Curcumin on Female Reproductive Processes
Planta Medica | September 2021
The present review summarizes the available knowledge concerning the action of curcumin, the best-known polyphenol among the rhizomes of Curcumas, on female reproductive processes and their dysfunctions. Curcumin affects a number of physiological processes, including female reproduction (puberty, reproductive aging, ovarian follicullogenesis and oogenesis, and fecundity). Curcumin can affect these processes via changes in the release and reception of pituitary and ovarian hormones, growth factors and cytokines. Furthermore, it can influence the response of ovarian cells to these substances and external environmental factors. Finally, curcumin can affect oxidative processes within the ovary and numerous intracellular signalling pathways related to ovarian cell proliferation and apoptosis. These effects suggest the applicability of curcumin for stimulation of female reproductive processes in vivo and in vitro, as well as for the prevention, mitigation, and treatment of various reproductive disorders from ovarian insufficiency and infertility to polycystic ovarian syndrome and ovarian cancer.

Curcumin Inhibits Replication of Human Parainfluenza Virus
BioMed Research International | September 2021
Curcumin is a natural phenolic compound extracted from a plant turmeric rhizome. It has a wide range of anti-inflammatory, antioxidant, and antitumor properties. Recent studies have found that curcumin has broad-spectrum antiviral capabilities. Here, we identify a novel role for curcumin as an antiviral drug against HPIV3 infection through its ability to affect IB formation and viral replication. This provides a theoretical basis for research and development of HPIV3 antiviral drugs, with implications for parainfluenza virus research and other similar viruses. Our studies found that curcumin has a significant antiviral effect on HPIV3 infection and has varying degrees of impact on multiple stages of the viral life cycle. Curcumin can disrupt the structural integrity of F-actin, downregulate the endogenous PI4KB expression, and interfere with the colocalization of PI4KB and IBs, thereby hindering viral IB formation and inhibiting viral replication. Mazumder discovered that curcumin could inhibit HIV-1 integrase, thereby inhibiting HIV-1 infection, and inhibit HCV replication by interfering with the Akt-SREBP-1 pathway. Curcumin can also interfere with binding of Zika and Chikungunya viruses to host cells to inhibit viral infection. To inhibit hepatitis B virus, curcumin can downregulate the metabolic molecule PGC-1. Although curcumin pretreatment does not affect plaque formation of enterovirus 71 (EV71), curcumin downregulates PI4KB expression in cells and affects the in vitro replication of EV71. Several studies have shown that curcumin has antiviral ability against enveloped and nonenveloped viruses, and the antiviral mechanisms in different viruses are also diverse. We verified the antiviral ability of curcumin against HPIV3 and preliminarily clarified that curcumin can inhibit IB formation by disrupting F-actin’s integrity. Simultaneously, curcumin can downregulate endogenous PI4KB level in cells, interfering with colocalization of PI4KB and IBs to affect IB formation, thereby inhibiting viral replication.

Turmeric and Curcumin: From Traditional to Modern Medicine
Studies on Biomarkers and New Targets in Aging Research | September 2021
The rhizome of turmeric (Curcuma longa L.) has been used as an herbal medicine, coloring agent, spice, and food additive for thousands of years in different parts of the world particularly in Asian countries. It has been used for a range of diseases in many traditional medical schools, including Islamic traditional medicine, Chinese traditional medicine, and Ayurveda. It has been used mainly for digestive problems, as a cardio-, hepato-, and neuroprotective agent as well as in many inflammatory conditions such as arthritis and for enhancing immune system. Curcumin, a diarylheptanoid derivative found in turmeric, has anti-inflammatory, antioxidant, and anticancer properties; controls obesity and metabolic problems; and improves memory and mood disorders. Therapeutically, curcumin exhibits promising potential in preclinical and clinical studies and is currently in human trials for a variety of conditions, including metabolic syndrome, nonalcoholic fatty liver disease, rheumatoid arthritis, migraine, premenstrual syndrome, ulcerative colitis, knee osteoarthritis, polycystic ovarian syndrome, atherosclerosis, liver cirrhosis, amyotrophic lateral sclerosis, depression, psoriasis, and Alzheimer’s disease. Among all beneficial activities reported for curcumin, the research toward the obesity and metabolic-preventing/suppressing aspects of curcumin is growing. These findings emphasize that most of the traditional applications of turmeric is due to the presence of its key constituent, curcumin. According to the traditional background of turmeric use and clinical values of curcumin, further preclinical studies for unstudied properties and clinical studies with larger sample sizes for confirmed activities are expected.

Efficacy and Safety of Curcumin Supplement on Improvement of Insulin Resistance in People with Type 2 Diabetes Mellitus
Evidence-Based Complementary and Alternative Medicine | September 2021
Curcumin is a chemical component extracted from the rhizome of some plants. It has a series of effects such as blood lipid lowering, antitumor, anti-inflammatory, and antioxidation and has been used as a food flavoring agent, preservative, and ancillary medication for some diseases (such as heart disease and tumors). In the treatment of diabetes, there is also evidence to support curcumin as a part of the diabetes treatment program. Based on the current evidence, curcumin may assist in improving insulin resistance, glycemic control, and decrease in TG and TC in patients with T2DM.

Curcumin functions as an anti-inflammatory and antioxidant agent on arsenic-induced hepatic and kidney injury
Environmental Toxicology | September 2021
As a plant polyphenol, curcumin is the most vital bioactive ingredient of turmeric and has a wide range of pharmacological activities. In the present study, we investigated the potential roles of curcumin against arsenic-induced liver and kidney dysfunctions in mice. Curcumin treatment (200 mg/kg) not only decreased the deposition of arsenic in liver and kidney, but also relieved the hepatic and nephritic biochemical indexes (Glutamic oxaloacetic transaminase [AST], Alanine aminotransferase [ALT], albumin, and creatinine) altered by arsenic at doses of 10 and 25 mg/L via drinking water. What's more, curcumin exerted influences on the activities of myeloperoxidase and on the secretion of inflammatory cytokines in liver and kidney tissues. In addition, the levels of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) phosphorylation were declining while NRF2-signaling targets were increasing in mice liver and kidney by curcumin administration. In conclusion, our results here suggest that curcumin could exert both anti-inflammatory and antioxidant functions on arsenic-induced hepatic and kidney injury by inhibiting MAPKs/NF-κB and activating Nrf2 pathways cooperatively.

Anti-Inflammatory Effect of Curcumin on the Mouse Model of Myocardial Infarction
Mediators of Inflammation | September 2021
Curcumin, an active ingredient extracted from natural plants, has been proven to have many physiological effects, including hypolipidemic, antitumor, anti-inflammatory, and antioxidation, and was used as treatment for drug-resistant tuberculosis, etc. Importantly, previous studies have shown that curcumin promotes heart repair after myocardial infarction and improves cardiac dysfunction, as well as improving the therapeutic efficacy of heart failure after myocardial infarction, but the specific mechanism is imperfect. In addition, curcumin has been found to suppress inflammation by inhibiting macrophage infiltration, and it can also regulate macrophage polarization. In this study, we found that curcumin not only attenuated ventricular remodeling and inflammation after MI but also reduced M1 but increased M2 macrophage activation in the MI mouse model. In addition, in vitro studies also revealed that some curcumin regulates the molecular mechanism of macrophage polarization, which was regulated AMPK expression. All in all, our research enriches the mechanism of curcumin in the treatment of myocardial infarction.

Effects of Curcumin against Influenza Using In Silico and In Vitro Approaches
Pharmaceuticals | September 2021
Curcumin has attracted considerable research interest because of its versatile pharmacological properties, including anti-inflammatory, antiviral, and anticancer effects. Previous studies have reported that curcumin inhibits the influenza virus by interfering with cellular signaling pathways, including Toll-like receptor and nuclear factor-κB pathways, and disrupting the viral envelope and liposomal membranes.

Curcumin: Implications for the Treatment of Multiple Sclerosis
Studies on Biomarkers and New Targets in Aging Research | September 2021
Curcumin is the active component of turmeric and a phenolic phytochemical. This phytochemical has anti-inflammatory properties and has been shown by multiple studies to downregulate NF-κB and its downstream gene targets including cyclooxygenase-2, tumor necrosis factor-α, interleukin-1, and interleukin-6.

Antimetastatic Effects of Curcumin in Oral and Gastrointestinal Cancers
Frontiers in Pharmacology | August 2021
For centuries, curcumin has been widely used as a dietary spice, and contemporary research studies have confirmed its efficacy in cancer therapy. Anticancer effects are the most pivotal properties of curcumin, which affect the different stages of cancer progression, including cancer cell formation, proliferation, and tumor invasion. According to extensive research, curcumin can suppress metastasis in GI cancers via regulating various signaling pathways. Curcumin has a crucial function in metastasis prevention by several mechanisms, including preventing transcription factors as well as their signaling pathways (e.g., NF-κB, STAT3, AP-1), multiple proteases (e.g., MMPs, uPA), inflammatory cytokines (e.g., CXCL1, IL-6, CXCL2, IL-8), modulation of miRNAs (e.g., miR181b, miR21), multiple protein kinases (e.g., FAK, MAPKs), and heat shock proteins (HLJ1). According to research, curcumin treatment leads to significant elevation in metastatic tumor cross-sectional volume (70%) and zone (46%). Curcumin may enhance LLC's metastatic growth in mice by elevating the concentration of VEGF, angiogenic factors, monocyte chemotactic protein-1 (MCP-1), and IL-1β.Curcumin or [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a polyphenolic extraction of Curcuma longa species. Curcumin had been used as a traditional Ayurvedic medicine due to its significant anti-inflammatory (Satoskar et al., 1986), antioxidant (Masuda et al., 2001), and antimicrobial (Negi et al., 1999) properties. Currently, curcumin is associated with powerful anticancer properties. Different animal studies have shown that curcumin has important roles in inhibiting primary tumorigenesis in numerous organs as metastatic sites, such as mammary glands (Inano et al., 1999) and gastrointestinal tract (Huang et al., 1994). Some investigations showed that curcumin has potential regulatory effects on the expression of proangiogenic growth factors (6–8). Curcumin inhibits angiogenic activities caused by fibroblast growth factor (bFGF) in rabbit and mouse models (Mohan et al., 2000). It also diminished the vascular endothelial growth factor (VEGF) serum levels in mice models of hepatocellular carcinoma (Yoysungnoen et al., 2006). Interleukin (IL)-1β and monocyte chemotactic protein-1 (MCP-1) are critical inflammatory cytokines in tumorigenesis. Accordingly, some studies demonstrated that these cytokines' expression levels reduced after curcumin intervention (Abe et al., 1999). Recent studies have also indicated that curcumin can modulate tumor immune responses and remodel the tumor immunosuppressive microenvironment, indicating its potential in the immunotherapy of cancer (Mukherjee et al., 2018; Bahrami et al., 2019a; Pan et al., 2019). Curcumin has antimetastatic activities, modulating T cells, B cells, macrophages, neutrophils, NK cells, dendritic cells and production of cytokines and chemokines. In addition, recent studies have shown that curcumin exerts immunosuppressive effects (Shafabakhsh et al., 2019). These findings showed that curcumin has crucial roles in the inhibition of angiogenesis and metastasis in GI cancers.

Curcumin as Prospective Anti-Aging Natural Compound: Focus on Brain
Molecules | August 2021
Curcumin is a natural dietary polyphenol extracted from Curcuma longa Linn with different biological and pharmacological properties including antioxidant, immunomodulatory, anti-inflammatory, anti-microbial, cardio-protective, nephro-protective, hepato-protective, anti-neoplastic, anti-rheumatic, and anti-aging. Curcumin, the yellow polyphenolic compound extracted from Curcuma longa species, is widely used in traditional Ayurvedic medicine to prevent and contrast many diseases, considering its antioxidant, immunomodulatory, anti-inflammatory, anti-microbial, cardio-protective, nephron-protective, hepato-protective, anti-neoplastic, and anti-rheumatic proprieties. In recent years, the investigations of curcumin have been focused on its application to aging and age-associated diseases. Aging is a physiological process in which there is a decreasing of cellular function due to internal or external stimuli. Oxidative stress is one of the most important causes of aging and age-related diseases. Moreover, many age-related disorders such as cancer, neuroinflammation, and infections are due to a low-grade chronic systemic inflammation. Curcumin acting on different proteins is able to contrast both oxidative stress than inflammation. In the brain, curcumin is able to modulate inflammation induced by microglia. Finally in brain tumors curcumin is able to reduce tumor growth by inhibition of telomerase activity. This review emphasizes the anti-aging role of curcumin focusing on its mechanism to counteract aging in the brain.

Antioxidant effects of curcumin and neuroaging
Factors Affecting Neurological Aging | August 2021
Curcumin, a plant-based polyphenol, is known to scavenge free radicals and promote antioxidant activity. This chapter gives an overview of the molecular evidence that curcumin prevents oxidative stress, cellular senescence, and death. In addition, curcumin’s role in protection against memory impairment as evidenced by brain imaging studies is reviewed. Although there are limited published clinical trials, there is preliminary evidence for curcumin improving memory and decreasing amyloid-β plaque accumulation. Consequently, curcumin has potential as a therapy in aging and aging-related disorders and further studies on its properties are warranted.

Pleiotropic nature of curcumin in strategies to treat gastric cancer
Phytotherapy Research | August 2021
Curcumin, isolated from the rhizomes of Curcuma longa L. has several medicinal properties like antiinflammatory, antioxidant, antiapoptotic, antitumor, and antimetastatic. Such pleiotropic nature of curcumin impedes the invasion and proliferation of GC by targeting several oncogenic factors like p23, human epidermal factor receptor2 including Helicobacter pylori. The side effect of chemotherapy, that is, chemotherapeutic resistance and radiotherapy could be reduced combination therapy of curcumin. Moreover, the photodynamic therapy of curcumin destroys the cancer cells without affecting normal cells.

Targeting of the tumor microenvironment by curcumin
BioFactors | August 2021
Curcumin is a plant-derived agent that has shown interesting properties for cancer therapy. It has shown that not only directly inhibit the growth of cancer cells, but can also modulate the growth and activity of immunosuppressant and tumor-promoting cells. In this review, we explain how curcumin modulates interactions within TME in favor of tumor treatment. The potential modulating effects of curcumin on the responses of cancer cells to treatment modalities such as immunotherapy will also be discussed.

Effect of curcumin on proinflammatory cytokines: A meta-analysis of randomized controlled trials
Cytokine | August 2021
 Curcumin has the potential for lowering inflammation.  There was a significant decrease in the serum levels of IL-1 and TNF-α compared to the placebo group following treatment.  The dose-responses analysis indicated that curcumin/turmeric supplementation resulted in IL-1 and IL-8 alteration in a non-linear model.  Subgroup analysis according to duration and dose of treatment and target population revealed diverse outcomes. Curcumin could have a beneficial effect in reducing the proinflammatory cytokines IL-1 and TNF-α.

Antidiabetic Properties of Curcumin: Insights on New Mechanisms
Studies on Biomarkers and New Targets in Aging Research | August 2021
Curcumin, a bioactive polyphenol derived from Curcuma longa L., exhibits therapeutic effects against diabetes while only negligible adverse effects have been observed. Antioxidant and anti-inflammatory properties of curcumin are the main and well-recognized pharmacological effects that might explain its antidiabetic effects. Additionally, curcumin may regulate novel signaling molecules and enzymes involved in the pathophysiology of diabetes, including glucagon-like peptide-1, dipeptidyl peptidase-4, glucose transporters, alpha-glycosidase, alpha-amylase, and peroxisome proliferator-activated receptor gamma (PPARγ). Recent findings from in vitro and in vivo studies on novel signaling pathways involved in the potential beneficial effects of curcumin for the treatment of diabetes are discussed in this review.

Curcumin: A Review of Its Effects on Epilepsy
Studies on Biomarkers and New Targets in Aging Research | August 2021
Curcumin (diferuloylmethane) is a major component of Curcuma longa and exhibits various pharmacological effects, including anti-inflammatory, antioxidant, and immunoregulatory properties. Here, we have reviewed the literature relating specifically to the antiepileptic effects of curcumin. The evidence suggests a protective effect of curcumin in the control of epileptic seizures, together with a protective effect on the relief of memory impairment, which may stem from its influence on monoamine levels in the brain.

Curcumin for the Treatment of Prostate Diseases: A Systematic Review of Clinical Trials
Studies on Biomarkers and New Targets in Aging Research | August 2021
Curcumin is a primary component of turmeric with several proven health benefits and is considered as a safe natural agent for both prevention and treatment of several diseases. It has been shown that this active compound of turmeric has several unique properties such as anti-tumour, anti-inflammatory, antioxidant, antithrombotic, chemosensitising and chemopreventive, anti-atherosclerotic and cardioprotective, lipid-modifying, antibacterial, antifungal, antiviral, analgesic, antidepressant and antirheumatic activities. Evidence suggests that curcumin has anticancer activity and, based on preclinical studies, it might be used to downregulate gene expression in prostate cancer cells. Also, due to the anti-inflammatory effects of curcumin, it has been suggested that this bioactive compound might have a beneficial impact on BPH and other inflammatory prostate conditions. The main finding of this systematic review is that curcumin supplementation alone or in combination with the other herbs had some favourable effects on prostate diseases without any considerable adverse effects.  In particular, curcumin appeared to have anti-inflammatory effects which could offer some therapeutic effects and improve patient outcomes.

The Clinical Use of Curcumin for the Treatment of Rheumatoid Arthritis: A Systematic Review of Clinical Trials
Studies on Biomarkers and New Targets in Aging Research | August 2021
Curcumin is one of the most studied hydrophobic polyphenols, derived mainly from Curcuma longa L. (turmeric). Curcumin has been widely and safely used in the treatment and prevention of various diseases. The potential protective mechanisms of curcumin have been claimed to be related to antioxidant, anti-inflammatory, anti-microbial, neuroprotective, anti-tumor, and immunomodulatory properties. Curcumin with anti-antioxidant, anti-inflammatory, and immunomodulatory properties might have beneficial effects on Rheumatoid Arthritis. Rheumatoid factor was significantly reduced after consumption of curcumin in all three relevant studies. None of the studies reported serious adverse effects with curcumin consumption. The present systematic review suggests that curcumin could be used as a safe agent to treat Rheumatoid Arthritis.

Effect of curcumin on proinflammatory cytokines: A meta-analysis of randomized controlled trials
Cytokine | August 2021
Curcumin has the potential for lowering inflammation. There was a significant decrease in the serum levels of IL-1 and TNF-α compared to the placebo group following treatment. The dose-responses analysis indicated that curcumin/turmeric supplementation resulted in IL-1 and IL-8 alteration in a non-linear model. Subgroup analysis according to duration and dose of treatment and target population revealed diverse outcomes. Curcumin could have a beneficial effect in reducing the proinflammatory cytokines IL-1 and TNF-α.

A Systematic Review of the Clinical Use of Curcumin for the Treatment of Osteoarthritis
Studies on Biomarkers and New Targets in Aging Research | August 2021
There is growing evidence that curcumin has anti-inflammatory properties and could be a potential therapeutic option for chronic inflammatory diseases. Hence, curcumin could potentially have a positive impact on osteoarthritis symptoms. There was a significant improvement in VAS and overall WOMAC scores with oral administration of various types of curcumin formulations with no severe adverse effects. In conclusion, different types of curcumin compounds may be beneficial as an alternative or complementary agent for the management of osteoarthritis.

Neuroprotective Effects of Curcumin in Cerebral Ischemia
ACS Chemical Neuroscience | August 2021
Curcumin, a polyphenol that is abundantly present in the rhizome of the turmeric plant (Curcuma longa), has shown promising neuroprotective effects in animal models of neurodegenerative diseases, including cerebral ischemia. In the central nervous system (CNS), neuroprotective effects of curcumin have been experimentally validated in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and cerebral ischemia. Curcumin can exert pleiotropic effects in the postischemic brain including antioxidant, anti-inflammatory, antiapoptotic, vasculoprotective, and direct neuroprotective efficacies. Importantly, neuroprotective effects of curcumin has been reported in both ischemic and hemorrhagic stroke models. A broad-spectrum neuroprotective efficacy of curcumin suggested that curcumin can be an appealing therapeutic strategy to treat cerebral ischemia.

5 Science-Backed Health Benefits Of Curcumin
Forbes Health | July 2021
“It’s one of the most powerful anti-inflammatories and a very powerful antioxidant,” says Melina Jampolis, M.D. Multiple studies suggest that curcumin has positive effects on Alzheimer’s disease. First, and most important, curcumin appears to both prevent the formation and encourage the breakup of the rogue proteins (beta-amyloid plaques) that form between the brain’s nerve cells and impair their communication (a hallmark of Alzheimer’s). Curcumin also seems to help clear away another suspect protein called tau that collects inside the neurons and is also implicated in causing Alzheimer’s disease. A wide variety of studies document curcumin’s effectiveness in reducing joint inflammation and pain just as well, but without the gastrointestinal side effects of non-steroidal anti-inflammatory drugs (NSAIDS). Curcumin can potentially benefit the brain in broader ways as well. The polyphenol’s antioxidant and anti-inflammatory properties may also help in preventing or reducing the symptoms of other neurodegenerative diseases like dementia, Huntington’s disease, multiple sclerosis and Parkinson’s disease. In clinical trials, curcumin reduced major depression and, in some cases, relieved anxiety in study subjects. “Curcumin seems to benefit mood by increasing brain-derived neurotrophic factor,” says Dr. Jampolis. Brain-derived neurotrophic factor (BDNF) is a protein that keeps neuronal cells healthy, and its production seems to be stimulated by plant-derived polyphenols like curcumin.  Because of curcumin’s antioxidant and anti-inflammatory actions, it may convey some protection against the development of these chronic illnesses. One of the newest areas of research—the role of gut microbiota in promoting or suppressing disease—hints that curcumin can change our gut microbiome in ways that have positive effects on the entire body and the mind. Beyond its two primary effects, curcumin also has antiseptic, anti-viral and anti-cancer properties. It has the potential to modulate the over-aggressive immune response some COVID-19 patients experience (the so-called “cytokine storm”) as well. Researchers are looking at it as both a preventative and a therapy for COVID-19.

Effect of moderate exercises and curcumin on hepatic transcriptional factors associated with lipid metabolism and steatosis in elderly male rat
Integrative/Functional Medicine | July 2021
Moderate aerobic exercise and curcumin alone or in combination completely masked this effect. Conclusion and implications: The findings revealed dyslipidemia and liver steatosis related to aging might be partly associated with changes in hepatic transcriptional factors which can be mitigatedmoderate aerobic exercise and curcumin.

Promising role of curcumin against viral diseases emphasizing COVID-19 management
Journal of Functional Foods
| July 2021
Curcumin has already acknowledged immense interest from both medical and scientific research because of its multifaceted activity. To date, the promising effects of curcumin were perceived against numerous inflammatory diseases. Besides, curcumin’s role as a medicine has been studied in many virus infections like influenza and HIV. The popular use of curcumin in research is mainly due to its pleiotropic properties including anti-inflammatory, anti-oxidant and anti-carcinogenic activities (Ahmad et al., 2020). Curcumin can inhibit the inflammatory mediators, oxidation processes, and oxidative stress thereby acts as an anti-inflammatory agent against many diseases (Wal et al., 2019). Praditya et al. (2019b) have shown curcumin as an anti-bacterial agent against several strains of Staphylococcus, Streptococcus, Helicobacter and Pseudomonas mainly by growth inhibition. They also reported the anti-fungal property of curcumin. Different studies identified the efficacy of curcumin against Human immunodeficiency virus (HIV), Herpes simplex virus (HSV), Hepatitis viruses etc. (Praditya et al., 2019a, Prasad and Tyagi, 2015, Vitali et al., 2020). Although there are some controversies, the majority of the studies support the potential role of curcumin in inhibiting viral replication and growth inhibition (Mathew & Hsu, 2018). Apart from these, long-term intake of curcumin can improve systolic blood pressure (Hadi et al., 2019), control obesity (Jarząb & Kukula-Koch, 2019), Type 2 Diabetes Mellitus (Pivari et al., 2019). Also, curcumin often acts as a cardio-protective, nephroprotective, anti-neoplastic, hepato-protective and anti-rheumatic compound. While the entire world is putting efforts into the discovery of a vaccine against coronavirus infection, the antiviral potential of curcumin against SARS-CoV-2 shows a promising role in COVID-19 management. Since ancient time, curcumin possesses a multifaceted role in several disease management. As an antiviral agent, existing literature suggested that targeting viral lifecycle and cellular responses are important strategies to combat viral infection. The present review emphasized the molecular mechanism of host-pathogen interaction and subsequent immune response in the host. In this background, curcumin can potentially inhibit the SARS-CoV-2 entry within human mainly by blocking the ACE2 receptor, hinder viral genome replication by altering viral non-structural protein activity. Not only viral entry, curcumin indeed can prohibit ‘cytokine storm’-induced multi-organ failure by constraining the inflammatory response and other cellular immune response.

Curcumin inhibits the viability, migration and invasion of papillary thyroid cancer cells
Experimental and Therapeutic Medicine | July 2021
Curcumin is a main phenolic active compound in C. Longa Linn, and it has numerous pharmacological activities such as anti-inflammatory, antibacterial and, especially, anticancer activities. The anticancer effects of curcumin are due to targeting a wide range of cellular and molecular pathways involved in cancer pathogenesis. For example, curcumin has been revealed to induce endoplasmic reticulum stress-associated apoptosis in human PTC cells via disruption of intracellular calcium homeostasis and to affect PTC cells by targeting the JAK/STAT3 signaling pathway. In summary, curcumin suppressed the cell viability, migration, invasion and EMT of TPC-1 cells. Moreover, curcumin treatment increased miR-301a-3p expression and inhibited STAT3 expression. Overexpression of miR-301a-3p inhibited cell viability, migration, invasion, and EMT and the JAK/STAT signaling pathway by targeting STAT3, and miR-301a-3p inhibitors and STAT3 overexpression reversed the curcumin-induced cell viability, migration, invasion and EMT of TPC-1 cells. Collectively, curcumin played an anticancer role in TPC-1 cells by regulating miR-301a-3p/STAT3, indicating that curcumin is a promising oncotherapeutic agent. These findings may provide a possible strategy for the clinical treatment of PTC.

Curcumin modulates gut microbiota and improves renal function in rats with uric acid nephropathy
Renal Failure | July 2021
Curcumin is a natural phenolic compound derived from the rhizome of the plant curcuma longa, and it is the main ingredient of turmeric. A large number of studies have confirmed that curcumin exerts a wide range of biological effects, including anti-tumor, anti-inflammatory, anti-oxidation, and anti-fibrosis. Based on the above pharmacological effects, there have been many animal experiments and cellular experiments using curcumin to prevent and treat various kidney diseases in recent years, and even a few preliminary reports on the clinical application of curcumin in the treatment of renal diseases. Moreover, curcumin has also been shown to have the effects of regulating intestinal flora and improving gut barrier function in multiple diseases, like diabetes, ulcerative colitis, and colorectal cancer. Curcumin treatment protected against the overgrowth of opportunistic pathogens in UAN, including Escherichia-Shigella and Bacteroides, and increased the relative abundance of bacteria producing short‐chain fatty acids (SCFAs), such as Lactobacillus and Ruminococcaceae. These results suggest that curcumin could modulate gut microbiota, fortify the intestinal barrier, attenuate metabolic endotoxemia, and consequently protect the renal function.

Anti-inflammatory effects of curcumin in acute lung injury
International Immunopharmacology | July 2021
Curcumin specifically promotes SIRT1 and inhibit NLRP3 inflammasome activation in vitro and in vivo. Curcumin’s inhibition of ferroptosis can be offset by the EX527 (inhibitor of Sirt1).  Curcumin reduces pyroptosis by inhibiting the expression of NLRP3. In conclusion, curcumin has protective effect against acute lung injury. It may inhibit inflammatory process by inhibiting the activation of NLRP3 inflammasome-dependent pyroptosis through the up-regulation of SIRT1.

A Novel Potent Sleep-Promoting Effect of Turmeric
Molecular Nutrition & Food Research | June 2021
Turmeric extract has a sleep-promoting effect owing to reduction in sleep latency and enhancement of NREMS via H1R blockade; therefore, it could be useful in insomnia.

Curcumin inhibits classical swine fever virus replication
Microbiology | June 2021
Previous reports have shown that Curcumin inhibits many viruses, including some important members of different genera of Flaviviridae family (Japanese encephalitis virus, dengue virus and hepatitis C virus). Curcumin inhibited classical swine fever virus replication by interfere lipid metabolism. In addition, our subsequent studies found that curcumin played an antiviral role by promoting the innate immune independent of NF-κB signaling pathway. Taken together, our finding highlights that curcumin is a potential candidate drug against classical swine fever virus for controlling classical swine fever.

Curcumin reverses doxorubicin resistance in colon cancer cells at the metabolic level
Journal of Pharmaceutical and Biomedical Analysis | June 2021
Natural product curcumin was demonstrated to have a variety of pharmacological effects, such as anti-tumor, anti-oxidation and anti-aging activities.  Curcumin increased the cytotoxicity of Dox in SW620/Ad300 cells. Curcumin reduced the biosynthesis of polyamine and D-glutamine metabolism to reverse MDR. Curcumin inhibited the ODC expression, thererby decreasing the biosynthesis of polyamine.  Curcumin could be a promising multidrug-resitance reversal agent for cancer treatment.

Curcumin suppresses the malignancy of non-small cell lung cancer
Biomedicine & Pharmacotherapy | June 2021
Curcumin exerts a suppressive effect in tumor growth by acting as a modulator of multiple molecular targets.  Curcumin, a traditional herbal medicine, is discovered in Curcuma longa. It is a polyphenol and has many activities, including controlling diabetes, improving brain function, oxidation, anti-inflammatory, anti-tumor, and so on. It has been reported that curcumin plays an important role in various cell signal transduction by acting as a modulator of multiple molecular targets. Also, curcumin plays a repressive role in the advancement of NSCLC. Zhang et al. manifested that curcumin synergistically constrained cell malignancy. Furthermore, curcumin played an anti-tumor activity in NSCLC cells. Curcumin has attracted the attention of scientific researchers all over the world because of its anti-cancer potential. Accumulated studies have revealed that curcumin can target cell signaling pathways related to cancer development. For example, curcumin elevated miR-99a expression in retinoblastoma cells, thereby blocking the JAK/STAT pathway and repressed cell malignancy. Moreover, curcumin inhibited the proliferation of glioblastoma cells via blocking the AKT/mTOR pathway. Recent research revealed that curcumin elevated nasopharyngeal cancer radio-sensitization through regulating the circRNA/miR/mRNA network. Herein, we discovered that curcumin curbed the malignancy of NSCLC cells through repressing the circ-PRKCA/miR-384/ITGB1 pathway.

Curcumin and rheumatoid arthritis: A systematic review of literature
International Journal of Clinical Practice | June 2021
Curcumin is a natural polyphenol and the main compound from the rhizome of Turmeric (Curcuma longa) and other Curcuma species. It has been widely used for different medical purposes, such as improvement of pain and inflammatory conditions in various diseases. Most studies have shown the curative effects of curcumin on clinical and inflammatory parameters of RA and reported different mechanisms; inhibition of mitogen-activated protein kinase family, extracellular signal-regulated protein kinase, activator protein-1 and nuclear factor kappa B are the main mechanisms associated with the anti-inflammatory function of curcumin in RA. The results of the only human study showed that curcumin significantly improved morning stiffness, walking time and joint swelling. In conclusion, curcumin seems to be useful, and it is recommended that more human studies be performed to approve the cellular and animal results and determine the effective and optimal doses of curcumin on RA patients.

The efficacy and safety of Curcuma longa Extract and curcumin supplements on osteoarthritis: a systematic review and meta-analysis
Bioscience Reports | June 2021
Curcuma longa Extract and curcumin may be a safer and effective supplement for osteoarthritis patients. It is recommended to use Curcuma longa Extract and curcumin supplement for osteoarthritis patients for more than 12 weeks. Curcumin is a natural active oxygen scavenger and active nitrogen provider, and has been proven to be effective in treating pain caused by arthritis and osteoarthritis. Compared with NSAIDs, Curcuma longa Extract and curcumin have similar effects on joint pain, function and stiffness. However, the incidence of adverse events in Curcuma longa Extract and curcumin was lower.  Compared with the NSAIDs group, Curcuma longa Extract and curcumin+NSAIDs can also relieve pain (decrease the VAS and WOMAC score-pain), improve the joint function (decrease the WOMAC score-function), and improve the joint stiffness (decrease the WOMAC score-stiffness); in terms of adverse events, the addition of Curcuma longa Extract and curcumin to NSAIDs did not increase adverse events. Our meta-analysis also showed that Curcuma longa Extract and curcumin can improve oxidative stress in patients with osteoarthritis. Our meta-analysis shows that the combination of Curcumin and NSAIDs does not increase the occurrence of adverse events and has better efficacy. This is a promising result, because adding Curcumin supplementation in the case of using NSAIDs may increase the efficacy and perhaps reduce the dosage of NSAIDs.

Study presents evidence supporting the use of curcumin as alternative treatment for kidney fibrosis
The Gary Null Show | June 2021
Curcumin is an effective alternative treatment for renal fibrosis According to several animal studies, curcumin can protect the kidneys by preventing the development of renal fibrosis. The researchers found that curcumin (3.125 and 25?micromol/L) effectively promoted HKC proliferation. After 72 hours of incubating HKCs with TGF-B1 and curcumin, curcumin caused the cells to maintain epithelial morphology in a dose-dependent manner. It also decreased the expression of EMT-related proteins, such as vimentin, a-SMA and FSP1, and increased the expression of E-cadherin and cytokeratin. In addition, the researchers noted that curcumin reduced Akt, mTOR and P70S6K phosphorylation, which effectively suppressed the activation of the Akt/mTOR pathway in HKCs. Based on these findings, the researchers concluded that curcumin is an effective alternative treatment for renal fibrosis because it can promote HKC proliferation and stop EMT by inhibiting the activation of the Akt/mTOR pathway activity.

The Role of Curcumin in Gastrointestinal Cancers
Advances in Experimental Medicine and Biology | June 2021
Curcumin has been used in combinations with many anti-tumor drugs to increase their anticarcinogenic properties. Taken together, curcumin falls within the category of plant-derived substances capable of preventing or treating gastrointestinal cancers. Curcumin is a natural compound derived from turmeric with a wide range of biological activities. Several in vitro and in vivo studies have investigated the effects of curcumin on gastrointestinal cancers. In the current review, we aimed to provide an updated summary on the recent findings regarding the beneficial effects of curcumin on different gastrointestinal cancers in the recent decade. For this purpose, ScienceDirect,” “Google Scholar,” “PubMed,” “ISI Web of Knowledge,” and “Wiley Online Library” databases were searched using “curcumin”, “cancer”, and “gastrointestinal organs” as keywords. In vitro studies performed on different gastrointestinal cancerous cell lines have shown that curcumin can inhibit cell growth through cycle arrest at the G2/M and G1 phases, as well as stimulated apoptosis and autophagy by interacting with multiple molecular targets. In vivo studies performed in various animal models have confirmed mainly the chemopreventive effects of curcumin.

Effect of eight-week curcumin supplementation with endurance training on glycemic indexes in middle age women with type 2 diabetes
Diabetes & Metabolic Syndrome: Clinical Research & Reviews | June 2021
Eight weeks of curcumin supplementation and endurance training, whether done separately or simultaneously, significantly reduced fasting blood glucose, glycosylated hemoglobin and serum insulin levels (P < 0.05). The combination of curcumin supplementation and endurance training compared to the other two interventions caused a significant further decrease in these glycemic indexes (P < 0.05). The findings of this study showed that eight weeks of curcumin supplementation and endurance training helped each other in improving the glycemic indexes of women with type 2 diabetes.

The protective effect of curcumin on rats with DSS-induced ulcerative colitis and its mechanisms
Research Square | May 2021
Curcumin is a traditional Chinese herbal medicine that is used for anti-inflammation in China and Southeast Asia. Curcumin has antioxidant, anti-inflammatory, anticancer and antiapoptotic properties. The advantages of curcumin, such as few adverse reactions, high levels of safety, and good compliance, have attracted the attention of many researchers. Studies have shown that curcumin can reduce airway inflammation by regulating the balance of Treg/Th17 cells in asthma models. In IBD model mice with genetic deletion of IL-10, an emulsion of curcumin in sodium carboxymethyl cellulose induced anti-inflammatory effects. The curcumin group exhibited significantly reduced DAI scores and improvements in histopathological damage. The expression of CD4+IL-17+ Th17 cells was significantly lower and the expression of CD4+CD25+Foxp3+ Treg cells was significantly higher in the curcumin group than in the DSS group.  Curcumin may be a new and effective treatment for IBD by regulating the balance of Treg/Th17 cells and the expression of IL-10 and IL-17A. The present study showed that compared with those of IBD rats in the DSS group, IL-10 levels of IBD rats in the curcumin group were significantly higher. Therefore, the protective effect of curcumin was related to IL-10. In summary, curcumin attenuated colonic tissue damage in DSS-induced UC rats by improving the Treg/Th17 cell balance and influencing the expression of inflammatory cytokines.

Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells
Oncology Reports | May 2021
Curcumin, a phytochemical from rhizomes of the plant Curcuma longa, has been reported to exert potential anticancer properties in various cancer types, including acute myeloid leukemia (AML). Collectively, the present study demonstrated that curcumin exerted anti-AML roles by inactivating AKT and these findings may aid in the treatment of AML.

Effects of curcumin supplementation on sport and physical exercise
Critical Reviews in Food Science and Nutrition | May 2021
Curcumin supplementation displayed significant reductionof inflammation derived from the physical exercise. After curcumin supplementation there was a significantimprovement in some aspects of muscle recovery and performance in exercise. Curcumin has recently drawn worldwide attention ofresearchers (Salehi et al.2019), who conducted studies thatindicated that its medicinal properties are associated withthe reduction of pain (Karlapudi et al.2018; Sun et al.2018), anti-inflammatory effects (Ghandadi and Sahebkar2017; Mollazadeh et al.2019), besides prevention and treat-ment of cardiovascular (Li et al.2020; Momtazi-Borojeniet al.2019) and gastrointestinal (GI) diseases (Ghosh et al.2018; Mazieiro et al.2018), cancer (Kunnumakkara et al.2017; Mizumoto et al.2019; Talib et al.2018) and otherchronic diseases (Kunwar and Priyadarsini2016; Prasadet al.2014; Salehi et al.2019; Sharan Patel et al.2019).Also, studies that employed animal models reportedpositive results of curcumin supplementation for physicalactivity and sport performance (Huang et al.2015), thussupporting muscle recovery and reduction of inflammation(Davis et al.2007), improvement of mitochondrial biogen-esis (Ray Hamidie et al.2015), reduction of oxidative stress(Kawanishi et al.2013), prevention of fatigue and muscledamage (Huang et al.2015; Sahin et al.2016).  The evidences presented indicate that cur-cumin supplementation in human beings is likely safe andbeneficial for sport and physical activity, due to the reduction of inflammation and oxidative stress, reduction of painand muscle damage, improved muscle recovery, sport performance, psychological and physiological responses (thermal and cardiovascular) during training, as well as the GI function.

Role of Curcumin in Regulating Long Noncoding RNA Expression in Cancer
Advances in Experimental Medicine and Biology | May 2021
Phytochemicals are various compounds produced by plants. There is growing evidence on their potential health effects. Some of these compounds are considered as traditional medicines and used as painkillers, anti-inflammatory agents, and for other applications. One of these phytochemicals is curumin, a natural polyphenol derived from the turmeric plant (Curcuma longa L.). Curcumin is widely used as a food coloring, preservative and condiment. It has also been shown to have antioxidative and anti-inflammatory effects. Moreover, there is growing evidence that curcumin alters long noncoding RNAs (lncRNAs) in many kinds of cancer. These noncoding RNAs can cause epigenetic modulation in the expression of several genes. This study reviews reports of curcumin effects on lncRNAs in lung, prostate, colorectal, breast, pancreatic, renal, gastric, and ovarian cancers.

The effect of curcumin and zinc co-supplementation on glycemic parameters in overweight or obese prediabetic subjects
Phytotherapy Research | May 2021
Curcumin and zinc have been studied as an antioxidant, antiinflammatory, and antidiabetic agents. Based on these results, zinc and curcumin supplementation exerted a beneficial effect on several key glycemic parameters.

Curcumin Reduces Neuroinflammation and Improves the Impairments of Anesthetics on Learning and Memory
Neuroimmunomodulation | May 2021
Curcumin has a protective effect on ISO-induced cognitive dysfunction, which may be achieved by regulating the expression of miR-181a-5p.

Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes
BioFactors | May 2021
Polyphenolic phytochemicals such as curcumin and its derivatives have anti‐amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self‐assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Anti-Inflammatory Effect of Curcumin on Rheumatoid Arthritis
Pharmaceuticals | May 2021
Recent studies reveal that curcumin, a natural dietary anti-inflammatory compound, can modulate the response of the cells engaging in RA course. Interestingly, many studies have described the potential role of curcumin as an epigenetic modifier. This potent herbal drug has been identified as an inhibitor of DNA methyltransferases (DNMTs), regulator of histone acetyltransferases (HATs), deacetylases (HDACs), and microRNAs, as well as a DNA binding agent. Curcumin has been found to significantly reduce H3ac levels in the IL-6 promoter as well as IL-6 mRNA expression in rheumatoid arthritis synovial fibroblasts (RASFs). The role of curcumin as an epigenetic modifier has been well documented in cancer, neurological disorders, and some inflammatory diseases. Curcumin is a polyphenolic substance naturally occurring in turmeric, especially in Curcuma Longa, with broad anti-inflammatory properties and proven positive effects in autoimmunological disease therapies, including Rheumatoid Arthritis. Curcumin is an antioxidant, which means it can efficiently reduce the level of reactive oxygen species (ROS), weaken redox signaling, and reduce inflammation [22]. In addition to having direct antioxidant properties, curcumin also blocks the activity of ROS-generating enzymes like lipoxygenase (LOX), cyclooxygenase (COX), xanthine dehydrogenase, and nitric oxide synthase (iNOS). Despite reducing ROS levels, curcumin also possesses numerous other properties that enable its usage as a potential therapeutic drug targeted against Rheumatoid Arthritis. Interesting insights into this matter are provided by recent studies, which found that this natural compound can suppress proinflammatory pathways related to the immune cells crucial in RA development. Therefore, curcumin’s daily consumption can decrease inflammation and oxidative stress, contributing to the immune system’s modulation and alleviating the rheumatoid arthritis course.

Curcumin and cancer biology: Focusing regulatory effects in different signalling pathways
Phytotherapy Research | May 2021
Curcumin is a bright yellow substance isolated from the plant rhizomes of Curcuma longa L. To this molecule a high therapeutic benefit has been underlined, being able to alter the development of cancer by different mechanisms, such as regulating multiple microRNA expression, modifying a series of signalling pathways, that is, Akt, Bcl‐2, PTEN, p53, Notch, and Erbb. Another major pathway that curcumin targets is the matrix metalloproteinase (MMP) gene expression. In this review, we have attempted to describe the curcumin regulatory effect on different cell signalling pathways involved in the progression of different types of cancers.

Curcumin prevents obesity by targeting TRAF4‐induced ubiquitylation in m6A‐dependent manner
EMBO Reports | May 2021
Curcumin, a natural polyphenolic compound present in turmeric, has been shown to have a protective effect on against obesity and metabolic diseases. m6A‐dependent TRAF4 expression upregulation by ALKBH5 and YTHDF1 contributes to curcumin‐induced obesity prevention. Our findings provide mechanistic insights into how m6A is involved in the anti‐obesity effect of curcumin.

Curcumin alleviates high-fat diet-induced hepatic steatosis and obesity in association with modulation of gut microbiota in mice
Food Research International | May 2021
Curcumin alleviated hepatic steatosis and insulin resistance in obese mice. Curcumin increased abundance of Bacteroides, Parabacteroides, Alistipes and Alloprevotella. Curcumin increased the caecal and colonic short chain fatty acids (SCFA) contents. Curcumin reduced endotoxin-producing Desulfovibrio bacteria and circulating serum LPS. The dominant bacterial taxa altered by curcumin were related with improvement of obesity.

The Effects of Curcumin on Diabetes Mellitus: A Systematic Review
Frontiers in Endocrinology | May 2021
The genus Curcuma (Zingiberaceae) includes perennial rhizomatous plants native to subtropical to tropical regions. The main part of the plant is the rhizomes, and the most prevalent active components are the curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin). Curcuminoids are nontoxic polyphenolic that exerts a wide range of biological activities, such as the production of significant immunosuppressants that inhibit the production of IL-2 and IL-12. This compound inhibits the expression of iNOS (inducible nitric oxide synthase), COX-2 (cyclooxygenase-2), lipoxygenase-5, and many other pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6, and IL-8. Curcuminoids can also regulate apoptosis and suppress neurotoxic factors in macrophages and alveolar monocytes stimulated by lipopolysaccharides. Besides, it inhibits phosphorylation and degradation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) and activates the γ receptor mechanism activated by peroxisome proliferator, reducing inflammation pattern induced by NF-κB pathway. The peculiar characteristics that attract scientists’ attention are the antioxidant and anti-inflammatory activities and the safety of its pharmacological profile. The mechanism of action in several molecular pathways is due to curcumin’s particular chemical structure, capable of having many molecular targets. The biological effects may include the inhibition of reactive oxygen species (ROS) production, playing a fundamental role, particularly for diseases related to oxidative stress and inflammation, such as DM. Figure 3 shows some systemic effects of curcumin. Curcumin is a bioactive component found Curcuma longa, which exhibits several physiological and pharmacological properties such as antioxidant, anti-inflammatory, anticancer, neuroprotective, and anti-diabetic activities. For these reasons, our objective is to systematically review the effects of Curcuma longa or curcumin on DM. Databases such as PUBMED and EMBASE were searched, and the final selection included sixteen studies that fulfilled the inclusion criteria. The results showed that curcumin’s anti-diabetic activity might be due to its capacity to suppress oxidative stress and inflammatory process. Also, it significantly reduces fasting blood glucose, glycated hemoglobin, and body mass index. The singular characteristic of this plant is the presence of curcumin, which shows antioxidant and anti-inflammatory properties. Besides that, curcumin has a potential role in preventing and treating several diseases due to various actions such as anti-bacterial, anti-diabetic, anti-viral, and anticancer activities. Curcuminoids have been shown to improve insulin resistance, decrease glucose and insulin levels, increase adiponectin release, and reduce the levels of leptin, resistin, interleukin (IL)-6 IL-1β, and tumor necrosis factor-α in patients with T2DM. These findings suggest that these compounds can affect glucose homeostasis and diabetic complications, and the vascular risk of patients with T2DM. Some studies have shown that supplementation of curcuminoids improves the lipid profile and increases the total antioxidant capacity of patients with T2DM, thus supporting other available evidence on the role of curcuminoids in modifying cardiometabolic risks.

Possible Mechanisms and Special Clinical Considerations of Curcumin Supplementation in Patients with COVID-19
Advances in Experimental Medicine and Biology | May 2021
Mechanisms and special clinical considerations of supplementation with curcumin as an anti-inflammatory and antioxidant compound in the setting of COVID-19 clinical research.

Anticancer Mechanism of Curcumin on Human Glioblastoma
Nutrients | May 2021
Curcumin is the most studied compound described as a potential anticancer agent due to its multi-targeted signaling/molecular pathways properties. Curcumin possesses the ability to modulate the core pathways involved in GBM cell proliferation, apoptosis, cell cycle arrest, autophagy, paraptosis, oxidative stress, and tumor cell motility. This review discusses curcumin's anticancer mechanism through modulation of Rb, p53, MAPK, P13K/Akt, JAK/STAT, Shh, and NF-κB pathways, which are commonly involved and dysregulated in preclinical and clinical GBM models.

Micronutrients and bioactive substances: Their potential roles in combating COVID-19
Nutrition | April 2021
A study has shown that curcumin interfered with the binding of enveloped viruses to cell surface. Derivatives of curcumin exhibited antiviral activity against enveloped viruses. Direct treatment of a virus with curcumin reduced the infectivity of the virus in a dose–time-dependent manner for enveloped viruses, as well as the vesicular stomatitis virus. Curcumin also exhibited antiviral properties against dengue virus and hepatitis C virus. Having immunomodulating, antiinflammatory, antioxidant, and antiviral properties, such micronutrients and bioactive substances are consequently promising alterative nutritional approaches to combat COVID-19 infection.

Curcumin suppresses colorectal cancer stem cells
Journal of Natural Medicines | April 2021
Curcumin is a polyphenol extracting from Curcuma longa. It has been demonstrated that curcumin possesses extensive therapeutic activities against multiple ailments, such as inflammation, metabolic syndrome, liver disease, arthritis, and neurodegenerative disease. In the recent years, researchers found that curcumin has played an important role in cancer prevention and treatment. For instance, curcumin induced apoptosis of castration-resistant prostate cancer cells, partially dependent on its iron-chelating properties; curcumin could overcome gefitinib-resistance in nonsmall-cell lung cancer cells via inducing autophagy-related cell death. Other studies indicated curcumin suppressed oncogenicity of human colon cancer cells, through covalent modification of SIRT1 at the cysteine 67 residue and the proteasomal degradation of oncogenic SIRT1. In this study, we observed that curcumin inhibited tumorsphere formation, decreased cell viability in a dose-dependent manner. Curcumin also promoted apoptosis of LGR5(+) colorectal CSCs. In addition, curcumin can induce autophagy in many tumor cells. For example, curcumin inhibited proliferation, induced the autophagy and apoptosis in gastric cancer cells. Similarly, our data suggest that curcumin increased tumor cell death partly by inducing autophagy, because the effect of curcumin-induced cell proliferation inhibition was decreased by co-treatment with the autophagy inhibitor, HCQ. Therefore, these results reveal that curcumin-induced autophagy may contribute to the antitumor effects of curcumin on LGR5(+) colorectal CSCs.  In summary, we found that curcumin suppresses the proliferation of LGR5(+) colorectal CSCs by inducing autophagy and transcriptionally repressing the oncogenic TFAP2A-mediated ECM pathway. Lastly, while our study entailed mostly in vitro experiments, further studies, especially in vivo, are needed to understand the mechanism of effect of curcumin in LGR5(+) colorectal CSCs and to evaluate this potential therapeutic approach to CRC. In addition, the correlation between TFAP2A-mediated ECM pathway and autophagy also deserves further study.

Beneficial Effects of Curcumin Supplementation on Sports Performance and Physical Exercise
Designs For Health | April 2021
Turmeric has three main bioactive components: curcumin, desmethoxycurcumin, and bisdemethoxycurcumin. These curcuminoids have many biological effects, including properties that are anti-inflammatory, antioxidant, anti-tumor, antimicrobial, and antiviral. This review investigated the evidence for the effects of curcumin supplementation for humans on sports performance and physical exercise. Curcumin possesses the ability to inhibit transcription factors (e.g., nuclear factor [NF]-κβ) that are responsible for activating pro-inflammatory enzyme and cytokine expression, such as cyclooxygenase (COX)-2, 5-lipoxygenase (LOX-5), tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-8, suggesting their importance in helping to reduce post-exercise inflammation. The treatment groups with doses ranging from 180 mg to 5 g of curcumin per day showed significant reductions in inflammation caused by physical exercise compared to the placebo group, whose participants displayed elevated IL receptor agonist activity of IL-6, IL-8, and IL-10, and TNF-α concentrations. Compared to the treatment group, a gastrointestinal (GI) barrier damage marker (fatty acid−binding protein) was elevated after aerobic exercise in the placebo group, suggesting curcumin may improve GI function during exercise-induced exertional heat stress. Overall, the results of this systematic review showed positive effects with no adverse symptoms or injuries reported. Curcumin supplementation improved exercise-induced muscle recovery, muscle performance, psychological and physiological parameters, function, and reduced inflammation, oxidative stress, pain, and muscle damage caused by aerobic and resistance training. Although larger clinical trials are needed, the evidence suggests that curcumin supplementation may be a safe and effective option for supporting sports and exercise performance in humans.

Curcumin suppresses colorectal tumorigenesis
Oncology Letters | April 2021
Curcumin, a natural product extracted from the rhizome of Curcuma longa, is a drug with strong pharmacological effects and limited side effects. Increasing evidence have confirmed that curcumin exerts antioxidant, antibacterial, anti-inflammatory, antiproliferation and anticancer effects. Furthermore, curcuminoids have been approved by the US Food and Drug Administration (FDA) as ‘Generally Recognized As Safe’ (GRAS) and clinical trials have demonstrated good tolerability and safety profiles, at doses between 4,000–8,000 mg/day. In another phase I clinical trial, curcumin (at doses 0.45–3.6 g) was administered to 15 patients with advanced CRC who were resistant to chemotherapy for 4 months. The results demonstrated that treatment with curcumin was well tolerated and there was no toxicity at any doses. Previous studies have reported several molecular mechanisms for the anticancer effects of curcumin . For example, curcumin inhibits Axin2 expression in the colorectal cancer line, HCT116, and modulates the Wnt/β-catenin signaling pathway. Yan et al demonstrated that Axin2 is upregulated and the Wnt/β-catenin signaling pathway is activated in human colon tumor samples. It has also been reported that curcumin can target colorectal stem cells via the Wnt pathway to inhibit their proliferation and drug resistance to chemotherapy, indicating the important role of the Wnt/β-catenin signaling pathway in the tumorigenesis of CRC. Another study demonstrated that curcumin inhibits the proliferation and induces apoptosis of human non-small cell lung cancer cells via the PI3K/Akt signaling pathway. Furthermore, the results of a squamous cell carcinoma study reported that curcumin inhibits cancer cell proliferation via the epidermal growth factor receptor signaling pathway. In addition to the effects of curcumin on CRC progression through the NBR2/AMPK/mTOR pathway, curcumin regulates the NF-κB and Src protein kinase signaling pathways by inhibiting IκBα kinase activation and IκBα phosphorylation. Collectively, these results indicate several molecular mechanisms of the anticancer effects of curcumin in vitro. However, the in vivo mechanism remains to be elucidated. Thus, the present study aimed to investigate the anticancer effects of curcumin and determine its underlying mechanisms in CRC, in vivo.

Protective Effects of Curcumin on Sperm and Stereological Parameters in Testes of Formaldehyde-Exposed NMRI Mice: An Experimental Study
International Journal of Medical Laboratory | April 2021
Curcumin (diferuloylmethane) is the main curcuminoid of turmeric, which is a known spice. It has been shown that curcuminoids are polyphenols and are responsible for the yellow-orange color of turmeric. Noorafshan and colleagues previously showed that curcumin protects the Leydig cells against metronidazole treatments. In another study, curcumin reduced testicular damage in diabetic rats by reducing oxidative stress.Moreover, Farombi et al. used curcumin to prevent oxidative changes and enhance sperm motility and reduce sperm abnormalities. This study showed that curcumin could reduce formaldehyde-induced damage to the testis structure and sperm parameters, possibly by inhibiting oxygen free radicals’ production.These results suggest that curcumin is a potential therapeutic agent on spermatogenesis caused by a testicular injury triggered by FA in mice.

Antiviral activities of curcumin and 6‐gingerol against infection of four dengue virus
Indonesian Journal of Biotechnology | April 2021
The compound curcumin showed antiviral properties as described. In conclusion, curcumin and 6‐gingerol exhibit antiviral properties against DENV infection and could provide a new therapeutic approach for dengue disease treatment strategies.

Telomerase: A Target for Therapeutic Effects of Curcumin in Cancer
Advances in Experimental Medicine and Biology | April 2021
Curcumin has been shown to be effective against several types of malignancies and has also been shown to have inhibitory effects on telomerase activity. Based on the findings obtained from the different studies here, we conclude that the telomerase inhibitory effects of curcumin are integral to its anticancer activity, and thus curcumin may be useful therapeutically in the cancer field.

Curcumin as Anti-infective Agents
Current Medicinal Chemistry | April 2021
Curcumin, a redox-active natural product, has for centuries been used in Asian traditional medicine for the treatment of various diseases. It is known for possessing multiple biological and pharmacological activities. Curcumin has been investigated extensively over the years for its anti-inflammatory, anticancer, antiparasitic, antiviral and antibacterial activities, and no toxicity is associated with the compound. Curcumin is still in clinical trials for the treatment of diseases, such as tuberculosis, acquired immunodeficiency syndrome (AIDS), Crohn’s disease, colorectal cancer and multiple myeloma, among many others as potential antibacterial, antifungal, antiparasitic and antiviral agents for the treatment of various infectious diseases.

The Antioxidant Effect of Curcumin and Rutin on Oxidative Stress Biomarkers
Molecules | April 2021
Curcumin, from the root of the turmeric plant Curcuma longa, is an extended pseudosymmetric polyphenol (diferuloylmethane). Zhou et al. showed that curcumin prevents bone loss in an experimental periodontitis model. In association with studies that do demonstrate an effect on the prevention of bone loss, these investigations have shown that curcumin has a profound effect on inflammation by significantly reducing the development of an inflammatory infiltrates within the periodontal lesion while simultaneously stimulating an increase in the collagen content, as well as an increase in the number of fibroblastic cells within the periodontium and associated lesions when curcumin was administered daily to rats with experimentally induced periodontitis. Curcumin, the major component of turmeric, has been shown to have anti-inflammatory, antimicrobial and antioxidant action. In vitro studies, animal studies and clinical studies have demonstrated that there is a positive association between curcumin and the evolution of periodontitis. It can be concluded that the oral administration of curcumin and rutin, single or combined, could reduce oxidative stress both in gingival tissue and blood and enhance the antioxidant status in hyperglycemic periodontitis rats. Modeling oxidative stress, these two antioxidants may have an inhibitory effect on inflammation.

Curcumin induces ferroptosis in non‐small‐cell lung cancer
Thoracic Cancer | April 2021
Emerging studies showed curcumin can inhibit glioblastoma and breast cancer cells via regulating ferroptosis. Curcumin is a yellow polyphenol compound derived from the turmeric plant, which shows anticancer properties through a variety of mechanisms, including inhibition of tumor proliferation, invasion and metastases, regulation of apoptosis, and autophagy. Recent studies showed that curcumin can treat glioblastoma and breast cancer via regulating ferroptosis. In conclusion, our results provide evidence that curcumin could induce ferroptotic cell death of NSCLC cells via activating autophagy.

Curcumin Ameliorated Oxidative Stress and Inflammation-Related Muscle Disorders
Antioxidants | April 2021
Curcumin has also been reported to possess diverse pharmacological effects including antioxidant and anti-inflammatory activities. Recently, it has been suggested that curcumin alleviated chronic kidney disease-induced muscle atrophy by inhibiting glycogen synthase kinase (GSK)-3β.  The present study demonstrated that curcumin  in C2C12 myoblast cells showed in vitro antioxidant and anti-inflammatory activities. Specifically, curcumin enhanced DPPH radical scavenging activity in a dose-dependent manner, and it did not affect the cell viability of C2C12 cells with concentrations up to 30 μg/mL. Furthermore, curcumin significantly suppressed H2O2-induced cell toxicity, ROS generation, and lipid peroxidation and restored GSH depletion, which involved an increase of antioxidant genes through Nrf2 activation, providing evidence that curcumin can protect cells by reducing oxidative stress. Besides, curcumin significantly inhibited LPS-mediated IL-6 productions. Therefore, curcumin could be a useful candidate against oxidative stress and inflammation-related muscle disorders.

Curcumin Reduces Cognitive Deficits by Inhibiting Neuroinflammation
ACS Omega | April 2021
Curcumin is a polyphenolic substance extracted from turmeric, a plant of the curcuma family. Toxicity studies have shown that it is quite safe even at high doses (up to 12 g in humans). Curcumin’s pharmacological action is exerted at multiple sites, including enzymes, transcription factors, growth factors, neurotransmitter receptors, inflammatory mediators, and a large number of protein kinases. It has anti-inflammatory, antitumor, antioxidative, and antibacterial effects. Curcumin has been used as a condiment in food in Southeast Asia for centuries. According to the initial epidemiological analysis of the Indian population, curcumin has a strong potential to treat Alzheimer’s disease. The incidence of Alzheimer’s disease was 4.4-fold lower in long-term curcumin users than those without curcumin in the United States. Curcumin, as an effective anti-inflammatory small molecule, was shown to inhibit the COX-2 expression in human colon cancer cells. Recently, Wang et al. have proven that curcumin can inhibit ApoE4-induced injury by upregulating the expression of peroxisome proliferator-activated receptor-γ to inhibit the activation of NF-κB signaling in SH-SY5Y cells. Apart from the anti-inflammatory role, curcumin also acts as a known antioxidant that scavenges reactive oxygen species. Zheng et al. found that curcumin can protect SH-SY5Y cells against appoptosin-induced intrinsic caspase-dependent apoptosis by increasing heme oxygenase-1 expression and reducing ROS production.  Chhunchha et al. also proposed that curcumin could reinforce the naturally occurring Prdx6 expression, attenuate ROS-based ER stress and NF-κB-mediated aberrant signaling, then improve the survival of mouse hippocampal cells (HT22), and may provide an avenue to treat and/or postpone diseases associated with ROS or ER stress. In the findings of Feng et al.,they indicated that curcumin could inhibit the PERK–eIF2α–CHOP axis of the ER stress response through the activation of SIRT1 in tert-butyl hydroperoxide (TBHP)-treated rat chondrocytes and ameliorated osteoarthritis development in vivo. Together, the previous studies focused either on the anti-inflammatory effect of curcumin in vitro under various stimuli or on its protection against ER stress in other inflammatory diseases.

Curcumin protects against inflammation and lung injury in rats with acute pulmonary embolism
Molecular and Cellular Biochemistry | April 2021
Curcumin decreased miR-21 expression by downregulating Sp1 to upregulate PTEN and to impair the NF-κB signaling pathway, thus suppressing lung injury and inflammation in APE rats.

Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19
Heliyon Cell Press | March 2021
Curcumin, a bioactive compound in turmeric, exerts diverse pharmacological activities and is widely used in foods and traditional medicines. This review presents several lines of evidence, which suggest curcumin as a promising prophylactic, therapeutic candidate for COVID-19. First, curcumin exerts antiviral activity against many types of enveloped viruses, including SARS-CoV-2, by multiple mechanisms: direct interaction with viral membrane proteins; disruption of the viral envelope; inhibition of viral proteases; induce host antiviral responses. Second, curcumin protects from lethal pneumonia and ARDS via targeting NF-κB, inflammasome, IL-6 trans signal, and HMGB1 pathways. Third, curcumin is safe and well-tolerated in both healthy and diseased human subjects. In conclusion, accumulated evidence indicates that curcumin may be a potential prophylactic therapeutic for COVID-19 in the clinic and public health settings.

Curcumin suppresses the stemness of non‐small cell lung cancer cells
Environmental Toxicology | March 2021
Curcumin has been shown to suppress the progression of lung cancer, however, the underlying mechanisms are largely unknown. Our results suggest that curcumin can attenuate the stemness of lung cancer cells through promoting TAZ protein degradation and thus activating Hippo pathway.

The Effect of Curcumin Supplementation on Overweight or Obese Adults
Nutrients | 2021
Curcumin has been shown to play a beneficial role in obesity management. Therefore, exploring the effects of certain herbs or dietary spices on obesity may be promising. Among these spices, curcumin, which is the primary component of the spice turmeric, has gained great interest for its multiple health benefits. Several randomized controlled trials have investigated the potential favorable effects of curcumin supplementation on anthropometric measures. The aim of this review is to evaluate the effect of curcumin supplementation on the anthropometric indices among overweight or obese adults. Curcumin supplementation may exert beneficial effects against obesity among overweight or obese adults.

Anticancer Mechanism of Curcumin on Human Glioblastoma
Nutrients | 2021
Curcumin is the most studied compound described as a potential anticancer agent due to its multi-targeted signaling/molecular pathways properties. Curcumin possesses the ability to modulate the core pathways involved in GBM cell proliferation, apoptosis, cell cycle arrest, autophagy, paraptosis, oxidative stress, and tumor cell motility. This review discusses curcumin’s anticancer mechanism. Curcuminoids (especially curcumin) have been gaining immense attention because of its anticarcinogenic, antitumor, antioxidant, and anti-inflammatory actions. Curcumin is the most abundant compound and has been widely studied as a potential therapeutic agent in chronic diseases, such as neurodegenerative, cardiovascular, pulmonary, metabolic, and autoimmune diseases. For instance, curcumin was able to restore oxidative stress and DNA methyltransferase (DNMT) functions against diabetic retinopathy. Curcumin also acts as a wound healing promoting agent by facilitating collagen synthesis and fibroblast migration. Several pre-clinical and clinical studies also reported its anticancer effects in colorectal cancer, pancreatic cancer, lung cancer, and GBM. Curcumin can modulate multiple cellular signaling pathways and molecular targets involved in GBM tumor growth, migration, invasion, cell death, and proliferatio. Retinoblastoma (Rb), p53, MAP kinase (MAPK), P13K/Akt, JAK/STAT, sonic hedgehog (Shh), and NF-κB pathways are the most common targeted dysregulated pathways found in GBM and modulated by curcumin. Moreover, curcumin is highly lipophilic and able to cross the blood–brain barrier.

Curcumin + Celecoxib: a synergistic and rationale combination chemotherapy for breast cancer
European Review for Medical and Pharmacological Sciences | March 2021
This study is designed to explore the synergistic inhibitory effect of the combination of curcumin and celecoxib on the growth of human breast cancer cells. Our findings show the prominent anti-proliferative effects of celecoxib and/or curcumin on MDA-MB-231 cells, providing a rationale for further detailed preclinical and potential clinical studies of this combination for breast cancer therapy. Further, these computed parameters suggested that curcumin possesses a high tendency to act as an adjuvant drug with celecoxib in the treatment of breast cancer.

Immune-Stimulatory Effects of Curcumin on the Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma
Cancers | March 2021
Curcumin is known to have immune-modulatory and antitumor effects by interacting with more than 30 different proteins. An important feature of curcumin is the inhibition of nuclear factor kappa of activated B-cells (NF-κB).  Curcumin was more effective in inhibiting PIC-dependent NF-κB activation and Treg attraction compared to known NF-κB inhibitors BAY 11-7082 or caffeic acid phenethyl ester. The presented results show, for the first time, the immune-modulating effects of curcumin in HNSCC, with potent inhibition of the Treg-attracting effects of PIC. Hence, curcumin presents a promising drug in cancer therapy as a supplement to already established treatments.

Curcumin with Promising Protection against Herpesvirus Infections and Their Associated Inflammation
Microorganisms | March 2021
Curcumin is the key component of the yellow pigment and the main bioactive molecule of turmeric. Chemically, this compound belongs to the class of natural phenolic compounds and has been broadly identified in diverse Curcuma spp. In 1910, curcumin was characterized as a symmetrical molecule of two 4-hydroxy-3-methoxyphenyl rings fastened by α,β-unsaturated carbonyl groups, while its synthesis was defined in 1913. Curcumin has been employed widely in the traditional medicine systems of various countries and regions in the world. Since the complete information about chemical structure and synthesis is acquired, curcumin has been extensively studied in various biological assays and has proven to induce numerous pharmacological and beneficial impacts on human health, including but not limited to the potential treatment of various viral infections such as human immunodeficiency virus, hepatitis B virus, hepatitis C virus, influenza A virus, human papillomavirus, respiratory syncytial virus, arboviruses, and noroviruses. Unlike the notable antimicrobial actions, this biomolecule induces several biological effects including but not limited to antioxidant, anti-inflammatory, and anticancer properties. We reviewed the curative properties of curcumin, a principal bioactive phenolic compound of the spice turmeric, in regard to various human and animal herpesvirus infections and inflammation connected with these diseases. According to the reviewed studies, this paper presents curcumin as a promising natural drug for the prevention and treatment of herpesvirus infections and their associated inflammatory diseases. In recent years, curcumin as a nutraceutical agent has attracted major attention in many research fields due to its great therapeutic potential against various biological targets. We have comprehensively reviewed the curative values of curcumin against numerous animal and human herpesviruses along with the mechanisms by which this compound induces antiherpetic properties, which were examined in vitro and in vivo investigations. Based on several structure-activity relationship studies, hydroxyl groups, carbonyl groups, and phenyl rings of curcumin were observed to be accountable for the induced anti-herpesvirus properties. In conclusion, this review proposes curcumin as a potent and safe drug for the therapy of herpesvirus infections as well as inflammation associated with these infections.

Roles of Curcumin in Sensitising the Cisplatin Effect on a Cancer Stem Cell-Like Population Derived from Non-Small Cell Lung Cancer Cell Lines
Molecules | March 2021
Natural compounds such as curcumin that contain high amounts of polyphenols can have a chemosensitivity effect that sensitises CSCs to cytotoxic agents such as cisplatin.  Curcumin significantly suppressed colonies formation by 50% and shrank the spheroids in cancer stem ce subpopulations, indicating inhibition of their self-renewal capability. This effect also was manifested by the down-regulation of SOX2, NANOG, and KLF4. Curcumin also regulated the niche of cancer stem cells  by inhibiting chemoresistance proteins, aldehyde dehydrogenase, metastasis, angiogenesis, and proliferation of cancer-related proteins. These results show the potential of using curcumin as a therapeutic approach for targeting cancer stem cells  subpopulations in non-small cell lung cancer. Curcumin (diferuloylmethane) is a naturally occurring polyphenol extract that is found in turmeric. Curcumin has long been used as a food, cosmetic, and traditional herbal medicine. Significant evidence indicated that curcumin’s anti-cancer potential against many types of cancer, including breast, pancreas, prostate, lung, melanoma, and head and neck cancers. Unlike many ‘targeted’ chemotherapeutic drugs that suffer from toxicity and resistance, curcumin by itself can target specific molecules and pathways without any associated toxicity or resistance. One of the most compelling reasons for exploring curcumin is its sensitiser properties, which influence a diverse range of molecular targets within cells. Combining curcumin with chemotherapy drugs led to the hypothesis that efficacy could be enhanced by adding two or more targeted agents to combat cancer cells’ resistance mechanism. Our previous study has shown that curcumin was able to increase the efficacy of cisplatin

Focus on Multi-targeted Role of Curcumin: a Boon in Therapeutic Paradigm
Environmental Science and Pollution Research | March 2021
After thoroughly studying several articles on combination therapy of curcumin through authenticated book chapters, websites, research, and review articles available at PubMed, ScienceDirect, etc., it has been observed that multi-targeted curcumin possess enormous anticancer potential and, with whatever drug it is given in combination, has always resulted in enhanced effect with reduced dose as well as side effects. It is also capable enough in overcoming the problem of chemoresistance. Combining all the factors together, we can conclude that combination therapy of drugs with curcumin should be explored extensively

Efficacy of curcumin/turmeric on liver enzymes in patients with non-alcoholic fatty liver disease
Integrative Medicine Research | March 2021
Meta-analysis of 4 randomized controlled trials including 228 subjects showed a trend toward significant reduction of ALT blood concentrations in subgroup with ≥1000 mg/day curcumin supplementation. Meta-analysis showed a significant reduction of AST in studies with 8-weeks administration. Conclusion This review suggests that curcumin/turmeric might have a favorable effect on NAFLD in higher dosage.

Curcumin suppresses tumor growth of gemcitabine-resistant non-small cell lung cancer
Clinical and Translational Oncology | March 2021
Curcumin has been reported to block cancer development by modulating multiple signaling pathways. The results showed that curcumin suppressed gemcitabine-resistant non-small cell lung cancer cell proliferation and induced apoptosis. Curcumin upregulated the expression of lncRNA-MEG3 and PTEN, and MEG3 overexpression could increase the level of PTEN expression, while MEG3 knockdown decreased the level of PTEN expression in gemcitabine-resistant non-small cell lung cancer cells. These findings show the antitumor activity of curcumin for potential clinical application in gemcitabine-resistant non-small cell lung cancer treatment.

Curcumin anti‐tumor effects on endometrial cancer with focus on its molecular targets
Cancer Cell International | March 2021
Curcumin is a phenolic antioxidant extracted from turmeric, which is frequently used as a spice and has a yellow color. The rhizome of the herb Curcuma longa is the origin of turmeric that contains turmerin protein as well as analogs of curcumin, demethoxycucumin, and bisdemethoxycurcumin. 1,7-bis(4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione is the chemical name of curcumin and C21H20O6 is its empirical formula. Since curcumin and its two analogs have the same molecular and biological characteristics, it is suggested that bisdemethoxycurcumin converts to demethoxycucumin, which in turn, transforms into curcumin. While curcumin plays a variety of beneficial roles, studies on animals and humans have concluded that it is a safe agent even at high doses. Curcumin acts as an anti-oxidative, anti-microbial, anti-malarial, anti-HIV, and anti-angiogenic agent. Furthermore, it can be used in the treatment of inflammation, skin wounds, and neurodegenerative diseases.  Curcumin has complex chemistry and it is capable of targeting some signaling pathways. Moreover, it can interact with several intracellular and extracellular molecules. These features lead to anti-tumor effects of curcumin on various cancer cells and is useful at different stages, including prevention, treatment, and controlling the symptoms of cancers. There are studies concerned with the anti-tumor effects of curcumin in the treatment of EC. Curcumin plays these roles by involving various targets, such as signaling pathways, proteins, genes, and RNAs. Induction of apoptosis, reducing inflammation, and inhibiting cell migration are the results of curcumin treatment. Furthermore, there are some miRNAs whose effects on EC have been identified and curcumin has been observed to impact on these miRNAs but in other cancers. Altogether, curcumin should be considered as a therapeutic target in EC and its anti-tumor effects on this cancer deserve further exploration.

The protective effects of curcumin in cerebral ischemia and reperfusion injury through PKC-θ signaling
Cell Cycle | March 2021
Curcumin, a known antioxidant, has been found to have neuroprotective effects. To determine the protective mechanism of curcumin in ischemic stroke, oxygen and glucose deprivation/reoxygenation (OGD/R) was used to treat PC12 cells to mimic the cerebral I/R cell model. Our results demonstrated that curcumin could reverse the MCAO/R-induced increase in Ca2+ concentration and blood–brain barrier (BBB) disruption. Our study demonstrates the mechanisms by which curcumin exhibited a protective function against cerebral I/R through PKC-θ signaling by reducing BBB dysfunction.

Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT
Oncology Reports | March 2021
Curcumin, a phytochemical from rhizomes of the plant Curcuma longa, has been reported to exert potential anticancer properties in various cancer types, including acute myeloid leukemia (AML).  The present study demonstrated the anti-AML effect of curcumin both in vitro and in vivo. Collectively, the present study demonstrated that curcumin exerted anti‑acute myeloid leukemia roles by inactivating AKT and these findings may aid in the treatment of acute myeloid leukemia.

Curcumin repairs intestinal mucosal injury induced by 5-FU chemotherapy for colon cancer
National Library of Medicine | March 2021
Curcumin maintained the integrity of mucosal surface and villi structure of jejunum to a large extent, and reduced pathological changes in a dose-dependent manner. Meanwhile, curcumin could increase the positive expression of occludin, claudin and ZO-1(P&lt;0.05 or P&lt;0.01), repair intestinal barrier function, downregulate the protein expression of IL-6, p-STAT3, vimentin and N-cadherin in jejunum tissues(P&lt;0.05 or P&lt;0.01), and upregulate the protein expression of E-cadherin(P&lt;0.05). Therefore, curcumin could repair the intestinal mucosal injury induced by 5-FU chemotherapy for colon cancer, and the mechanism may be related to the inhibition of IL-6/STAT3 signal and the inhibition of epithelial-mesenchymal transition(EMT) process.

Effect of Curcumin, Exelon and their Combination on Brain in Alzheimer’s Disease-Induced Rats
 Journal of Advances in Medicine and Medical Research | March 2021
Curcumin is a natural product derived from Curcuma longa (more commonly known as turmeric). Curcumin has anti-inflammation and antioxidant activities, so it can decrease inflammation, amyloid accumulation and oxidative stress which has ability to scavenge free radicals. Also, it has protective potent from lipid peroxidation, and scavenges nitric oxide (NO)-based radicals. Curcumin has ability to inhibit formation of Aβ plaques and lower soluble Aβ levels due to its metal chelation properties as it binds to redox-active metal ions such as iron and copper. These complexes may cause a net protective effect through decreased Aβ aggregation. Curcumin is safe product which large quantities can consumed without toxicity. The results obtained from the present study revealed that curcumin can be effective in various types of oxidative associated Alzheimer’s disease and encouraged further in vitro studies to realize the accurate bio efficacy and bioavailability pathways of curcumin. Regarding the above-mentioned results which demonstrated the biological activities of curcumin in either protecting or treating brain, it is highly recommended to estimate curcumin as a safe and effective natural product for oxidative associated Alzheimer’s diseases. According to these results, curcumin as a dietary supplement has a protective role against the beginning of Alzheimer’s diseases. The intake of a significant content of curcumin in the daily regimen or as dietary supplementation along with specific therapeutic options can provide perfect prevention and treatment for Alzheimer’s diseases.

Synergistic Roles of Curcumin in Sensitising the Cisplatin Effect on a Cancer Stem Cell-Like Population Derived from Non-Small Cell Lung Cancer Cell Lines
Molecules | March 2021
Significant evidence indicated that curcumin’s anti-cancer potential against many types of cancer, including breast, pancreas, prostate, lung, melanoma, and head and neck cancers. Unlike many ‘targeted’ chemotherapeutic drugs that suffer from toxicity and resistance, curcumin by itself can target specific molecules and pathways without any associated toxicity or resistance. One of the most compelling reasons for exploring curcumin is its sensitiser properties, which influence a diverse range of molecular targets within cells. Combining curcumin with chemotherapy drugs led to the hypothesis that efficacy could be enhanced by adding two or more targeted agents to combat cancer cells’ resistance mechanism. Our previous study has shown that curcumin was able to increase the efficacy of cisplatin by enhancing the cisplatin-induced metastatic inhibition and apoptosis of the highly migratory CSC subpopulation of NSCLC cell lines.Natural compounds such as curcumin that contain high amounts of polyphenols can have a chemosensitivity effect that sensitises CSCs to cytotoxic agents such as cisplatin.  Results show the potential of using curcumin as a therapeutic approach for targeting CSC subpopulations in non-small cell lung cancer. Results of this study show that either alone or in combination with cisplatin, curcumin can suppress CSC properties; thus, it could be an effective therapeutic strategy to prevent the emergence of chemoresistance in NSCLC by eliminating CSCs.

How curcumin affects hyperglycemia-induced optic nerve damage: A short review
Journal of Chemical Neuroanatomy | March 2021
Curcumin is effective in preventing the progression of diabetic complications and improving complications. Curcumin has healing effects in optic nerve damage with its anti-oxidant properties.

Effects of curcumin administration on Nesfatin-1 levels in blood, brain and fat tissues of diabetic rats
European Review for Medical and Pharmacological Sciences | March 2021
Curcumin administration caused significant improvement in fasting blood glucose levels.  For the first time, we found marked improvements in nesfatin-1 levels in blood, brain, and fat tissues of type 2 DM rats. Thus, considering the crucial role of nesfatin-1 in regulation of glucose metabolism, it is logical to expect an interactive relationship between curcumin and nesfatin-1.

Curcumin Supplementation Enhances Bone Marrow Mesenchymal Stem Cells to Promote the Anabolism of Articular Chondrocytes and Cartilage Repair
Cell Transplantation | March 2021
Curcumin displayed multiple pharmacological activities including anti-inflammatory, antioxidant, and anticancer, and has been employed in different studies involving several pathologies such as cardiovascular disease, depression, Alzheimer’s disease, epilepsy, Parkinson’s disease, cancer, osteoporosis, rheumatic arthritis, and osteoarthritis. It could inhibit the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) and synthesis of reactive oxygen species by reducing the production of IL-1, IL-6, IL-8, and tumor necrosis factor α via various pathways, and is emerged as an effective therapeutic agent. For osteoarthritis treatment, curcumin supplementation exhibited effects mainly based on its anti-inflammation, antioxidant, and antiapoptosis potentials15. In clinical trials, curcumin served as a natural product medicine displayed nearly no side effects, thus making it a potential alternative to NSAIDs and some other medications with known severe adverse effects. In the current study, curcumin enhanced the BMSC function for the proliferation and migration of articular chondrocytes, and anabolic gene expression of ECM in articular chondrocytes in vitro, and the regeneration of articular cartilage in vivo. These results indicated potential clinical application of curcumin cooperation with BMSCs in cartilage repair for osteoarthritis treatment.

Curcumin for amyloidosis and lipid metabolism - a novel insight
eLife Shinshu University | March 2021
Curcumin is a polyphenol compound produced by plants of the Curcuma longa species and has been reported to have many physiological activities, which include anti-oxidation, anti-inflammatory, anti-cancer, and anti-amyloid properties. In previous studies, curcumin has been shown to suppress the aggregation and cytotoxicity of many amyloid proteins in vitro, such as amyloid ß (Aß), α-synuclein, transthyretin, and prion protein, and has also been reported to inhibit the deposition of Aß fibrils in a mouse model of Alzheimer's disease.  These findings demonstrate the novel agonistic effect of curcumin on PPARα, which is an important transcription factor for lipid metabolism, and may have far-reaching significance for the treatment of amyloidosis and other metabolic disorders. In addition, it has been regarded that curcumin, as an agonist of PPARγ, exerts anti-inflammatory, anti-cancer and antioxidant activities in the past. However, this study demonstrates that curcumin is a PPARα/γ dual activator and may affect expression levels of proteins involved in amyloid deposition and other metabolism functions in a complex manner. By focusing on the PPARα pathway, the group hope to provide an opportunity to reconsider the mechanism of the physiological effects of curcumin.

A protective effect of curcumin on cardiovascular oxidative stress indicators in systemic inflammation induced by lipopolysaccharide in rats
Biochemistry and Biophysics Reports | March 2021
Administration of curcumin attenuated oxidative stress and inflammation in the serum, aorta and heart tissues induced by lipopolysaccharide LPS.

Anti-inflammatory Effect of Curcumin on Human Vitreous in Patients With Diabetic Retinopathy
Frontiers in Neurology | March 2021
Curcumin, a yellowish non-flavonoid polyphenol that constitutes the main active compound of Curcuma longa, is widely known for its antioxidant and anti-inflammatory properties. Many studies have also described its marked protective effect on retinal cells against oxidative stress and inflammation. Curcumin is a well-known bioactive molecule, largely employed in supplement formulation due to its anti-inflammatory properties. Our study highlighted the ability of curcumin to reduce cytokine levels in the vitreous of diabetic patients. We also observed an additional anti-inflammatory effect when curcumin was combined with homotaurine and vitamin D3, suggesting that these molecules can regulate the inflammatory network between the vitreous and retina at different levels. This effect is confirmed by the gene expression experiment which demonstrated that the combination of curcumin, vitamin D3, and homotaurine down-regulate the cyclinD1 gene and the pro-inflammatory cytokine genes TNFα and IL6 expression.

Curcumin protects cells from oxidative stress and inflammation
International Journal of Molecular Medicine | March 2021
Curcumin is a well‑known antioxidant, the present study demonstrates that curcumin protects BEAS‑2B cells against PM2.5‑induced oxidative damage and inflammation, and prevents cell apoptosis by increasing the activation of NRF2‑related pathways. It is thus suggested that curcumin may be a potential compound for use in the prevention of PM2.5‑induced tissue injury.

Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle
British Journal of Nutrition | March 2021
Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cAMP levels. The present results suggest that curcumin increases cAMP levels via inhibition of PDE4A phosphorylation, which induces mitochondrial biogenesis through a cAMP/PKA/AMPK signalling pathway. Our data also suggest the possibility that curcumin utilizes a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.

Catechin and curcumin interact with S protein of coronavirus SARS-CoV2 and ACE2 of human cell membrane
Scientific Reports | February 2021
Several recent studies have suggested that natural polyphenolic compounds like catechins (GTCs; Green Tea Catechins) and curcumin (diferuloylmethane; from turmeric) have antiviral activities against a broad spectrum of viruses such as Human Immunodeficiency Virus (HIV), Herpes Simplex Virus, Influenza Virus, Hepatitis B and C Viruses (HBV and HCV respectively)14, Adenovirus15 and Chikungunya virus (CHIKV). Diverse mechanisms have been suggested to explain the antiviral activities of both the polyphenolic compounds. Curcumin has been demonstrated as a potent inhibitor of monophosphate dehydrogenase, a rate limiting enzyme in the de novo synthesis of guanine nucleotide22. Further, it has also been observed that GTCs and curcumin inhibit the expression of ACE2, as evident from animal studies.Both catechin and curcumin bind the interface of ‘RBD/ACE2-complex’ and intervene in causing fluctuation of the alpha helices and beta-strands of the protein complex. Protein–protein interaction studies in presence of curcumin or catechin also corroborate the above findings suggesting the efficacy of these two polyphenols in hindering the formation of S Protein-ACE2 complex. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols for therapeutic strategy against SARS-CoV2.

ASU study looks at how Curcumin supplements might help post-COVID
AZFamily.com | February 2021
Researchers at Arizona State University are conducting a study into if whether or not two supplements can help reduce inflammation after having COVID-19. An ASU grad student is part of a research team, hoping to learn whether or not two supplements reduce inflammation after COVID-19. "It can either be Curcumin, which comes from the spice turmeric," said ASU Grad Student Samantha Fessler. "...the other one is Palmitoylethanolamide, and that comes from things like eggs and peanut oil...using these supplements with the flu, they've been proven to improve inflammation associated with the flu viral infection and also post-recovery from other types of chronic issues."

The potential role of curcumin in the prevention of COVID-19
Archives of Microbiology | February 2021
Due to the new coronavirus’ unexplored nature, we shed light on curcumin for its potential role against the disease. The current study showed the use of curcumin against the coronavirus and its possible role in developing medicine against it. Curcuma longa produces turmeric (diferuloylmethane), named Indian saffron in Europe, with its medicinal uses, including antiviral and anti-inflammatory actions. It has shown that curcumin has its inhibitory effects on the virus, including HIV, smallpox, measles, and chickenpox are being among its target. In the current study, we showed the possible use of curcumin in the prevention of COVID-19 by targeting the virus replicase protein Nsp9. Turmeric is the principle source of curcumin, and in India it is used as an essential daily ingredient in the food preparation while it has its own antiviral, antifungal, antiallergic properties. Hence, it is preferred over other medicinal compounds in the present study. As curcumin also showed the antiviral properties, the interaction of curcumin and Nsp9 may be useful in understanding the novel SARS Cov-2.  This supports the use of curcumin to reduce the pathological consequences that emerged due to coronavirus infection. So, by targeting the ssRNA of coronavirus at its initial replication stage, through curcumin, when it enters the human is a matter of immediate in-vivo research to possibly overcome the COVID-19 and explore the inhibitory pathways of curcumin to prevent the new coronavirus replication machinery in the human system.

Curcumin: reclaiming the lost ground against cancer resistancee leydig testosterone
Cancer Drug Resistance | February 2021
Curcumin, a polyphenol, has a wide range of biological properties such as anticancer, antibacterial, antitubercular, cardioprotective and neuroprotective. Moreover, the anti-proliferative activities of Curcumin have been widely studied against several types of cancers due to its ability to target multiple pathways in cancer. A large number of reported studies and increasing interest of researchers have reinforced the claim of curcumin being one of the most sought after natural product in the fight against cancer. Curcumin, is a polyphenolic compound of up to 5% present in turmeric. Curcumin as a phytochemical has been widely explored for its therapeutic potential through in vitro and in vivo investigations. It has been shown to possess biological activity against a large spectrum of physiological conditions, which include antioxidant, chemo-protective, anti-diabetic and anti-proliferative activity against cancer cells. Curcumin has shown commendable potential during in vitro and in vivo studies against vrious cancers. It has also been established through clinical trials that curcumin does not show any adverse effect upto a daily dose of 8 g to 12 g. The combinatorial treatment of curcumin has been shown to sensitize the drug-resistant cancer towards existing anticancer drugs and this aspect of combinatorial treatment can be exploited to fully utilize the curative potential of curcumin. In the near future, curcumin may play an important role in chemotherapeutic regimes against different types of cancers.

Curcumin has the potential to improve motor skills in Parkinson’s disease
Emerging Investigators | February 2021
Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice widely used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of Parkinson’s disease strongly support the clinical application of curcumin in Parkinson’s disease. With India’s apparent resistance to Parkinson’s disease and the Parkinson’s disease clinical applications done with a spice Indians use almost daily, curcumin becomes a logical treatment in PD cases.  Curcumin does have an impact on Parkinson’s disease symptoms, we can conduct further experimentation to see which amount of curcumin in diets have an optimal impact of curcumin in the brain.

A Review of the Possible Effects of Curcumin in the Treatment of COVID-19
Journal of Military Medicine | February 2021
Curcumin is a natural polyphenolic compound, which could be a potential treatment option for patients with Covid-19. In this study, we review some of the possible effects of curcumin, such as inhibiting virus entry into the cell, inhibiting virus replication and viral protease, as well as modulating some intracellular messenger pathways. To comprehensive literature review, information from an internet search of English language databases PubMed, Scopus, Web of Science and ScienceDirect as well as Persian language databases such as SID using related keywords based on MESH such as COVID-19, SARS-COV-2 , Curcumin and curcuminoid between January 2020 and January 2021 were collected. This review provides some possible effects of curcumin and its mechanisms for the treatment of COVID-19.

Ten Days of Curcumin Supplementation Attenuates Subjective Soreness and Maintains Muscular Power Following Plyometric Exercise
Journal of Dietary Supplements | February 2021
Curcumin has become a popular product used to decrease inflammation and enhance recovery from exercise. Purpose: To determine the effects of curcumin supplementation on delayed onset muscle soreness and muscle power following plyometric exercise. Conclusion: These data suggest curcumin reduces soreness and maintains muscular power following plyometric exercise.

Curcumin: Natural Antimicrobial and Anti Inflammatory Agent
Journal of Pharmaceutical Research International | February 2021
Various studies, conducted as in vitro assays, have revealed different therapeutic applications of curcumin due to its different molecular mechanisms. Findings of the present in vitro study confirmed consideration of curcumin as a natural antimicrobial and anti-inflammatory agent. Test curcumin solutions demonstrated strong antibacterial, antifungal and anti-inflammatory activity. With an increase of curcumin concentration antimicrobial and anti-inflammatory activity increased, which implied that observed activity is dependent upon the concentration of curcumin. In conclusion, the present study emphasises the potential application of curcumin as a natural antimicrobial and anti-inflammatory agent.

Oral supplementation of curcumin for three months reduces p-CS plasma levels in hemodialysis patients, suggesting a gut microbiota modulation
 International Urology and Nephrology | February 2021
Nutritional strategies, such as bioactive compounds present in curcumin, have been proposed as an option to modulate the gut microbiota and decrease the production of uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS) and indole-3 acetic acid (IAA). After three months of supplementation, the curcumin group showed a significant decrease in pCS plasma levels [from 32.4 (22.1–45.9) to 25.2 (17.9–37.9) mg/L, p = 0.009], which did not occur in the control group.

Management of altered metabolic activity in Drosophila model of Huntington’s disease by curcumin
bioRxiv | February 2021
Curcumin is bioactive component of turmeric (Curcuma longa Linn), well-known for its ability to modulate metabolic activities. We found that curcumin effectively managed abnormal body weight, dysregulated lipid content and carbohydrate level in Huntington’s disease flies. In addition, curcumin administration lowered elevated reactive-oxygen-species (ROS) levels in adult adipose tissue of diseased flies, and improved survival and locomotor function in Huntington’s disease flies at advanced disease stage. Altogether, these findings clearly suggest that curcumin efficiently attenuates metabolic derangements in Huntington’s disease flies and can prove beneficial in alleviating the complexities associated with Huntington’s disease. Phytochemicals like curcumin that can regulate multiple targets in complex diseases like Huntington’s disease, with least side-effects and maximum benefits, provide a better hope for the treatment of terminally-ill Huntington’s disease patients. Our findings show that curcumin is beneficial in suppression of neurodegeneration with amelioration of metabolic dysregulation. Though curcumin may not completely prevent neurodegeneration or metabolic impairments during terminal stages, it can effectively delay the inception and progression of HD at initial and moderate disease forms. Therefore, curcumin may prove to be a safe and suitable treatment regimen for management of HD that could be of great relief for the patients.

Effects of Curcumin on Glycemic Control and Lipid Profile in Polycystic Ovary Syndrome
Nutrients | February 2021
Curcumin has been studied to adjunctly treat broad spectrum of disease from type 2 diabetes mellitus to telogen effluvium. Curcumin elicits antidiabetic effects via several mechanisms, including the increase in glycolysis and glycogen synthesis and the decrease in gluconeogenesis in the liver, as well as the increase in glucose uptake, glycolysis, and glycogen synthesis in the skeletal muscle. Curcumin has also been known to reduce plasma cholesterol and triglyceride by increasing the activity of lipoprotein lipase and through mechanisms which alter lipid and cholesterol gene expression. In addition, the anti-inflammatory effects of curcumin have been demonstrated to reduce the oxidative stress in patients with PCOS. Previous literature reveals that curcumin significantly improves fasting blood glucose and triglyceride in patients with metabolic syndrome. In vivo study further demonstrates similar effects in the PCOS model. Curcumin significantly improves fasting glucose, fasting insulin, Homeostasis Model Assessment of Insulin Resistance, and quantitative insulin sensitivity check index. It also significantly improves high-density lipoprotein and total cholesterol. Curcumin may improve glycemic control and lipid metabolism in patients with PCOS and metabolic abnormality without significant adverse effects.  Curcumin may improve glycemic control and lipid metabolism in patients with PCOS and metabolic abnormality without significant adverse effects. Further studies are advocated to investigate the potential effects of curcumin on hyperandrogenism.

Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia
Oncology Reports | February 2021
Curcumin is the main polyphenol component extracted from rhizomes of the plant Curcuma longa, and its therapeutic benefit has been demonstrated in various cancer types, including AML. However, the underlying mechanism is complex and remains poorly understood, as curcumin has multiple targets and is involved in various signaling pathways. Previous studies have reported that curcumin can exert its antitumor effects by acting as an inhibitor of kinases, such as protein kinase B (AKT/PKB) in head and neck cancer cells, JAK1 in retinoblastoma cells and p38MAPK in endothelial cells. The present study demonstrated the anti‑AML effect of curcumin both in vitro and in vivo, and this effect was increased by the combination with afuresertib. Afuresertib has been reported to exert antitumor effects in ovarian cancer, malignant pleural mesothelioma and chronic lymphocytic leukemia. However, to the best of our knowledge, its role in AML has not been previously reported. The present study was the first report that afuresertib could potentially be used for the treatment of AML.In conclusion, the present study demonstrated that curcumin decreased the survival and proliferation of AML cells in vitro, as well as AML cell proliferation in hematopoietic tissue and dissemination into non‑hematopoietic tissues. Mechanistically, curcumin treatment suppressed AKT activation, leading to cell cycle arrest and apoptosis.

The Multifaced Actions of Curcumin in Pregnancy Outcome
Antioxidants | February 2021
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), also known as diferuloylmethane, is a polyphenolic yellow substance coming from the rhizomes, the most commonly used plant part, of Curcuma longa Linn (Zingiberaceae family). Curcumin structure is similar to other bioactive non-volatile curcuminoids such as dimethoxy-curcumin and bisdemethoxy-curcumin, differing only for the number of methoxy groups on their aromatic rings. This plant has been used since ancient times for both food and pharmaceutical purposes, showing a variety of beneficial effects in the organism reducing glycemia, hyperlipidemia, insulin resistance  and steatosis in non-alcoholic fatty liver disease (NAFLD). Moreover, due to the cytotoxic effects of curcumin on tumor cells, this compound showed good effects also as an anticancer agent inhibiting tumor proliferation and inducing apoptosis in many cancer types including breast, colon, lung and gastric cancer. In addition, curcumin showed anti-metastatic, radioprotective and chemosensitizer effects reducing the adverse effects of chemotherapeutic drugs. Curcumin is generally recognized as a safe substance and its use in humans did not show any toxic effects at the dose of 6 g/day orally for 4–7 weeks. Curcumin has been extensively studied in various fields, showing a wide range of action, including Antioxidant, anti-inflammatory, anti-toxicant, anti-apoptotic, anti-diabetic and immunomodulatory actions, demonstrated by in vitro studies and animal models, suggest the use of this compound as a therapeutic agent in counteracting several pregnancy complications. Inflammation, oxidative stress, Reactive Oxygen Species (ROS) generation and apoptosis are common conditions usually found in almost all of the pathological placental conditions mentioned above; for this reason, curcumin could play a key role in improving pregnancy outcome in these complications. To date, there are many clinical trials studying the efficacy of curcumin in many types of cancer that generally consider curcumin as well tolerated and efficient adjuvant therapy ameliorating the response to chemotherapy and radiotherapy reducing the side effects of these therapies. Clinical effects of curcumin have also been shown in other pathologies. In fact, curcumin improved the severity of patients affected by non-alcoholic fatty liver diseases (NAFLD) disease decreasing the serum concentrations of inflammatory cytokines and chemokines such as TNF-α and MCP-1. Moreover, curcumin intake in women with polycystic ovarian syndrome (PCOS) significantly increased gene expression of PGC1α and activity of the Gpx enzyme reducing oxidative stress. Another clinical trial showed that curcumin was able to improve the symptoms in patients affected by knee osteoarthritis. Beneficial curcumin effects were also found in clinical trials focused on its role in body weight regulation, finding a role for curcumin in reducing BMI and increasing weight loss in addition to decreased serum levels of IL1β, IL-4 and VEGF. Moreover, curcumin administration in two clinical trials showed that curcumin could decrease glucose levels in patients with type 2 diabetes mellitus. Due to its multifaced role in regulating different signaling and the encouraging data obtained in animal models and in vitro studies, curcumin intake during pregnancy could be beneficial in almost all the pregnancy complications mentioned in this review.

Antioxidant Activity of Curcumin Protects against the Radiation-Induced Micronuclei Formation
International Journal of Radiation Biology | February 2021
Curcumin when treated at a dose of 0.5 μg/mL attenuated micronuclei formation after γ-irradiation by inhibiting the formation of radiation-induced free radicals.

Curcumin significantly alleviated cognitive deficits induced by cerebral ischemia.
Brain Research | February 2021
Curcumin ameliorates acute cerebral ischemia-induced cognitive dysfunction in mice. Curcumin promotes hippocampal NSCs proliferation and differentiation into neurons. Curcumin promotes hippocampal neurogenesis through Wnt/β-catenin signaling pathway.

Recent Advances in the Synthesis and Development of Curcumin, its Combinations, Formulations and Curcumin-like Compounds as Antiinfective Agents
Current Medicinal Chemistry | February 2021
Curcumin, a redox-active natural product, has for centuries been used in Asian traditional medicine for the treatment of various diseases. It is known for possessing multiple biological and pharmacological activities. Curcumin has been investigated extensively over the years for its anti-inflammatory, anticancer, antiparasitic, antiviral and antibacterial activities, and no toxicity is associated with the compound. Despite its potency and safety profile, curcumin is still in clinical trials for the treatment of diseases, such as tuberculosis, acquired immunodeficiency syndrome (AIDS), Crohn's disease, colorectal cancer and multiple myeloma, among many others, as it is yet to be qualified as a therapeutic agent.

The effect of curcumin on serum copper, zinc, and zinc/copper ratio in patients with β-thalassemia intermedia: a randomized double-blind clinical trial
Annals of Hematology | February 2021
Due to its significant therapeutic effects, curcumin has led many studies to focus on curcumin.  Curcumin might exert a net protective effect on copper toxicity in thalassemia intermedia patients. The investigation also implicated that curcumin represents an approach to regulating zinc homeostasis and may be useful as a complementary treatment of patients with thalassemia intermedia, especially in patients with zinc deficiency or low serum zinc/copper ratio.

Curcumin promotes AApoAII amyloidosis and peroxisome proliferation in mice by activating the PPARα signaling pathway
Elife | February 2021
Curcumin is a polyphenol compound that exhibits multiple physiological activities. Curcumin, a polyphenol compound, is extracted from the rhizome of Curcuma longa and has a long history of use in traditional medicines. In in vitro experiments, curcumin has been shown to suppress the aggregation and cytotoxicity of Aβ, αSyn, islet amyloid precursor protein (IAPP), ATTR and prion protein (PrP). In 2001, the first evidence of the efficacy of curcumin against Aβ amyloidosis in a transgenic model mice was reported. Curcumin was found to suppress amyloid deposition in a mouse model of Alzheimer's disease and improve memory function. It was subsequently demonstrated that the amount of amyloid present in TTR-and tau-transgenic mice were reduced by curcumin supplementation. Curcumin is a compound with multiple physiological activities, which includ eanti-oxidation, anti-inflammatory, anti-cancer, lipid metabolism regulation and anti-amyloid properties.

Curcumin and Metabolic Diseases: The Role of Gut Microbiota
Nutrients | January 2021
Turmeric, also known as Curcuma longa L. belongs to Zingiberaceae (or ginger family) and is a golden-colored spice. Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is the principle curcuminoid of turmeric used in traditional medicine to cure various kinds of malady, as well as being a food additive and coloring agent in Asian cuisines and in beverage industries. Hewlings and Kalman stated the beneficial effects of curcumin in the treatment of chronic diseases, such as gastrointestinal, neurological disorders, cardiovascular disease, diabetes, and several types of cancer. Enzymes of the large intestine metabolise curcumin, and it is carried out in two phases. In phase-1 metabolism, it yields three metabolites, 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin), 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-3-heptanone (hexahydrocurcumin), and 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-diol (octahydrocurcumin) under reduction. After that, curcumin and its metabolites subject to conjugation through phase-II metabolism to yield sulfate and glucuronide O-conjugated metabolites. Curcumin metabolites have properties and potency similar to curcumin and exhibit the same physiological and pharmacological properties. It has been stated that curcumin and gut microbiota have bidirectional interactions such as gut microbiota regulation by curcumin and biotransformation of curcumin by gut microbiota.  Carmody et al reported that the biological properties of curcumin depend on the activity of metabolites produced by gut microbiota digestion. The curcumin metabolic pathways by GM include reduction, methylation, demethoxylation, hydroxylation, and acetylation, and the main products are 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (tetrahydrocurcumin), 3-(4-Hydroxy-3-methoxyphenyl)propanoic acid (dihydroferulic acid), and 1-(4-hydroxy-3-methoxyphenyl)-2-propanol. Furthermore, curcumin can also be metabolized by Pichia pastoris into four major metabolites, include 1,7-bis(4-hydroxy-3methoxyphenyl) heptan-3,5-diol, 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl) heptan-3-one, 5-hydroxy-1,7-bis(4-hydroxyphenyl) heptane-3-one, and 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl) heptan-3-one [101,103]. Many GM, such as E. coli, E. fergusonii (ATCC 35469) Blautia sp. (mrg-pmf1), Bifidobacterium (Bifidobacteria longum BB536, Bifidobacteria pseudocatenulaum G4), Lactobacillus (Lactobacillus casei and Lactobacillus acidophilus), Enterococcus faecalis JCM 5803, Pichia anomala, and Bacillus megateriumdcmb-002, are found biologically relevant in the biotransformation and degradation of curcumin.

Curcumin, a traditional spice component, can hold the promise against COVID-19?
European Journal of Pharmacology | January 2021
Curcumin, known for its pharmacological abilities especially as an anti-inflammatory agent, can be hypothesized as a potential candidate in the therapeutic regimen. COVID-19 has an assorted range of pathophysiological consequences, including pulmonary damage, elevated inflammatory response, coagulopathy, and multi-organ damage. This review summarizes the several evidences for the pharmacological benefits of curcumin in COVID-19-associated clinical manifestations. Curcumin can be appraised to hinder cellular entry, replication of SARS-CoV-2, and to prevent and repair COVID-19-associated damage of pneumocytes, renal cells, cardiomyocytes, hematopoietic stem cells, etc. The modulation and protective effect of curcumin on cytokine storm-related disorders are also discussed. Collectively, this review provides grounds for its clinical evaluation in the therapeutic management of SARS-CoV-2 infection.

The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19
Metabolism | January 2021
The antiviral actions of curcumin against multiple viruses (influenza and hepatitis viruses, herpes viruses, human papilloma virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus and other coronaviruses), bacteria and fungi have been established by experimental evidence. Remarkably, recent evidence from in silico studies has demonstrated that curcumin prevents SARS-CoV-2 entry into cells by blocking the viral binding sites and the cell ligands (spike protein, ACE-2 receptors and basigin), downregulating trans-membrane serine protease 2 (TMPRSS-2), and by interfering with viral replication through the interaction with various viral proteins Curcumin (diferuloylmethane) is a natural phenol found in turmeric (Curcuma longa), a member of the ginger family of plants. Curcumin modulates inflammation preventing the subsequent cytokine storm by inhibiting multiple transcription factors such as nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT-3), and downregulating the proinflammatory cytokines, as this has been demonstrated in human macrophages after influenza virus infection. Additionally, curcumin inhibits ACE modulating angiotensin II synthesis and downregulating inflammation, while it also promotes fibrinolysis and the anticoagulation process. Notably, bromelain substantially increases the absorption of curcumin after oral administration. To the best of our knowledge, this is the first report highlighting the significance of bromelain and, most importantly, the potential preventive value of the synergistic effects of bromelain and curcumin against severe COVID-19.

The potential anti-cancer properties of curcumin in liver cancer
In Vivo | January 2021
Curcumin is a polyphenol that exerts a variety of pharmacological activities and plays an anti-cancer role in many cancer cells. Curcumin increased the expression of the GSDME N-terminus and proteins involved in pyrolysis, promoted HspG2 cell pyrolysis and increased intracellular ROS levels. Moreover, inhibition of the production of intracellular ROS with n-acetylcysteine (NAC) improved the degree of apoptosis and pyrolysis induced by curcumin. Curcumin induces HspG2 cell death by increasing apoptosis and pyroptosis, and ROS play a key role in this process.  This study improves our understanding of the potential anti-cancer properties of curcumin in liver cancer.

The role of curcumin, a potent constituent of turmeric in pleiotropic health beneficial effects
 Journal of Biologically Active Products from Nature | January 2021
Curcumin (1,6- heptadiene- 3,5 - dione- 1,7 - bis (4-hydroxy-3-methoxyphenyl) - (1E,6E) or diferuloylmethane), isolated from Curcuma longa, is a highly promising natural compound that has several health benefits.  Supplementation of curcumin provided significant (p < 0.05) protection against HgCl2 induced alterations by ameliorating the levels of ROS, PCO, SA, and -SH in erythrocytes membrane and plasma. Thus, the curcumin protects against HgCl2 induced oxidative stress. It also provides an insight into the role of curcumin, a potent constituent of turmeric in pleiotropic health beneficial effects.

 Anti-inflammatory effects of oral supplementation with curcumin: a systematic review and meta-analysis of randomized controlled trials
Nutrition Reviews | January 2021
Curcumin, a bioactive polyphenol from turmeric, is a well-known anti-inflammatory agent in preclinical research. Thirty-two trials (N = 2,038 participants) were included and 28 were meta-analyzed using a random-effects model; effect sizes were expressed as Hedges’ g (95%CI).  Pooled data (reported here as weighted mean difference [WMD]; 95%CI) showed a reduction in C-reactive protein (−1.55 mg/L; −1.81 to −1.30), interleukin-6 (−1.69 pg/mL, −2.56 to −0.82), tumor necrosis factor α (−3.13 pg/mL; −4.62 to −1.64), IL-8 (−0.54 pg/mL; −0.82 to −0.28), monocyte chemoattractant protein-1 (−2.48 pg/mL; −3.96 to −1.00), and an increase in IL-10 (0.49 pg/mL; 0.10 to 0.88), with no effect on intracellular adhesion molecule-1.  These findings provide evidence for the anti-inflammatory effects of curcumin and support further investigation to confirm dose, duration, and formulation to optimize anti-inflammatory effects in humans with chronic inflammation.

Curcumin has been reported to exhibit protective effects on degeneration in articular cartilage diseases
Cell Biology International | January 2021
Articular cartilage damage and chondrocyte apoptosis are common features of rheumatoid arthritis and osteoarthritis. Curcumin pretreatment reduced IL‐1β‐induced articular chondrocyte apoptosis. Additionally, treatment with curcumin increased autophagy in articular chondrocytes, and protected against IL‐1β‐induced apoptosis.  These results indicate that curcumin may suppress IL‐1β‐induced chondrocyte apoptosis through activating autophagy and restraining NF‐κB signaling pathway.

Curcumin, the primary active ingredient in turmeric, reportedly exerts potent antifibrotic effects
Basic & Clinical Pharmacology & Toxicology | January 2021
These results indicate that curcumin is a promising treatment agent for RIF, and its antifibrotic effects may be mediated by the inhibition of NLRP3 inflammasome activity through the regulation of autophagy and protection of mitochondrial function in UUO rats.

Curcumin Suppresses Cell Growth
Life Sciences | January 2021
Curcumin induced Ac-p53 and p21 to suppress cell proliferation.  Curcumin increased p-Akt and attenuated fluoride-mediated apoptosis and DNA damage.  Curcumin suppressed fluoride-induced p-p21 and increased p21 in the nuclear fraction.

Dichloroacetic acid-induced dysfunction in rat hippocampus and the protective effect of curcumin
Metabolic Brain Disease | January 2021
Various doses of curcumin attenuated DCAA-induced oxidative stress, inflammation response and impaired synaptic plasticity, while elevating cAMP, PKA, p-CREB, BDNF, PSD-95, SYP levels. Thus, curcumin could activate the cAMP-PKA-CREB signaling pathway, conferring neuroprotection against DCAA-induced neurotoxicity.

Curcumin protects radiation-induced liver damage in rats through the NF-κB signaling pathway
Complementary Medicine and Therapies | January 2021
Curcumin has been demonstrated to exert anti-oxidant, anti-fibrotic, anti-inflammatory, and anti-cancer activities. Our study highlights that curcumin treatment reduces the liver damage caused by radiation through the inhibition of the NF-κB pathway.

 Oral administration of curcumin shows hepatoprotective effects
Environmental Toxicology | January 2021
Curcumin pretreatment develops an amelioration of these effects in APAP‐overdose, R‐exposure, or R/APAP treatments. In conclusion, oral administration of curcumin shows hepatoprotective effects against APAP‐overdose induced hepatic damage in normal and gamma‐irradiated rats through prospective regulation of the therapeutic targets CYP2E1, Nrf2, and NF‐κB, via organizing the miR‐122 and miR‐802 gene expression.

Curcumin, as a good all-natural drug for the treatment of IBD, possesses good prospects in clinical application
Molecular Medicine Reports | January 2021
Curcumin is an all-natural compound extracted from plants. It has many biological activities including anti-inflammatory, anti-infective and immune-regulating, and it protects the intestinal mucosa and repairs the function of intestinal tissue. Other similar studies have shown that in the DSS-induced colitis model, curcumin is found to significantly improve intestinal inflammation, repair the intestinal mucosa and inhibit the expression of TNF-α and p38MAPK. Curcumin itself has anti-inflammatory and anti-infective effects. At the same time, curcumin can reduce and inhibit the exudation of neutrophils and macrophages, regulate intestinal immune disorders, reduce intestinal endothelial cell swelling and increase permeability, which further reduces intestinal inflammation. Curcumin can significantly decrease the DAI and SI of the mice with colitis. Curcumin, as a good all-natural drug for the treatment of IBD, possesses good prospects in clinical application.

Effect of Curcumin on Triple-Negative Breast Cancer
AIP Conference Proceedings | January 2021
Curcumin has been reported to efficiently inhibit cancer cell lines, including MCF7, K562, HeLa,and 4T1. Previous study of curcumin on 4T1 breast cancer cells showed that the IC50 values were 93,14 μM. The main mechanisms of action by which curcumin exhibits its 040024-2 unique anti-cancer activity include inducing apoptosis and inhibiting proliferation, invasion, and metastasis of tumors by suppressing a variety of cellular signaling pathways. Several research on various breast cancer cell lines demonstrate the anti-cancer activity of curcumin through the inhibition of NF-κB activity.  Curcumin, the yellow pigment isolated from turmeric, has been reported to suppress NF-κB. Several studies reported that curcumin inhibits NF-κB through inhibition of IKK phosphorylation and inhibition of translocation to the nucleus. Curcumin selectively inhibits NF-κB p105 mRNA expression on 4T1 breast cancer cell line by interacting with the backbone of Ile residue in RH domain region. This study highlights the potency of curcumin to be developed as a chemotherapeutic targeted NF-κB for triple-negative breast cancer in the future.

Curcumin has a certain antagonized effect on cardiac arrhythmia and has potential application prospects
Frontiers in Physiology | January 2021
Curcumin is a natural yellow polyphenolic substance, the main active alkaloid extracted from the rhizome of turmeric, a rhizomatous herbaceous perennial plant belonging to the family Zingiberaceae, which has been used as an antiseptic and antipyretic folk medicine for centuries. Previous researches have shown that curcumin has extensive pharmacological activities and has been put into clinical practice. Increasing evidence showed that curcumin has a protective effect against cardiovascular disease. For instance, curcumin can prevent the development of heart failure by inhibiting p300 histone acetyltransferase activity, antagonized sodium fluoride intoxication in rat heart, prevented isoprenaline (ISO)-induced cardiac hypertrophy, and can have a protective effect against the myocardial infarction injury. In addition, curcumin was reported to prevent the QTc prolongation in ISO-induced myocardial infarction.  Curcumin is also a multi-ion channel blocker that inhibits ICa.L and IKr and preferentially blocks INa.L, shortens APD, suppresses EADs and DADs at the cellular level, prevents I/R-induced arrhythmia at the organ level, and may have potential antiarrhythmic property. Curcumin can prevent the occurrence of arrhythmias after reperfusion, which is beneficial for the recovery of isolated heart suffering from I/R injury.

New evidence for the potential anti-inflammatory and cardiovascular protective effects of curcumin
Evidence-Based Complementary and Alternative Medicine | January 2021
Curcumin is the most active component of spice turmeric (also called curry powder), mainly found in turmeric roots (Curcuma longa L.). It has long been studied for its antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and anticancer properties. In the recent years, curcumin has been extensively investigated for its therapeutic value. Its anti-inflammatory effect which is equivalent to that of steroidal and nonsteroidal drugs, e.g., indomethacin and phenylbutazone, is one of the most studied properties. In various inflammation-related chronic illnesses such as cardiovascular disease, cancer, diabetes, and obesity, curcumin has shown good therapeutic effects. The present study shows that curcumin suppresses aldosterone-induced CRP generation in VSMCs by interfering with the ROS-ERK1/2 signaling pathway. These results reveal a mechanism through which curcumin represses inflammation and confers cardiovascular protection. Our findings further confirm the anti-inflammatory and cardiovascular protective effects of curcumin and suggest its potential clinical use in cardiovascular inflammation.

Curcumin may be an attractive natural candidate for further investigation and development in the quest for Parkinson's disease therapeutics
International Journal of Molecular Sciences | January 2021
The polyphenolic ingredient of dietary turmeric (Curcuma longa), curcumin, has attracted attention due to its multiple benefits to patients with various diseases including Parkinson's disease. Several studies have demonstrated that curcumin treatment significantly inhibits the toxin-induced loss of dopaminergic neurons in both cultured cells and animal models. Curcumin was found to exert neuroprotective effects mediating anti-oxidant, anti-inflammatory, and anti-apoptotic properties and improve neurological functions in various animal models of Parkinson's disease. Our results demonstrated that intragastric curcumin treatment (200 mg/kg) significantly improved the abnormal motor behavior and offered neuroprotection against the reduction of dopaminergic neurons, as determined by tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and caudoputamen. In conclusion, this study demonstrates that curcumin has a neuroprotective effect in a 6-hydroxydopmine (6-OHDA) rat model of PD via an α7-nAChR-mediated mechanism. The findings of the present study demonstrate that curcumin improves the survival of TH striatal fibers and neurons in SNpc and diminishes abnormal turning behavior in a 6-OHDA-induced rat model of PD. In the present study, abrogation of the protective effects of curcumin by pretreatment with MLA, an α7-nAChR-selective antagonist, clearly demonstrates that neuroprotective effects of curcumin are mediated by α7-nAChRs. Our findings clearly demonstrate that α7-nAChRs may be an attractive therapeutic target for PD and curcumin appears to be the first agent of natural origin to modulate α7-nAChRs in PD. Integrating our earlier observation that curcumin acts as a type II PAM of α7-nAChRs and potentiates receptor function by significantly decreasing desensitization, it is apparent that the PAM action of curcumin on α7-nAChRs exerts beneficial effects in mediating neuroprotective effects. Time-tested safety and neuroprotective efficacy of curcumin and preliminary clinical success of agents targeting nicotinic receptors in Parkinson's disease.

Curcumin has been reported to exhibit protective effects on degeneration in articular cartilage diseases
Cell Biology | January 2021
Articular cartilage damage and chondrocyte apoptosis are common features of rheumatoid arthritis and osteoarthritis.  These results indicate that curcumin may suppress IL‐1β‐induced chondrocyte apoptosis through activating autophagy and restraining NF‐κB signaling pathway.

Curcumin and NAC may be effective against noise-induced hearing loss
Indian Journal of Otolaryngology and Head & Neck Surgery |  January 2021
We investigated the effectiveness of N-acetyl cysteine (NAC) and curcumin, which have known antioxidant and anti-inflammatory effects, in reducing acoustic trauma. There was a statistically significant difference in the third measurements in both groups 2 and 3, possibly due to curcumin and NAC treatment. This study showed that curcumin and NAC may be effective against noise-induced hearing loss.

Curcumin exhibits beneficial effect on bone fracture healing
Medical Science Monitor | January 2021
Curcumin has been used for a very long time in traditional medicine because of several pharmacological properties. Multiple properties of curcumin include its role as an anti-inflammatory, antioxidant, and anti-fibrotic agent. Additionally, studies have shown tumor growth inhibitory effect and myocardial injury protecting property of curcumin. Although studies on the use of curcumin in bone trauma treatment are limited, reports suggest that curcumin may have a positive effect in bone remodeling. The current study investigated curcumin for bone trauma treatment in a rat model and evaluated the related mechanism. Curcumin activates autophagy and inhibits mTOR activation in bone tissues of rats with trauma. The curcumin promoted myeloid-derived suppressor cell (MDSC) proliferation and increased expansion of MDSCs in a rat model of trauma. Therefore, curcumin may have beneficial effect in patients with bone trauma and should be evaluated further for development of treatment.

A novel application of curcumin in tumor therapy
Archives of Biochemistry and Biophysics | January 2021
Curcumin promotes cancer-associated fibroblasts apoptosis via ROS-mediated endoplasmic reticulum stress. Curcumin is a natural polyphenol derived from turmeric, which has been shown to inhibit the growth of many types of tumor.  We found that curcumin induced the apoptosis and cell cycle arrest of CAFs, which is mainly caused by the ROS-mediated endoplasmic reticulum stress pathway. Our study suggests that curcumin selectively inhibits prostate-CAFs by inducing apoptosis and cell cycle arrest in G2-M phase, indicating a novel application of curcumin in tumor therapy.

Curcumin may be an alternate to antimicrobial drugs for the therapeutic management of endometritis
Molecular Biology Reports | January 2021
Curcumin inhibited the basal and LTA+LPS induced production of PGE2 and upregulation of PIC production. It was apparent that LPS, but not LTA, is a potent stimulator of PGE2 from the bubaline endometrial stromal cells. Curcumin downregulated the expression of LPS and/or LTA induced PICs and PGE2 and may be an alternate to antimicrobial drugs for the therapeutic management of endometritis.

Curcumin represents a promising therapy for Diabetes mellitus induced cognitive impairments and memory deficits
Neurobiology of Disease | January 2021
Curcumin, derived from the rhizome of Curcuma longa Linn, is a bright yellow spice that shows strong anti-inflammatory, anti-oxidant, and anti-tumor activities. Many studies have reported neuroprotective effects of curcumin in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Our previous study has also demonstrated a protective effect of curcumin on LPS- induced neuroinfammation in vitro. The present study revealed that curcumin treatment effectively protected against DM/CCH-induced cognitive dysfunction, as well as attenuated neuronal injury and death in the CA1, CA3, and DG regions of the hippocampus. Molecular-biology analysis revealed that the underlying mechanisms of curcumin’s protective effects were associated with inhibiting neuroinflammation. We demonstrated that curcumin attenuated DM/CCH-induced cognitive defcits and hippocampal neuronal damage in rats, and that its underlying mechanisms were associated with inhibiting neuroinflammation, regulating the TREM2/TLR4/NF-κB pathway, suppressing excessive apoptosis, and mitigating NLRP3-dependent pyroptosis. These findings suggest that curcumin may be useful as a pharmacological strategy for ameliorating Diabetes mellitus /CCH-induced memory deficits.

Curcumin exhibited renoprotective, antioxidant, anti-inflammatory properties, especially curcumin exerted the most pronounced effect as an anti-inflammatory and anti-apoptotic reflecting its powerful effect against bacteria and sepsis-induced kidney injury
Future Journal of Pharmaceutical Sciences | January 2021
Curcumin a polyphenol extracted from turmeric gained interest as a potentially safe and inexpensive treatment for kidney diseases. Inflammatory markers were greatly reduced by both curcumin and propolis, only curcumin pretreatment attenuated NF-kB activation in kidney tissue of septic rat.

The protective effect of curcumin on ACR-intoxicated brains
BMC Pharmacology and Toxicology | January 2021
Curcumin is well known for its classic and strong anti-oxidative and anti-inflammatory activities. As the most active constituent in turmeric, a common spice, with a strong safety record, curcumin has been considered to be a potential natural neuroprotective agent under limelight. Based on its known antioxidant, anti-inflammatory and anti-apoptosis activities, curcumin has been shown to protect the neurons against cerebral ischemia-reperfusion injury, dysfunction linked with Parkinson’s disease mediated by Bisphenol-A, sleep-deprivation induced memory impairments, and depression. Prasad and Muralidhara have demonstrated the neuroprotective effect of curcumin in an ACR model of neurotoxicity in an insect species, Drosophila melanogaster. A recently published study reported that curcumin would exert a protective effect against ACR-induced spatial memory impairment in rats. The phenolic structure in curcumin confers electron-capturing properties, which destabilize ROS, explaining the well-accepted antioxidant effects. Curcumin alleviated the augmented production of MDA and the reduction of antioxidant capacity induced by ACR, thus might play a role in the detoxification of reactive oxygen species generated by ACR.  Curcumin could improve the ACR-induced neuroinflammation, which was in accord with its proven anti-inflammatory property.

Curcumin: Could This Compound Be Useful in Pregnancy and Pregnancy-Related Complications?
Nutrients | January 2021
Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries.  The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin’s effects on pregnancy and pregnancy-related complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. Curcumin, a compound extracted from the rhizome of Curcuma longa, has been extensively studied in light of a wide range of properties, including anti-inflammatory, antioxidant, anti-toxicant, antiapoptotic, immunomodulatory, neuroprotective, hepatoprotective, antiangiogenic, anti-hypertensive, and antidiabetic activities, emerging as a candidate therapeutic agent for several diseases. Curcumin, also called diferuloylmethane, is a lipophilic polyphenol extracted from the rhizome of Curcuma Longa (commonly known as turmeric). It has been widely used in traditional Indian and Chinese medicine for thousands of years. The pharmacological effects of turmeric have been attributed mainly to curcuminoids, comprising curcumin and two related compounds, demethoxycurcumin and bisdemethoxycurcumin, which are contained in commercial curcumin. Curcumin is a potent anti-inflammatory and antioxidant agent that exerts a myriad of biological activities by influencing multiple signaling pathways. Curcumin is able to interact with a large number of molecular and cellular targets and regulates gene expression also by modulating epigenetic modifications (i.e., DNA methylation, histone modification, and microRNA expression). This compound, by mutually interacting with intestinal microflora, ameliorates gut microbiome dysbiosis, and influences the “gut–brain–microflora axis” to preserve and favor brain health. The overall result of these different activities is the improvement in several disease states, including inflammatory, metabolic, endocrine, cardiovascular, gastrointestinal, neurological, respiratory, viral, skin diseases, and cancer, as highlighted by the impressive number of in vitro and in vivo studies summarized in recent papers. Numerous clinical trials have shown good tolerability, safety, and efficacy of curcumin in the treatment of multiple chronic diseases—including cardiovascular diseases, diabetes, neurodegeneration, arthritis, and cancer—at doses up to 6–12 g/day. In light of this, the United States Food and Drug Administration (FDA) has “Generally Recognized As Safe” (GRAS) curcumin as an ingredient in various food categories (0.5–100 mg/100 g) [29]; and the European Food Safety Authority (EFSA) Panel on Food Additives and Nutrient Sources added to Food (ANS), defined the Allowable Daily Intake (ADI) value of 0–3 mg/kg bw/day of curcumin as a food additive.

Archived studies and news on curcumin and turmeric
1984 - 2020

 
How may Curcumin effect aging and longevity as an antiaging agent?
Effect of Curcumin on Vascular Aging | Growing evidence indicates curcumin as a promising antiaging agent. The effects of curcumin feeding have been largely investigated in animal models, unanimously reporting a suppression of intermediated oxidative stress and inflammation. By chelating nitrogen dioxide (NO2), curcumin administration in mice significantly attenuates nitric oxide- (NO-) associated vascular endothelial dysfunction and generation of advanced glycation end-products (AGEs), leading determinants of age-related large elastic artery stiffening. As an additional mechanism, curcumin fixes lysosomal membranes and reduces the function of lysosomal acid hydrolases, thus preventing the aberrant deposition of different connective tissue components in aging endothelium. curcumin mitigated hypertrophy in the aging heart via suppression of p300, the global transcription activator. Beneficial effects of curcumin on vascular aging also concern the development of age-related macular degeneration (AMD), one of the most important causes of blindness in elderly. Curcumin remarkably increases the viability of retinal pigment epithelial cells (RPECs) modulating their proliferation apoptosis and OS. Overall, those evidences suggest potential application of curcumin as an innovative approach to AMD, as for other ocular diseases (e.g., ocular dryness, conjunctivitis, uveitis, pterygium, and glaucoma). Even curcumin has been found to prevent the development of cataract in diabetic rats by decreasing AGE accumulation and serum LPO. Curcumin reverses those effects in cultured ECs, whereas in experimental models, prolonged curcumin feeding decreased ROS generation and promoted cerebrovascular endothelium-dependent relaxation, finally leading to improved cerebrovascular function. Neuroprotective effects of curcumin due to UCP2 overexpression suppression especially target hippocampal neurogenesis in the CA1 area, thus affecting spatial learning and memory. Curcumin also prevents detrimental effects of chronic cerebral hypoperfusion by maintaining cholesterol homeostasis. Curcumin also contributes to maintain cholesterol homeostasis, otherwise upset by chronic cerebral ischemia. Indeed, curcumin promotes cholesterol efflux.
Effect of Curcumin on Longevity and Lifespan |  Curcumin was shown to increase the fecundity, reproductive lifespan, and child viability of D. melanogaster. It has been shown that curcumin supplementation of D. melanogaster elevated the developmental duration and longevity of adult Drosophila possibly through epigenetic programming of the pace of life. Curcumin increased longevity was observed in two distinctive strains of D. melanogaste as a result of the delayed expression of aging genes, improved locomotion, and chemoprevention as well. Curcumin was also shown to reduce OS, DNA damage, and number of mutagenic phenotypes induced via high-dose ionizing irradiation. Also, in vivo experiments on curcumin -fed diets (0.5 and 1.0 mg/g of diet) were effective in extending the average lifespan in both females (6.2% and 25.8%, respectively) and males (15.5% and 12.6%, respectively). Also, in C. elegans, curcumin effectively improves lifespan and aging by lowering intracellular ROS and lipofuscin. The effects of curcumin on C. elegans longevity are manifested by body size and pharyngeal pumping rate. This evidence indicates that curcumin would exert its effects independently of the Age-1-DAF-16 pathway but rather through other constituents of the IIS pathway. With regard to cognitive impairment, the in vivo experiment demonstrated that curcumin can improve learning and memory also reducing Aβ plaque formation in the context of Alzheimer disease. D. melanogaster is a promising animal model for research in AD. By increasing amyloid fibril conversion, curcumin reduces the generation of prefibrillar/oligomeric species of Aβ, ultimately protecting against neurotoxicity. The human β-amyloid precursor cleavage enzyme (BACE-1) is another critical enzyme targeted by curcumin in the D. melanogaster model of Alzheimer disease.
Effect of Curcumin on Cell Senescence | The antiaging effect of curcumin does not rely on delayed cellular senescence. As reported by Banji et al., curcumin (40 mg/kg) and piperine (12 mg/kg), especially when combined, counteract D-gal-induced senescence in male Wistar rats by targeting OS and lipofuscin deposition, finally leading to higher hippocampal volume and function with improved spatial memory and serotoninergic signaling. Another study even reported how long-time curcumin therapy may progressively reverse cognitive dysfunction in D-gal-induced senescent mice by delaying the aging process and improving cognitive functions and locomotor activity, as well as restoring the mitochondrial enzyme complex function curcumin. In a recent study, curcumin supplementation rejuvenates senescence-associated changes in thymus among D-gal-induced senescent mice through promotion of proliferating cells, preventing cells from apoptosis, and enhancing the transcription of the autoimmune regulator. Curcumin feeding (50 mg/kg) was also tested in senescence-accelerated mouse prone mice resulting in increased hippocampal SOD activity as well as upregulation of p-calcium/calmodulin-dependent kinase II. Overall, these findings suggest a role of curcumin in improving cognitive difficulties and the expression of hippocampal plasticity-associated proteins. With regard to vascular function, curcumin administration significantly mitigated premature senescence in HUVECs, characterized by a reduction of senescence-related β-galactosidase-positive cells, cell division, levels of senescence-related protein p21 RNA, OS, and apoptosis. Curcumin is also associated with enhanced eNOS phosphorylation and NO generation, in addition to upregulating Sirt1 transcription, translation, and enzymatic activity. In light of these mechanisms, diets containing curcumin  were demonstrated to significantly extend mean lifespan in male C57BL/6 mice and delayed the OS-caused premature senescence. As recently demonstrated, Sirt1 signaling also mediates the anti-inflammatory effects of curcumin in C57BL/6 mice fed with high fat diet in addition to improved myocardial structure and function in streptozocin-induced diabetic mice fed with THC (120 mg/kg/d). Even more recently, it has been hypothesized that the antiaging effect of curcumin may rely on the control of core clock genes. Curcumin treatment in middle aged male Wistar rats restored the phase and daily pulse. Moreover, it has been shown that curcumin mitigated mouse ovarian aging, upgraded embryonic development, promoted oocyte maturation and fertilization via improvement of ovarian hormones, and elevated the amounts of SIRT1 and 3 genes as well as attenuation of aging-associated oxidative stress and cell death. Besides, curcumin can reduce oxidative stress, inflammation status, and lipofuscin deposition in aged rat liver.
 
How may Curcumin work against Neurological and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington’s Disease, and cognitive decline or impairment?

Effect of Curcumin on Alzheimer's Disease |  Evidence has accumulated that curcumin has neuroprotective properties and is a candidate for the treatment of Alzheimer’s disease. In an Alzheimer’s disease transgenic mouse, curcumin decreased oxidative stress and repaired amyloid pathology. Antioxidant and anti-inflammatory features of curcumin helped to minimize the manifestation of Alzheimer’s disease, which is characterized by inflammation and oxidation. Recent studies have indicated that curcumin treatment can promote the decomposition of β-amyloid in brain tissues and prevent the aberrant production and accumulation of β-amyloid, which reduces the hyperphosphorylation of tau protein and effectively prevents the degeneration and injury of brain neurons. Curcumin has protective effects for several risk factors of neurodegeneration and is used in the treatment of Alzheimer's disease as well. In vivo studies show the beneficial effects of curcumin on cognition with a dose-dependent manner that higher dosages is more effective as compared to lower dosages. Based on the preclinical findings, curcumin can help stabilizes/prevents cognitive decline in Alzheimer's disease. In their review, Pluta and colleagues focus on the role and mechanisms of curcumin in inhibiting ischemia/reperfusion brain injury and potential therapeutic strategies in the treatment of ischemic brain damage of the Alzheimer’s disease phenotype. Comparably, Ferreira and colleagues also delineate neuroprotective characteristics by summarizing what is known about the role of curcumin on transthyretin amyloidosis. According to previous reports, curcumin modulates abnormal transthyretin (TTR) aggregation and inhibits its deposition in the tissue. As the gut–brain axis is linked to neurodegeneration, curcumin exerts neuroprotective effect against neurodegenerative disorders by restoring the intestinal barrier function and a healthy gut microbiome. These findings highlight the importance of neuroprotective effect of curcumin against brain damage by regulating both inflammation and oxidative stress. This is consistent with previous findings where curcumin was shown to reduce significantly the mRNA expression of NF-kB and TLR4 and showed protective effects against glutamate neurotoxicity. Studies have shown that curcumin has a therapeutic effect on Alzheimer’s disease by several molecular mechanisms, including decreasing oxidative damage and constraining the creation of the Aβ fibrils in vitro. The anti-inflammation effects of curcumin as a food additive were evaluated in the APPSw mice (Alzheimer-like model) at several doses. The results have indicated that low-dose curcumin (160 ppm) reduced GFAP, which is an astrocytic marker associated with inflammatory processes. Furthermore, the effect of curcumin on spatial memory (an Alzheimer’s disease symptom) in Alzheimer’s disease rat models has shown that curcumin significantly decreases GFAP mRNA in hippocampal astrocytes, which improves the spatial memory in the Alzheimer’s disease rat model. Ambegaokar et al. reported that the inhibition property of curcumin is dose and time-dependent. For example, curcumin concentrations of 15–30 μM are more effective for short trials (<24 h), while its concentrations of 5–15 μM are better suited for longer periods (4–6 days). These data suggest that curcumin may be more effective in preventing AD in low doses if used for long periods. Accumulating data show that Aβ can increase the expression of COX-2, IL-1, and IL-6, while decreasing the peroxisome proliferator-activated receptor-gamma (PPARγ) in amyloid-beta protein precursor transgenic mice, and curcumin can inhibit this function in amyloid-beta-treated astrocytes. Most of the literature about curcumin indicates that this spice has especially strong properties against AD. For instance, the incidence of Alzheimer’s disease among Indian people (who regularly consume these spices) is very low when compared with the reported incidence in Western countries. Only 0.7% of 70–79 years old people in India are affected by AD; however, about 3.1% of Americans in this age range are also affected. Up to now, the potential anti-amyloid therapeutic methods for Alzheimer’s disease treatment have been focused on the amyloid cascade theory, on which the use of Aβ vaccines and metal-complexing agents is based. Strimpakos et al. reported that curcumin has anti-amyloidogenic properties, thus acting against AD-induced Aβ fibrils in vitro and improving cognitive functioning in vivo. Interestingly, another study analyzing the curcumin-mediated neuroprotective effects on brain aging induced by d-galactose in in vitro and in vivo models revealed an anti-aging effect through regulating neuronal loss, apoptosis in D-galactose induced brain aging, and anti-oxidant enzyme expression. Furthermore, curcumin improved neuronal length and cellular senescence down-regulated expression of p16 and p21 and upregulated expression of antioxidant enzymes, including SOD-1, GPX-1, and catalase. Administration of curcumin ameliorated the cognitive impairment and suppressed apoptosis in the cerebral cortex by downregulating Bax and poly (ADP-ribose) polymerase expression and increasing Bcl-2 expression [86]. In neurodegenerative diseases, such as AD, PD, ALS, microglia play an important role by inducing oxidative stress, redox imbalance and neuroinflammation. The activated microglia are represented by M1 (pro-inflammatory) and M2 (anti-inflammatory) functional phenotypes based on the surface molecules and cytokine expression profiles. Different natural products show therapeutic properties on microglia and consequent prevent neurodegenerative diseases; they act by inhibition of microglia polarization and production of inflammatory mediators. In microglia, curcumin acts on different molecular targets. Curcumin inhibited LPS-induced NF-kB and activator protein-1 (AP-1) DNA bindings in BV2 microglial cells decreasing inflammatory mediators. Peroxisome proliferation-activated receptor-γ (PPARγ) is a transcription factor and nuclear receptor protein that regulates inflammatory responses in microglia, astrocytes and when is activated, PPARγ suppresses the production of proinflammatory cytokines and inflammatory pathways by binding the peroxisome proliferator response element. Curcumin activates PPARγ which reduces NF-κB cytokine production in a mouse model of AD, in rat hippocampal primary cell lines and primary astrocytes. Moreover, our group has found that curcumin suppresses LPS induced inflammatory response in microglia cells by down regulation of PI3K/Akt and JAK/STAT/SOCS signaling pathway. In addition, curcumin induces anti-inflammatory mediators, such as HO-1/NRF-2 consequently reducing oxidative stress and neuroinflammation. Curcumin treatment improved neuron loss and degeneration, while also inhibited cellular senescence and oxidative stress by upregulating antioxidant enzyme expression in RA-induced SY5Y cells. In line with the findings described above, the protective effect of curcumin against cognitive impairment has been demonstrated in diabetes mellitus/chronical cerebral hyperperfusion-induced cognitive deficit model. Moreover, curcumin treatment attenuated the neuronal death and suppressed neuroinflammation induced by microglial activation. These protective effects involved the modulation of triggering receptor expressed on myeloid cells 2 (TREM2)/TLR4/NF-kB pathway. Curcumin treatment reduced nod-like receptor protein 3 (NLRP3) dependent pyroptosis. Since NLRP3-dependent pyroptosis has been reported to be involved in the progression of neurodegenerative diseases, this result suggests that curcumin may be useful as pharmacological strategy for neurodegenerative diseases. Further studies are needed for better understanding of curcumin’s promising effects in preventing the neuronal loss and cognition-decline related to aging. The pleiotropic activities of curcumin provide multiple ways to tackle TTR pathophysiology, through direct interaction of curcumin with TTR, or indirect effects affecting signaling pathways associated with TTR amyloid fibril formation and clearance. Bielak-Zmijewska and coworkers summarize scientific data on curcumin’s ability to postpone progression of age-related diseases in which cellular senescence is directly involved. They furthermore point out that curcumin causes elongation of the lifespan of model organisms and alleviates aging symptoms. In addition, they discuss thoroughly curcumin’s ability to modulate cellular senescence. Common brain disorders, including depression and Alzheimer’s disease, have been linked to diminished levels of an important neurologic growth hormone called brain-derived neurotrophic factor. Reports suggest Curcumin has neuroprotective action in Alzheimer’s disease, major depression, epilepsy, and other neurodegenerative disorders. The hippocampus region of brain is associated with memory and cognition. Studies have shown that hippocampus undergoes structural and biochemical changes with normal aging that results in age-related deterioration in hippocampus-dependent cognition. Curcumin has been found to ameliorate age-related memory deficits in aged mice. In elderly, regular curcumin intake improves cognitive function and ameliorates age-related spatial memory deficits. An Australian study, in the Journal of Psychopharmacology in 2015, found that curcumin improved attention and working memory and reduced mental fatigue in older people who took it for four weeks, compared to a placebo. Several studies have shown that curcumin, the active medicinal compound in turmeric, can increase levels of BDNF in the human brain and therefore delay or even reverse a range of common neurological disorders. One of the main drivers of this process is brain-derived neurotrophic factor (BDNF), which is a type of growth hormone that functions in your brain (20). Many common brain disorders have been linked to decreased levels of this hormone, including depression and Alzheimer's disease. Interestingly, curcumin can increase brain levels of BDNF. By doing this, it may be effective in delaying or even reversing many brain diseases and age-related decreases in brain function. It may also improve memory and make you smarter, which seems logical given its effects on BDNF levels. However, controlled studies in people are needed to confirm this. In addition, scientists are beginning to suspect that the neurologic powers of curcumin don’t just stop there, with research suggesting that this compound may improve memory and increase cognitive capacity. Curcumin, thanks to its wide range of effects, seems to help the brain resist buildup of harmful plaque in brains with Alzheimer's.  A study in the Annals of Indian Academy of Neurology explored curcumin's potential for use in the treatment for Alzheimer's disease. Some of the key points included: Curcumin may help the macrophages, which play an important role in our immune system, clear the amyloid plaques found in Alzheimer's disease. Curcumin has anti-proliferative actions on microglia. Microglia are immune cells of the central nervous system that become active in response to any number of stressors on the body. However, if the microglia have been stimulated to react too often, they become hyper-reactive, which can trigger system-wide inflammation that can be difficult to stop. Curcumin has powerful antioxidant and anti-inflammatory properties. "Overall, curcumin decreases the main chemical for inflammation and the transcription of inflammatory cytokines …The exposure to curcumin also impaired the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF-)." As chronic neuro-inflammation is considered one of the major factors in the development of Alzheimer's, it's possible too that curcumin may help in the treatment of other inflammatory disorders. Researchers found that Curcumin not only reduces oxidative damage and inflammation, but also reduces amyloid accumulation and synaptic marker loss and promotes amyloid phagocytosis and clearance. Curcumin worked to prevent synaptic marker and cognitive deficits caused by amyloid peptide infusion and abeta oligomer toxicity in vitro, and may help the immune system clear the brain of amyloid beta, which forms the plaques found in Alzheimer's disease. Clinical trials are in progress at UCLA with Curcumin for Alzheimer's. In the Alzheimer’s Disease Anti-Inflammatory Prevention Trial, researched showed that reducing inflammation has positive effects on patients with Alzheimer’s. Curcumin significantly lowered several inflammation markers, in addition to reducing plaque on the brain (a sign of Alzheimer’s) by 43 to 50 percent. The effect of curcumin (turmeric) on Alzheimer's disease: An overview Neuroprotective activity has also been shown in curcumin. In Alzheimer’s disease (AD), a peptide called β-amyloid (Aβ peptide) aggregates into oligomers and fibrils and forms deposits known as amyloid (or senile) plaques outside neurons in the hippocampus and cerebral cortex of patients. Another feature of AD is the accumulation of intracellular neurofibrillary tangles formed by phosphorylated Tau protein. Abnormal microglial activation, oxidative stress, and neuronal death are also associated with the progression of the disease. Curcumin has been found to inhibit Aβ fibril formation and extension and to destabilize preformed fibrils in vitro. Metal chelation by curcumin might interfere with metal ion (Cu2+/Zn2+)-induced Aβ aggregation. Curcumin might also affect the trafficking of Aβ peptide precursor (APP) and the generation of Aβ peptides from APP. Abnormally activated microglia and hypertrophic astrocytes around amyloid plaques in AD brains release cytotoxic molecules, such as proinflammatory cytokines and ROS, which enhance Aβ formation and deposition and further damage neurons. Curcumin was found to reduce the inflammatory response triggered by Aβ peptide-induced microglial activation and increase neuronal cell survival. When injected into the carotid artery of a transgenic mouse model of AD, curcumin was found to cross the blood-brain barrier, bind to amyloid plaques, and block the formation of Aβ oligomers and fibrils. In other animal models of AD, dietary curcumin decreased biomarkers of inflammation and oxidative damage, increased Aβ peptide clearance by macrophages, dismantled amyloid plaques in the brain, stimulated neuronal cell growth in the hippocampus, and improved Aβ-induced memory deficits. As a result of promising findings in animal models. a few recent clinical trials have examined the effect of oral curcumin supplementation on cognition in healthy older adults and AD patients. A significant reduction in mental fatigue and higher levels of calmness and contentedness following cognitive test sessions were observed in individuals who consumed curcumin (either acutely or chronically) compared to the placebo group. Additionally, the results of cognitive ability tests suggested that curcumin treatment had limited benefits on cognitive function, as shown by better scores in measures of sustained attention and working memory compared to placebo. The results of a six-month trial in 27 patients with AD found that oral supplementation with up to 4 g/day of curcumin - containing all three major curcuminoids - was safe. Curcumin also helps inhibit plaque that research has linked to neuron damage in the brain and a sign of the disease. There may be good news on the horizon because curcumin has been shown to cross the blood-brain barrier. It’s known that inflammation and oxidative damage play a role in Alzheimer's disease, and curcumin has beneficial effects on both. In addition, a key feature of Alzheimer's disease is a buildup of protein tangles called amyloid plaques. Studies show that curcumin can help clear these plaques. Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the presence of hyperphosphorylated tau protein in neurofibrillary tangles, selective neuronal loss, progressive memory and cognitive impairment (Campbell and Gowran 2007). The molecular pathogenesis of AD involves extracellular deposition of beta-amyloid (Ab) peptides in the hippocampus and curcumin is known to reduce Alzheimer’s pathology (Serafini et al. 2017) possibly due to its anti-aggregatory properties (Cole, Teter, and Frautschy 2007). In a clinical study, curcumin administration (1 or 4 g, 6 months trial) significantly increased the levels of antioxidant vitamin E without inducing any adverse events in patients with AD (Baum et al. 2008). In preclinical studies, curcumin is known to reduce Aboligomer and fibril formation (Yang et al. 2005; Xiong et al. 2011), inhibit the neurotoxicity of Abin the brain (Jiang et al. 2012; Sun, Zhao, and Hu 2013), suppress Ab-induced inflammation (Lim et al. 2001; Lu et al. 2014) and markedly reduce the levels of IL- 1b(Griffin et al. 2006) and inducible nitric oxide synthase (iNOS) (Begum et al. 2008) in transgenic mouse brain. Several studies demonstrated dose-dependent neuroprotective effect of curcumin against Ab-induced toxicity. Curcumin exhibited anti-aggregatory effect against Ab plaque formation by metal chelation (Huang et al. 2004; Tamagno et al. 2005), anti-oxidant effects (Hamaguchi et al. 2009), cholesterol lowering effects (Fassbender et al. 2001; Refolo et al. 2001), inhibition of presenilin-2 and/or by increasing degrading enzymes such as insulin-degrading enzyme and neprilysin (Wang et al. 2014). Curcumin potentiate heat shock proteins production in response to cellular stress, which protects neuronal cells from Ab neurotoxicity and prevent Ab aggregation and accumulation (Scapagnini et al. 2006; Ohtsuka and Suzuki 2000; Cummings et al. 2001).
Effect of Curcumin on Parkinson’s Disease | Dietary curcumin is an important candidate in the prevention or treatment of Parkinson’s disease.  Curcumin is suggested to be an effective therapeutic and nutraceutical agent for Parkinson’s diseasetreatment. Interestingly, curcumin was found to inhibit the synthesis of MOA-B enzyme (Khatri and Juvekar, 2016), which would lead to an increase in the level and availability of DA in the brain. Neuroprotective effects of curcumin in a 6-hydroxydopmin e animal model of Parkinson’s disease (El Nebrisi et al., 2020) indicated an increase in the survival of striatal TH fibers and SNpc neurons, decreased abnormal turning behavior, and exerted neuroprotective properties. These findings provide evidence that α7-nicotinic acetylcholine receptors could be a potential therapeutic target and curcumin would be the first natural source that is found to modulate nicotinic receptors in Parkinson’s disease. Recent evidence indicates decreased superoxide dismutase 1 (SOD1) expression in reactive astrocytes in the damaged substantia nigra, thus leading to inflammation and oxidative stress that contribute to the degeneration of dopaminergic neurons in Parkinson’s disease. Curcumin, through the preservation of SOD1 expression in reactive striatal astrocytes in hemiparkinsonian mice, has anti-inflammatory properties. Gui et al. showed that curcumin, through the inhibition of CYP2E1 (the cytochrome P450 2E1) expression and its activity in reducing ROS and maleic dialdehyde in astrocytes, leads to protection of the mesencephalic astrocytes against LPS-induced toxicities. These results indicate that curcumin could affect the metabolism of several compounds in the CNS and provide evidence for the therapeutic approach in Parkinson’s disease using curcumin at low concentration. Studies show that the oral administration of curcumin (150 mg/kg/day for a week) in mouse models of Parkinson’s disease reversed GFAP and inducible nitric oxide synthase protein expression and also decreased proinflammatory cytokine in the striatum, suggesting that curcumin can improve motor performance in a mouse model of Parkinson’s disease. In addition, curcumin, through the Bcl-2-mitochondria-ROS-inducible nitric oxide synthase pathway, can protect against MPP+ (1-methyl-4-phenylpyridinium)- and MPTP− (1-methyl-4-phenyl-1,2,3,6-tetrahydro­pyridine)-induced apoptosis in PC12 cells. Curcumin can significantly inhibit NF-κβ translocation and activation in astrocytes. In one  study, chronic curcumin administration (50, 100 or 200 mg/kg, p.o., for 3 weeks) significantly ameliorated behavioral alterations like locomotor activity and motor-coordination in mouse model of Parkinson’s disease. In the similar study, curcumin administration reduced oxidative damage and mitochondrial dysfunction in brain homogenate by reducing AChE activity. Curcumin administration decreased malondialdehyde (MDA) and nitrite while increased superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) levels in the brain homogenate of rotenone induced mouse model of Parkinson’s disease (Khatri and Juvekar 2016). It has been demonstrated that curcumin administration alleviate motor dysfunction and increase tyrosine hydroxylase activity in rotenone induced Parkinson’s disease rat model. Curcumin administration phosphorylates Nrf-2 and Akt thereby attenuated oxidative damage of dopaminergic neuron (Cui, Li, and Zhu 2016). Moreover, dietary curcumin supplementation 0.5% or 2.0% (w/w) attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurotoxicity in mice via increasing the expression of glial cell line-derived neurotrophic factor and TGF-b1 in nigrostriatal dopaminergic system and thus slowing the progression of Parkinson’s disease (He et al. 2015b). Curcumin administration increased monoaminergic neurotransmitters such as norepinephrine and dopamine in hippocampal homogenate and alleviated hippocampal damage in 6-hydroxydopamine induced Parkinson’s disease in rat. In addition, curcumin treatment upregulated the expression of BDNF, TrkB and PI3K in the hippocampus (Yang et al. 2014). Curcumin treatment (200 mg/kg, for 1 week) significantly attenuated loss of tyrosine hydroxylase, sustained SOD1 level and diminished activation of microglia and astrocytes in the striatum.
Effect of Curcumin on Cognitive Impairment | Curcumin has been reported to improve neuropsychological functions. curcumin has several inhibitory effects on combining aging and Alzheimer’s disease pathophysiology, such as the suppression of amyloid precursor protein (APP) and Aβ synthesis and the overexpression of ApoE and Nrf2 gene, as well as the prohibition of p-mTOR and p-NF-κB. Curcumin prevents D-gal-induced brain aging and cognitive impairment through increments of antioxidant enzymes and inhibition of apoptosis. Beneficial effects of curcumin on mental abilities and functional capacities are associated with a LPO reduction in brain tissue, especially in the hippocampal area. Curcumin improves the redox state in this area and prevents the decline of hippocampal long-term potentiation by maintaining synapse input specificity. Recently, Olesen et al. described that the dysfunction of synaptic mitochondria of the hippocampus causing memory loss during aging. They showed that curcumin feeding significantly improved integration and activity of the synaptic mitochondrial of the hippocampus, inhibiting mitochondrial swelling and enhancing the production of synapses surrounding the mitochondria in mice.
Effect of Curcumin on Multiple Sclerosis and Amyotrophic Lateral Sclerosis | Curcumin was studied to determine if it could help ALS patients, particularly those with bulbar involvement, survive longer (Ahmadi et al., 2018). Curcumin therapy reduced the development of ALS and oxidative damage in a double-blind therapeutic trial (Chico et al., 2018). Recent studies suggest that curcumin, through reduced MMP-9 enzyme activity and decreased release of IL-6 in the astrocyte population of CNS, might beneficially cause anti-inflammatory responses in neurodegenerative diseases, such as multiple sclerosis. Curcumin represents some potential for treatments of various autoimmune diseases related to Th17 cells including MS. Curcumin, through interfering with protein kinase C activity and Ca2+ entry, can eliminate both PMA and thapsigargin-induced ROS generation by the dose-dependent manner. Curcumin can prevent the production of H2O2 and NO; the free radicals produced by macrophages and astrocytes in vitro. In EAE, curcumin has important roles in lymphocyte proliferation inhibition, reductions of IL-17 production by Th17 cells, and Toll-like receptors 4 and 9 (TLR 4 and 9) downregulations. Xie et al. reported that in EAE mice or rats, curcumin shrinks inflammatory cells, including Th17 cells, and hinders its infiltration and differentiation in the CNS. Curcumin has the promising potential for treating multiple sclerosis. Curcumin delivering to the animal models through intraperitoneal injection or oral administration leads to NF-κβ pathway activation decreasing in rat and mouse microglial cell cultures and also in the rat brain. Furthermore, curcumin can also reduce NF-κβ activation in human cell lines and can neutralize ROS in vitro and can stimulate the Nrf2-ARE pathway similarly in the brain and skeletal muscles of mice and also in isolated rat astrocytes. SOD1-misfolded and -aggregated proteins in the motor neurons have an important role in disease pathogenesis, and its targeting treatment can decrease ALS progression in animal models. As previously shown, curcumin can constrain SOD1 aggregation in vitro. Curcumin through gene expression can also stimulate the clearance of the aggregated protein in PALS and Alzheimer’s disease blood cells. Up to the present time, several studies confirm that regimens’ treatment can cause motor neuron enhancement (although there are several different descriptions for these improvements). Furthermore, a small pilot trial revealed some advantage of curcumin in PALS.
Effect of Curcumin on Huntington’s Disease | Studies using established yeast models showed that curcumin inhibits mHTT aggregation, by acting through endosome-sorting complexes required for transport machinery and also destabilizes preformed aggregates. Curcumin, by downregulation of Vps36, a component of the endosome-sorting complexes required for transport-II complex, prevents recruitment of misfolded protein to the perivascular compartment, thus inhibiting the formation of large aggregates. The amyloid-binding ability and anti-amyloid properties of curcumin, along with its ease of oral administration, make it an attractive therapeutic candidate for several neurodegenerative diseases.
 
How may Curcumin work against diabetes?

Because of its anti-inflammatory property, curcumin represents a promising therapeutic option for Type 2 Diabetes. Curcuminoids have been demonstrated in diabetes mellitus type 2 patients to improve insulin resistance, reduce glucose and insulin levels, enhance adiponectin secretion, and lower levels of leptin, resistin, interleukin (IL-6, IL-1β), and TNF-α (Hajavi et al., 2017).  Curcumin and its three derivatives (dimethoxy curcumin, bisdemethoxycurcumin, and diacetyl curcumin) were reported for their antioxidant capabilities (Faizal et al., 2009). Curcumin’s ability to decrease blood sugar levels in human patients was first reported in 1972. A male patient who had diabetes for 16 years ingested 5 g of curcumin over a period, after which his fasting blood sugar decreased from 140 to 70 mg/dl. Ingestion of curcumin along with insulin synergistically reduced the blood sugar level. Furthermore, when the insulin dosage was decreased to the minimum, the anti-diabetic effect of curcumin was persistent. Interestingly, when the ingestion of curcumin and turmeric was discontinued for a week, random blood sugar levels increased to 140 mg/dl. Therefore, ingestion of a daily 5-g dose of curcumin was resumed, which promptly reduced the fasting blood sugar level to 110 mg/dl. Blood urea in this patient after 3 months of turmeric therapy was 20 to 22, and the patient’s electrocardiogram was normal. Turmeric therapy was not associated with any palpable adverse effects; rather, the beneficial effects of turmeric as a good appetite stimulant and effective laxative were observed. More recently, a randomized, double-blind, placebo-controlled clinical trial assessed the efficacy of curcumin in delaying development of Type 2 Diabetes in the prediabetes population.  After 9 months of treatment, 16.4% of participants in the placebo group were diagnosed with  Type 2 Diabetes, whereas none were diagnosed with  Type 2 Diabetes in the curcumin-treated group (Fig. 6a). In addition, the participants of curcumin-treated group showed a better overall function of β cells, with higher HOMA-β and lower C-peptide levels. The curcumin-treated participants also exhibited a lower level of HOMA-IR and higher adiponectin when compared with the placebo group. The authors of this study concluded that the curcumin may be beneficial in a prediabetes population. Curcumin has been shown to equal in effectiveness to the drug metformin in the management of diabetes, but without negative side effects. In the study curcumin was shown to lower blood glucose levels and reverse insulin resistance by suppressing glucose production in the liver. Among those verging on type 2 diabetes, curcumin capsules seem to help stall the onset of the disease. The study that returned these results found that while a little more than 16% of people taking a placebo wound up with a diabetes diagnosis, no one taking curcumin received one. A clinical trial from Thailand, published in Diabetes Care in 2012, found that people with prediabetes who took curcumin for nine months had improved function of insulin-producing cells in the pancreas, along with a significantly reduced risk of developing type 2 diabetes. Other studies suggest that curcumin can improve insulin sensitivity. Another study found curcumin improved metabolic function and reduced the risk of plaque buildup in the arteries of type-2 diabetes patients. Curcumin also acts as an anti-diabetic and antioxidant in patients with type-1 diabetes. Curcumin acts directly on liver cells to help prevent them from becoming fatty, and studies have concluded that Curcumin may have an anti-diabetic effect by decreasing serum fatty acid through the promotion of fatty acid oxidation and utilization. Curcumin also works directly on pancreatic beta cells to help them produce insulin normally. By helping the liver and the pancreas, Curcumin is taking stress off the two most important organs whose function declines before the onset of type 2 diabetes. Curcumin also influences key hormones, supports major body organs, and regulates inflammatory signaling all in ways that help correct or prevent metabolic problems. Curcumin helps lower inappropriately high levels of leptin (reducing leptin resistance) while boosting the all-important levels of the adiponectin (which lowers insulin resistance). Curcumin also helps activate the fat-burning gene signal PPAR gamma, which also helps to make more new, metabolically-fit fat cells. Curcumin directly reduces major inflammatory events from occurring inside white adipose tissue (tumor necrosis factor alpha, interleukin-6, and monocyte chemotactic protein-1). By lowering such inflammation, the source of overweight-induced disease is targeted. Oxidative stress and inflammation have been implicated in the pathogenesis of type 2 diabetes mellitus and related vascular complications. A large body of preclinical evidence suggests that the antioxidant, anti-inflammatory, and glucose-lowering activities of curcumin and its analogs may be useful in the prevention and/or treatment of type 2 diabetes. In a nine-month, randomized, double-blind, placebo-controlled study in 237 subjects with impaired glucose tolerance (pre-diabetes), no progression to overt diabetes was reported with a daily ingestion of a mixture of curcuminoids (0.5 g), while 16.4% of placebo-treated participants developed diabetes. In addition, curcumin supplementation was shown to reduce insulin resistance and improve measures of pancreatic β-cell function and glucose tolerance. Supplemental curcumin was found to be as effective as lipid-lowering drug atorvastatin (10 mg/day) in reducing circulating markers of oxidative stress (malondialdehyde) and inflammation (endothelin-1, TNFα, IL-6) and in improving endothelial function. Another randomized controlled trial also reported that oral curcumin supplementation (1.5 g/day) for six months improved endothelial function, insulin sensitivity, and metabolic markers associated with atherogenesis (plasma triglycerides, visceral fat, total body fat) in participants with type 2 diabetes. Finally, in a two-month randomized, double-blind, placebo-controlled study in 40 individuals with type 2 diabetic nephropathy (kidney disease), daily curcumin ingestion (66.3 mg) significantly reduced urinary concentrations of proteins and inflammation markers (TGF-β, IL-8), suggesting that curcumin might be helpful with slowing the progression of kidney damage and preventing kidney failure. The research on curcumin suggests it can work as a hypoglycemic agent—lowering and helping control blood glucose (blood sugar) levels in people with type 2 diabetes. This can ultimately prevent those with the disease from developing other serious health complications associated with diabetes, such as neuropathy (damage to the nervous system) and nephropathy (kidney disease). A study published in the journal Biochemistry and Biophysical Research Community explored how curcumin might be valuable in treating diabetes, finding that it activates AMPK (which increases glucose uptake) and suppresses gluconeogenic gene expression (which suppresses glucose production in the liver) in hepatoma cells. Interestingly, they found curcumin to be 500 times to 100,000 times (in the form known as tetrahydrocurcuminoids(THC)) more potent than metformin in activating AMPK and its downstream target acetyl-CoA carboxylase. Diabetic neuropathy is a type of neuronal damage, associated with chronic diabetes, characterized by demyelination and deterioration of nerve fibers, alterations in the micro- vasculature and loss of sensory fibers that leads to pain, foot ulcers, amputations, depression, phobias, anorexia, loss of memory and reduction in complex reasoning skills (Patel and Udayabanu 2013).

Curcumin treatment (50 mg/kg, for 8 weeks) upregulated BDNF in frontal cortex and hippocampus alongside reduced oxidative damage in the hippocampus of diabetic db/db mice (Franco-Robles et al. 2014). Curcumin administration significantly increased Na (þ) -K (þ) -ATP activity, reduced lactate dehydrogenase (LDH) activity and lactic acid content as well as stimulates Ca (þ) -Mg (þ) -ATP activity in brain homogenate of alloxan induced diabetic mice. In addition, curcumin administration ameliorated energy metabolism in the brain homogenate of diabetic mice (Miao, Cheng, and Li 2015). Curcumin administration (60 mg/kg, p.o., for two weeks) downregulated the expression of glucose transporter (GLUT) type 3, muscarinic receptor type 3, a7-nicotinic receptor and AChE in brain- stem and cortex of streptozotocin induced diabetic rats. In addition, it reduced the expression level of insulin receptor and choline acetyltransferase in brainstem. Curcumin treatment upregulated the gene expression of choline acetyltransferase, SOD and insulin receptor in cortex. It is known to upregulate the expression level of muscarinic cholinergic receptor 1 in brainstem and cerebral cortex (Kumar et al. 2013) as well as attenuate cognitive deficits in streptozotocin induced diabetic rats (Kumar et al. 2011). Curcumin treatment (60 mg/kg, p.o., for 15 days) downregulated the expression level of dopaminergic D1 and D2 receptor in the cortex. In addition, curcumin administration significantly upregulated dopaminergic D1 receptor and downregulated D2 receptor in the cerebellum of diabetic rodents. Curcumin treatment upregulated phospholipase C and transcription factor cAMP response element-binding protein expression in the cerebellum and cortex of streptozotocin induced diabetic rats resulting in amelioration of emotional and cognitive performance (Kumar et al. 2010). Curcumin administration (60 mg/kg, p.o., for 16 days) upregulated the glutamate decarboxylase while downregulated Bax, caspase 3 and caspase 8 expressions in the cerebral cortex. In addition, curcumin administration attenuated NMDA and AMPA receptor mediated oxidative stress and excitotoxicity in the cerebral cortex of streptozotocin induced diabetic rats (Jayanarayanan et al. 2013). Curcumin supplemented (0.5%) with animal’s diet decreased b-d-glucuronidase activity (Chougala et al. 2012), nitric oxide level, total oxidant status, MDA level and oxidative stress index. Diabetes mellitus, commonly referred to as diabetes, is a chronic metabolic disorder characterized by hyperglycemia, glycosuria, negative nitrogen balance, polydipsia and sometimes ketonemia. In a randomized, double-blind, placebo-controlled trial, oral curcumin extract supplementation (three capsules per day, each curcumin capsule has curcuminoid content of 250 mg) for nine months ameliorated b-cell function, lowered C-peptide and increased homeostasis model assessment-b, reduced insulin resistance and increased the adiponectin level in type 2 diabetic subjects as compared to placebo group (Chuengsamarn et al. 2012). In another clinical study, curcumin administration lowered the level of HbA1c and fasting blood glucose as well as partially reduced LDL-cholesterol and body mass index in diabetic subjects (Rahimi et al. 2016). A recent meta-analysis revealed that, curcumin or combined curcuminoids supplementation effectively lowered the level of fasting blood glucose in individuals with some degree of dysglycemia. In addition, isolated curcumin supplementation significantly decreased HbA1c as compared to placebo and suggested its beneficial role as adjuvant in the treatment of dysglycemic patients (de Melo, Dos Santos, and Bueno 2018). In animal study, curcumin administration is reported to reduce glucose intolerance through induction of glucagon-like peptide-1 secretion. In addition, curcumin administration is known to reduce insulin resistance by downregulating phosphorylation of IRS-1 serine residue and upregulating phosphorylation of IRS-1 tyrosine in the skeletal muscle of rats fed with high fructose. Curcumin treatment also reduced glucose intolerance, hyperinsulinemia and homeostasis model assessment-insulin resistance (HOMA-IR) level. Curcumin treatment decreased C reactive protein and TNF-levels besides downregulated the protein kinase theta (PKCh) and COX-2 protein expressions. Additionally, curcumin significantly downregulated extracellular kinase 1/2 (ERK 1/2) and p38 protein expressions in skeletal muscle. Further, curcumin treatment ameliorated the activity of GPx and attenuated the activation of inflammatory cascades (Maithilikarpagaselvi et al. 2016). Curcumin treatment significantly reduced systolic blood pressure, LDL-cholesterol, triglycerides, aspartate transaminase (AST), alanine transaminase (ALT), total cholesterol, glycemia, total oxidative status, MDA and nitrative stress. A recent study demonstrated that, curcumin administration (100 mg/kg, p.o., daily for 8 weeks) attenuated splenic damage and improved immunity in streptozotocin-induced diabetic rats via antioxidant, anti-inflammatory and anti-apoptotic mechanisms  (Rashid et al. 2017). Curcumin treatment is known to attenuate diabetes and its associated complications like liver disease, adipocyte dysfunctions, pancreatic beta cell dysfunction, vascular dysfunction, nephropathy, neuropathy, retinopathy etc. (Zhang et al. 2013b). In cell culture studies, curcumin treatment suppressed palmitate-mediated insulin resistance, inhibited the ubiquitin-proteasome system, reduced the endoplasmic reticulum (ER) protein aggregation and activated the autophagy signaling in human umbilical vein endothelial cells (Ye et al. 2017). The suggested anti-diabetic mechanisms of curcumin effects are ameliorating b-cell dysfunction, insulin signaling, glucagon like peptide-1 secretion, and reducing glucose intolerance, hyperglycemia, hyperinsulinemia, HOMA-IR level, hyperlipidemia, islet apoptosis and necrosis etc. Therefore, these finding demonstrate that curcumin supplementation in diabetic population may be beneficial.
 
How may Curcumin work against CANCER?

In recent years, in-depth studies of cancer progression have revealed that curcumin suppresses tumors by interfering with all aspects of tumor progression, which is the action of some of the most promising anticancer drugs. First, at the root of cancer progression, curcumin has been shown to elevate the ubiquitination level of TAZ that increases proteasome-degrading TAZ protein, thereby activating the hippo pathway and negatively regulating cancer stem cell function. Additionally, curcumin significantly impedes the self-healing of circulating cancer stem cells, limiting stem cell metastasis. Curcumin also alters the expression of more than 700 genes linked to carcinoma development, such as those involved in DNA recovery or associated with the cell cycle, cell proliferation, or metastasis in NCI-H460 human lung cancer cells. Researchers revealed that curcumin not only changes the expression of many genes, but also alters signaling pathways. Through further investigation, it was found that those curcumin-altered genes induce cell death and control extracellular matrix receptors, repressing NSCLC cell proliferation and migration. These observations indicate that curcumin governs NSCLC tumor growth and exhibits cytotoxic mechanisms at the genetic level. Curcumin possesses various biological activities, such as anticancer effects on various cancers, such as breast, liver, lung, gastric and prostate cancers. The anticancer effects of curcumin have been extensively studied in different cancers, such as breast, lung, colorectal, head and neck, gastric, bladder, prostate, thyroid, liver, ovarian, oral, pancreatic, cervical, tongue and brain cancers. Because of its multitargeting activities, curcumin has exhibited activities against numerous cancer types in human clinical trials. Probably the first indication of curcumin’s anticancer activities in human participants was shownby Kuttan and co-workers, who conducted a clinical trial involving 62 patients with external cancerous lesions. Curcumin was found to produce remarkable symptomatic relief as evidenced by reductions in smell, itching, lesion size, and pain. Kuttan and his colleague’s work was the first to demonstrate curcumin’s anti-cancer potential in both in vitro and in vivo experimental models (Kuttan et al., 1985). Curcumin activates DNA damage response, laying the foundation for the therapeutic use of these nutraceuticals in prostate cancer chemoprevention (Horie, 2012). The general anti-carcinogenic effect of curcumin involves mechanisms like induction of apoptosis and inhibition of cell-cycle progression in rat aortic smooth muscle cells (Chen and Huang, 1998). The antiproliferative effect is regulated partly through hindrance of protein tyrosine kinase activity and c-myc mRNA expression, while the apoptotic effect may partly be mediated via preventing the functioning of protein tyrosine kinase, protein kinase C, and expressions of c-myc mRNA and bcl-2 mRNA (Chen and Huang, 1998). Curcumin inhibits the transcription factor NF-κB (Figure 6) and various downstream gene products like c-myc, Bcl-2, COX-2, nitric oxide synthase (NOS), Cyclin D1, TNF-α, ILs, and matrix metallopeptidase 9 (MMP-9) and has anti-proliferative activities in a diversity of malignancies. Curcumin, either alone or in combination with other agents, has demonstrated potential against colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, multiple myeloma, lung cancer, oral cancer, and head and neck squamous cell carcinoma. Curcumin was found to exert its anticancer activities in many different types of cancer cells by regulating a variety of signaling pathways.  Curcumin induces cell death in numerous animal and human cell lines, including leukemia, melanoma, and carcinomas of the breast, lung, colon, kidney, ovaries and liver. It appears to function by caspase­dependent and independent (mitochondrial) mechanisms, which are associated with the presence and absence of p53. Curcumin has been studied as a beneficial herb in cancer treatment and been found to affect cancer growth, development and spread at the molecular level. Studies have shown that it can contribute to the death of cancerous cells and reduce angiogenesis (growth of new blood vessels in tumors) and metastasis (spread of cancer). Multiple studies indicate that curcumin can reduce the growth of cancerous cells in the laboratory and inhibit the growth of tumors in test animals. There is also evidence that it may prevent cancer from occurring in the first place, especially cancers of the digestive system like colorectal cancer. Curcumin is capable of inhibiting the growth of cancer cells in skin, oral, intestinal, and colon cancers. Animal models show that not only does curcumin block growth of cancer cells in these models, but it also increases the number of cancer-fighting enzymes in the system.  A 2011 study works to quantify the prohibitive properties of curcumin on cancer cells in head and neck squamous cell carcinomas. This type of cancer is the 6th most commonly-diagnosed cancer in the United States. That study showed curcumin not only works as a treatment for squamous cell carcinomas with incredibly promising results, but it has also been shown to demonstrate powerful anti-cancer properties. Part of the excitement surrounding the potential anti-cancer benefits of curcumin revolves around the safety of use of the compound. It is considered pharmacologically safe, which means there are no known drug interactions or specific reactions among patients, making it extremely well-tolerated. For more evidence that turmeric with curcumin in particular being a powerful anti-cancer compound, we need only look at the rates of cancer in parts of the world where turmeric is consumed in higher quantities. Over the years, cancer research has examined the role curcumin plays in treating this disease. Curcumin is antimutagenic as it potentially helps to prevent new cancers that are caused by chemotherapy or radiation therapy used to treat existing cancers. It effectively inhibits metastasis (uncontrolled spread) of melanoma (skin cancer) cells and may be especially useful in deactivating the carcinogens in cigarette smoke and chewing tobacco. Curcumin generates an anticancer effect by inhibiting nuclear factor kappa B (NF-κB), and also reduces the formation of glycation end products which induce inflammation. Curcumin also mediates anticancer activity by targeting many other enzymes/pathways, maintaining levels of vitamins C and E, preventing peroxidation of lipid, and DNA damage. Curcumin targets transformed cells without altering primary astrocytes. It also promotes apoptosis, and shows a synergistic effect in combination cisplatin and doxorubicin drugs. An active constituent of turmeric suppresses carcinogenesis in multiple human carcinomas, which include ovarian cancers, stomach cancer, colon cancer, breast cancer, head and neck cancer. Curcumin suppresses the carcinogenesis by targeting diverse molecular targets of cellular division and apoptosis. The beneficial effects of curcumin on various transcription factors, oncogenes, and signalling proteins are well known. It also targets various stages of carcinogenesis from the initial stage to tumorigenesis, growth, invasion, and metastasis. Animal studies involving rats and mice as well as in vitro studies utilizing human cell lines have demonstrated curcumin's ability to inhibit carcinogenesis at three stages: Tumor promotion, angiogenesis, and tumor growth. In two studies of colon and prostate cancer, curcumin inhibited cell proliferation and tumor growth. The anticarcinogenic effects of turmeric and curcumin are due to direct antioxidant and free-radical scavenging effects and their ability to indirectly increase glutathione levels, thereby aiding in hepatic detoxification of mutagens and carcinogens and in inhibiting nitrosamine formation. A number of laboratory studies on cancer cells have shown that curcumin does have anticancer effects. These studies have found that curcumin can significantly inhibit the growth, development and movement of cancer throughout the body. It seems to be able to kill cancer cells and prevent more from growing. It has the best effects on breast cancer, bowel cancer, stomach cancer and skin cancer cells. An American study that combined curcumin with chemotherapy to treat bowel cancer cells in a laboratory showed that the combined treatment killed more cancer cells than the chemotherapy alone. Another American study seemed to show that curcumin helped to stop the spread of breast cancer cells to other parts of the body. Doctors think that curcumin stays in the digestive system and is absorbed by the cells in the bowel. Several studies have shown that curcumin taken as capsules does get absorbed by the gut and is present in the blood. One of the mechanisms by which it does this is reducing the growth of new blood vessels in tumors (otherwise known as angiogenesis) and can also directly contribute to the death of cancerous cells. Scientists discovered that turmeric is effective in killing cancer cells and also preventing their growth. According to the American Cancer Society, tests indicate that curcumin "interferes with several important molecular pathways involved in cancer development, growth and spread" and has boosted the effects of chemotherapy in animals. Curcumin has the potential for treatment of cancers including colon, breast, prostate, lung, skin and bowel. Curcumin shows a strong ability to kill cancer cells as well as inhibit their growth, boost antioxidant levels and balance the immune system. It seems to work on improving mitochondrial function at a cellular level. Even against drug-resistant strains of leukemia, curcumin caused cell death of cancer cells. Curcumin has been shown to substitute chemotherapy for colorectal cancers, and in multidrug resistant cancers. The ability of curcumin to regulate a variety of signaling pathways involved in cell growth, apoptosis, invasion, metastasis, and angiogenesis in preclinical studies elicited scientific interest in its potential as an anticancer agent in tumor therapy. Curcumin is one of the most powerful and promising chemopreventive and anticancer agents, and epidemiological evidence demonstrates that people who incorporate high doses of this spice in their diets have a lower incidence of cancer. Curcumin's epigenetic modulation has been studied by the US National Cancer Institute (NCI) and academic investigators around the world. Because of low toxicity and great efficacy in multiple in vitro and in vivo cancer models, Curcumin was selected for further development, put through extensive toxicology testing and has successively made it through the first stages (Phase I) of clinical testing abroad and is currently in clinical trials at several sites in the U.S. A phase I clinical trial looked at giving curcumin to 25 patients with pre cancerous changes in different organs. This study seemed to show that curcumin could stop the precancerous changes becoming cancer. Numerous mechanisms have been described for the anticancer activity of Curcumin. Curcumin inhibits the NF-ŒB and STAT3 signaling pathways, which play key-roles in the development and progression of cancer. It inhibits a highly expressed transcription factor Sp-1 and its downstream genes, including ephrin type-B receptor 2 precursor, HDAC4, calmodulin and ADEM10 which serve as an important mechanism to prevent metastasis. Curcumin enhances the expression of several extracellular matrix components and inhibits the phosphorylation of focal adhesion kinase (FAK) and CD24 expression, thus prevents cancer formation, migration and invasion (Vallianou et al. 2015; Shi et al. 2001; Zhou et al. 2013). In addition, the potential mechanism of the anti-invasive effect of curcumin includes downregulation of Akt, EGFR, cyclin D1, cMET and upregulation of DNAJ/heat shock protein (HSP) 40 chaperone. Recent studies revealed that ER stress and autophagy might involve in apoptosis process. Mechanistically, autophagy inhibition could increase curcumin induced apoptosis by inducing ER stress (Vallianou et al. 2015). Further, the anticancer effects induced by phytoconstituent curcumin in malignant cells are mediated via the modulation of multiple signaling pathways and its effectors. Curcumin induced anti-carcinogenic effects includes down-regulation of the insulin-like growth factor type-1 receptor (IGF-1R), EGFR/avian erythroblastosis oncogene B1 (erbB1), erbB2/human epidermal growth factor receptor 2 (HER2), Wnt/b-catenin and sonic hedgehog/glioma associated oncogene (SHH/GLIs), and their respective downstream signaling effectors. Curcumin modulates intra-cellular signal transduction elements such as p21, p27, inhibitor of growth family member 4 (ING4), cyclin D1, c- Myc, VEGF, ICAM-1, MMPS, uPA, COX-2, CXCR-4, Bax, Bad, Bak, Noxa, p53, modulator of apoptosis, caspases etc. resulting in reversal of cancer incidence, progression and relapse (Figure 4) (Jordan et al. 2016; Mimeault and Batra 2011; Kasi et al. 2016). A2012 study indicates that rates of colorectal cancer in India are among the lowest in the developed world. Another study from 2016 shows that Indian women are less likely to be diagnosed with breast cancer, as well. Part of the reason for the lowered cancer rates in India has been attributed to diet, with turmeric and curcumin being major dietary contributors in that part of the world. Combining curcumin with anticancer drugs like gemcitabine in pancreatic cancer, docetaxel in breast cancer, and imatinib in chronic myeloid leukemia may be safe and well tolerated. A recent single-arm, phase II trial combining three cycles of docetaxel/prednisone and curcumin (6 g/day) was carried out in 26 patients with castration-resistant prostate cancer. The level of prostate-specific antigen (PSA) was decreased in most patients and was normalized in 36% of them, and the co-administration of curcumin with drugs showed no toxicity beyond adverse effects already related to docetaxel monotherapy. Many registered phase I/II clinical trials designed to investigate the effectiveness of curcumin alone or with first-line treatment in patients with breast, prostate, pancreatic, lung, or colorectal cancer are under way. Research into preventing cancer: A phase I clinical trial looked at giving curcumin to 25 patients with pre-cancerous changes in different organs. This study showed how curcumin could stop the precancerous changes becoming cancer. A number of laboratory studies on cancer cells have shown that curcumin does have anticancer effects. It kills cancer cells and prevent more from growing. It has the best effects on breast cancer, bowel cancer, stomach cancer and skin cancer cells. A study that combined curcumin with chemotherapy to treat bowel cancer cells in a laboratory showed that the combined treatment killed more cancer cells than the chemotherapy alone. An American study in mice showed that curcumin helped to stop the spread of breast cancer cells to other parts of the body. Doctors think that curcumin stays in the digestive system and is absorbed by the cells in the bowel. Several studies have shown that curcumin taken as capsules does get absorbed by the gut and is present in the blood. A number of activities of curcumin, which are exerted in a chemopreventive and a directly therapeutic manner, indicate that it may be a potential anticancer remedy. Researchers at M.D. Anderson Cancer Center in Houston, TX state that Curcumin has “enormous” potential to prevent and treat cancer. Curcumin was able to suppress tumor formation, growth, and even metastasis according to their review. Currently, there are clinical trials being conducted on the effects of Curcumin on patients with bowel cancer. According to the American Cancer Society, tests have shown that curcumin can kill cancer cells in laboratory dishes, and also slow the growth of the surviving cells. Furthermore, it has been found to reduce the development of several forms of cancer in lab animals, while also shrinking various animal tumors. A review - Anticancer Potential of Curcumin: Preclinical and Clinical Studies - in Anticancer Research concluded that, "…it is quite apparent that curcumin has tremendous potential for prevention and therapy of various cancers." Another study on the role of curcumin in cancer therapy found that,  curcumin is a potent anti-inflammatory agent with strong therapeutic potential against a variety of cancers. Curcumin has been shown to suppress transformation, proliferation and metastasis of tumors, and called for additional and larger controlled studies to determine its full potential. Inhibition of proliferation of tumor cells, induction of apoptosis (a mode of cell death), inhibition of transformation of cells from normal to tumor, inhibition of invasion and metastasis and suppression of inflammation have been linked with the activity of curcumin. Resistance to chemo and radiotherapy is the major reason for cancer relapse. This arises due to the presence of a subpopulation of cancer cells, having self-renewal capabilities called Cancer Stem Cells (CSCs). Studies have confirmed that curcumin could inhibit the breast cancer stem cell population by downregulating the expression of stem cell genes Oct4, Sox2 and Nanog and also the Epithelial-Mesenchymal Transition (EMT) as observed by the down-regulation of mRNA levels of Vimentin, Fibronectin and β-catenin and up-regulation of mRNA levels of E-cadherin (Hu et al., 2019). A combination of sub-optimal dose of 5-FU and curcumin elicits synergistic antitumor potential in murine models as evaluated by a reduction in the tumor-related parameters. Mechanistically, curcumin down-regulates 5-FU induced up-regulation of Thymidylate Synthase (TS), which is responsible for 5-FU chemoresistance (Vinod et al., 2013; Haritha et al., 2021). Another study reported that cervical cancer cells can be sensitized by curcumin to paclitaxel-induced apoptosis through down-regulation of NF-κB, Akt and Bcl2 (Bava et al., 2011). The chemopreventive agent curcumin also act as a potent radiosensitizer in human cervical tumor cells. Curcumin pre-treatment increased reactive oxygen species production and overactivation of the mitogen-activated protein kinase pathway in HeLa and SiHa cells when treated with Ionising Radiation (Javvadi et al., 2008).  Mechanism of action of curcumin mainly involves down-regulation of transcription factor NF-κB by inhibition of Notch signalling, which is involved in cell proliferation, apoptosis, maintenance of stem cell and their renewal. This results in a reduction in expression of NF-κB regulated genes, which includes Bcl-2, cyclin D1 and VEGF (O’riordan et al., 2005). Curcumin is a strong inhibitor of Protein Kinase C (PKC) and several oncogenes such as c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt and CDKs. Curcumin also inhibits of the Notch-1 downstream target Hes-1 in esophageal cancer cells. Hes-1 is an important notch signalling target and mediator (Subramaniam et al., 2012). The curcumin analog, 2-pyridylcyclohexanone has also been shown to decreases basal STAT3 phosphorylation and promotes apoptosis in esophageal cancer cell, ESCC cells (Wang et al., 2018). Curcumin quenches free radicals, induces antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), and up-regulates antioxidative protein markers, Nrf2 and HO-1 that led to the suppression of cellular oxidative stress. In cancer cells, curcumin aggressively increases ROS that results in DNA damage and subsequently cancer cell death (Ak and Gülçin 2008). Curcumin was found to suppress inflammatory cytokines such as IL-6, IL-8, granulocyte macrophage colony stimulating factor and TNF-α as well as IKKβ kinase in the saliva of HNSCC patients. Kim SG., et al., also suggested that IKKβ kinase could be a plausible biomarker for the detection of the effect of curcumin in head and neck cancer as curcumin inhibited IKKβ kinase activity and this resulted in the reduced expression of a number of cytokines (Kim et al., 2011). Molecular docking studies further aids in identifying the role of curcumin in numerous signalling cascades involved in carcinogenesis and confirms the already suggested molecular mechansims responsible for the chemopreventive efficacy of curcumin. Using inverse molecular docking several proteins associated with cell proliferation and tumor formation namely, macrophage colony stimulating factor 1 receptor, aldo-keto reductase family 1 member C3, amiloride-sensitive amine oxidase and tyrosine-protein phosphatase non-receptor type 11 were identified as potential targets of curcumin. Curcumin was previously reported to inhibit the NFkB mediated activation of genes linked to cell survival and proliferation (Divya and Pillai 2006). Proteins such as MMP-2, NAD-dependent protein deacetylase sirtuin-2, core histone macro-H2A.1, NAD-dependent protein deacetylase sirtuin-1 and epidermal growth factor receptor were also revealed to be targets of curcumin, the binding of which regulates the activity of NF-kB (Furlan et al., 2018). These results provide a mechanistic explanation for the anticancer effects of curcumin. Targeting Phosphodiesterase 4 (PDE4) has been reported to be a potential therapeutic strategy against inflammatory disorders (I Sakkas et al., 2017). Studies suggest that curcumin may exhibit its anti-cancer property through the inhibition of PDE2 and PDE4 (Abusnina et al., 2015). Furlan et al. also gives evidences for the inhibitory effect of curcumin on PDE4 (Furlan and Bren 2021).
Curcumin as an Anti-Inflammatory
| It has been observed that chronic inflammation is responsible for several diseases, such as tumor progression, autoimmunity, allergies, and arthritic syndromes. Numerous researches revealed that curcumin can decrease pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1, and IL-8 by interfering with several signaling and transcription factors such as NF-кB, JAKs/STATs, and MAPK pathways (64). The anti-inflammatory activity of curcumin mainly depends on its potentiality to inhibit NF-kβ activation. Curcumin inhibits inflammation by downregulating cytokines, IL-1, IL-8, and TNF-α. Curcumin blocks TNF-mediated NF-кB activation in human myeloid ML-1a cells by suppressing activator proteins. Curcumin also blocks NF-кB activation by hydrogen peroxide and phorbol esters. IL-1β-mediated ICAM-1 and IL-8 gene expression are also inhibited by curcumin, which finally leads to the inhibition of NF-кB activation. JAK/STAT is an important signaling pathway in maintaining inflammation in immune cells. It transduces signal type 1 and 2 cytokine receptors in response to pro-inflammatory cytokines. Curcumin inhibits JAK/STAT pathway by blocking the phosphorylation of JAK-1 and -2 and STAT-1 and -2 in IFN-γ, gangliosides, and LPS-activated microglial cells. Curcumin has a distinct role in the inflammatory MAPK pathway. Curcumin significantly lowers the PGE2 (prostaglandin E2) level and the expression of TNF-α and IL-6 by preventing phosphorylation and activation of p38 MAPK functioning. Curcumin can suppress LPS-induced phosphorylation of p38, JNK, and ERK1/2-mediated MAPKs pathways and subsequently inhibit the ROS production by microglial cells (70). Kim et al. validated that if immature DCs cells pre-treated with curcumin, it blocked the LPS-induced maturation function of DCs by preventing phosphorylation of p38-, JNK-, and ERK1-/2-mediated MAPK signaling, which consequently checks the inflammation occurrence .It is well known that the human body is capable of self-healing after a short-term inflammatory response, but long-term chronic inflammation could lead to initiation of the cancer process. Many studies have shown that inflammatory factors (including interleukins, TNF-α, NF-ϰB) and the ROS production-induced inflammation infiltrate the inflammatory microenvironment leading to DNA damages and ultimately initiation of cancer. By acting on several signaling pathways, especially the WNT/β-catenin pathway, curcumin can have anticancer effect by inhibiting chronic inflammation and oxidative stress. The chronic inflammatory microenvironment of tumors could also be targeted by curcumin.
Immunomodulatory Role of Curcumin | Curcumin can inhibit the expansion of T cells triggered by plant lectin concanavalin A (Con A), according to a report on the role of the genus Curcuma and its bioactive metabolites to control the immunological response. Curcumin inhibits lymphoma B-cell proliferation by lowering the potency of c-MYC, BCL-XL, and NF-κB. Curcumin has also been demonstrated to suppress the production of ROS in macrophages. Curcumin also stimulates NK cell apoptosis by modulating the NF-κB pathway and inhibiting BCL-XL and Cyclin D. Curcumin inhibits IL-1 and IL-6 inflammatory cytokines such as from LPS-stimulated dendritic cells and suppresses the expressions of CD80, CD86, and MHC class II by dendritic cells. Curcumin also causes reduced LPS-induced MAPK activation and NF-κB p65 translocation in dendritic cells (Nair et al., 2017) along with impaired activation of Th1 responses. Curcumin significantly suppressed the formation of IL-6, IL-8, TNF-α, and MCP-1 from higher glucose-cultured monocytes, according to Jain et al. (2009). Curcumin decreased NOS activity and macrophages’ ability to secrete nitric oxide (NO). In the management of immune modulation, curcumin treatment can promote the activation of immune component cells, including reduce excessive activation of inflammation and allergy, and enhance endogenic immune activity to fight foreign pathogens or cancer cells. Remarkably, curcumin can suppress intracellular NF-κB, MAPKs, JAKs/STATs, β-catenin, and the Notch-1 pathway by regulating the expression and secretion of pro-inflammatory cytokines, such as IL-1β, TNF-α, IL-2, IL-6, IL-10, which mediate inflammatory pathways. In the managements of clinical treatment, curcumin can also be applied to autoimmune diseases therapies, such as lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, psoriasis, etc. Curcumin treatment can restore cellular immune-reactive T cells and assist the body to fight endogenous cancer cells and exogenous pathogens. In vitro and in vivo data showed curcumin can hinder cancer cell proliferation or cause cancer cell apoptosis. Curcumin as an immunomodulator interacts not just with various cellular components, such as DCs, macrophages, natural killer cells, and both B and T lymphocytes, but also with modulatory molecules involved in the processes of inflammation and cell proliferation with their downstream signaling. In recent times, curcumin has gained the potential therapeutic interest to cure neoplastic disease, because of its significance as an anti-inflammatory and anti-proliferative substance. The anti-cancer properties of curcumin also modulate several other signaling pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, angiogenesis, and metastasis. The effectiveness of curcumin has been proven in the restoration of CD4+ and CD8+ cells in the TME and in directing Th2 cytokine bias towards Th1-type response again. It increases Th1-type immune responses and upregulates IFN-γ mRNA expression. Curcumin effectively reduces Treg cell population and levels of IL-10 and TGFβ. It also can reduce the expression of CTLA4 and FOXP3 both at protein and mRNA levels (55). Interestingly, curcumin has the potentiality to encounter all “six hallmarks” of cancer cells and checks tumor outgrowth in the host. Hence, it is considered very interesting to envision the role of curcumin concerning cancer immunotherapies as an immunomodulator.
Effects of Curcumin on Immune Cells |  Curcumin has the potentiality to modulate the proliferation and activation of T cells. Depending on the dose, it can both suppress and induce the proliferation of T cells. Several studies reported that curcumin downregulates the proliferation of T cells induced by concanavalin A (Con A), phytohemagglutinin (PHA), and phorbol-12-myristate-13-acetate (PMA). Tomita et al. reported that curcumin can suppress the proliferation of HTLV-1-infected T cells and primary ATL cells through cell cycle arrest and induction of apoptosis. Research carried out by Hussain et al. stated that in T cell acute lymphoblastic leukemia, curcumin blocks constitutively activated targets of PI3-kinase (AKT, FOXO, and GSK3) in T cells, which lead to the inhibition of proliferation and induction of caspase-dependent apoptosis. On B cell: Curcumin prohibits the proliferation of B-cell lymphoma cells via downregulation of c-MYC, BCL-XL, and NFκB activities. It also blocks Epstein–Barr virus (EBV)-induced immortalization of B-cells. On macrophage: Curcumin modulates macrophage activities, prevents generation of ROS in macrophages, and stimulates enhanced phagocytosis of peritoneal macrophages in mice. On Natural Killer cell: Curcumin works against natural killer T cell lymphoma cell lines, where it induces apoptosis by controlling the NFκB pathway and suppression of BCLXL, Cyclin D1, etc.. On DC: Curcumin can reduce the expression of CD80, CD86, and class-II antigens by DCs. Curcumin suppresses the release of inflammatory cytokines like IL-1β, IL-6, and TNF-α from LPS-stimulated DCs. Curcumin also modulates phosphorylation of MAPK and nuclear translocation of NFκB in DCs.
Curcumin as an Anti-Proliferative and Anti-Metastatic Substance | Curcumin acts upon numerous cell proliferation signaling pathways that are intensely associated with cancer progression. Curcumin inhibits NF-кB signaling by suppressing IкB kinase activity. Curcumin suppresses the other proliferation signaling pathways, such as PI3K, AKT, mTOR, AP1 (JUN and FOS), JNK, JAK/STAT, PKC, CMYC, MAPK, ELK, CDKs, iNOS, and Wnt/β-catenin, which confirmed its vital role in the prevention of cancer progression. Cyclin D1, the proto-oncogene that is highly expressed in several types of cancer and acts in cell cycle progression and proliferation, is also suppressed by curcumin. Along with this, curcumin also inhibits excessive TGFβ receptor signaling and EGF- and EGFR-mediated signaling pathway and remarkably controls epithelial-to-mesenchymal transition, metastasis, and tumor progression, respectively. A significant activity of the telomerase enzyme has been observed in cancer cells, which prevents telomere shortening and stimulates continuous cell proliferation signaling. Curcumin prevents human telomerase (hTERT) activities and reduces hTERT-mRNA expression that led to telomere shortening. By targeting telomerase activities, controlling replicative cell senescence and mortality, curcumin ultimately controls the uncontrolled cell proliferation of cancer cells. Numerous studies have reported the incredible potentiality of curcumin to inhibit cell migration, invasion, and colony formation in vitro and decrease tumor growth and metastasis in vivo. Curcumin downgrades the expression of matrix metalloprotease, CCRX4, COX2, ELAM1, and ECAM1, which are essential for metastasis. Besides, curcumin also hampers the functioning of SLUG, SNAIL, FAK, TWIST, and other essential transcription factors that play a crucial role in the metastasis process.
Curcumin as an Apoptotic and Anti-Angiogenic Substance

Curcumin has been suggested as an enhancer of apoptosis in cancer cells. It has the ability to modulate a wide range of signalling pathways involved in apoptosis resistance in cancer cells. Curcumin also triggers programmed cell death in colon cancerous cells and inhibits micro-inflammation in the gastrointestinal system linked to inflammatory bowel illnesses, according to laboratory research (Nita, 2003). Okanlawon et al. (2020) determine the influence of the inclusion of powdered C. longa on carcass yield and intestinal increase in rabbit production. Farombi et al. (2007) explored the combined effects of curcumin and kolaviron (a bioflavonoid extracted from Garcinia kola seeds) on DBP-induced testicular injury in rats. Curcumin treatment of mice infected with human prostate cancer cells resulted in a lowered microvessel density, cell proliferation, an improvement in apoptosis. Endothelial cells derived from bovine aorta exposed to curcumin (5–15 μM) under normoxic (oxygen tensions within 10–21%) or hypoxic (oxygen tensions within 1–5%) conditions were reported to increase heme oxygenase activity and resistance to oxidative stress. Consumption of alcohol sensitizes the pancreas to give an inflammatory response through NF-κB activation via protein kinase C epsilon. One pilot study concluded that an oral dosage of 500 mg of curcumin with 5 mg of piperine could restore lipid peroxidation in patients suffering from tropical pancreatitis (Durgaprasad et al., 2005).A common property for most cancer cells is some mutations in tumor suppressor genes, especially p53 and PTEN. Mutations in these genes lead to them escaping cell death and also resistance to therapy. Curcumin has the ability to reverse the activities of both p53 and PTEN. Inhibition of mir-21 has a key role in the activation of PTEN, leading to inhibition of the PI3K/AKT pathway. Suppression of AKT following treatment with curcumin can cause degradation of MDM2, which leads to activation of p53. Furthermore, suppression of AKT can reduce the expression of anti-apoptotic genes such as COX-2, NF-κB and Bcl-2. Downregulation of these genes by curcumin has shown its potential to sensitize a wide range of cancer cells to chemotherapy and radiotherapy. In addition to the regulation of a wide range of genes in cancer cells, curcumin has been shown to modulate the tumor microenvironment in favor of tumor suppression. Inhibition of some immunosuppressive cells' cytokines such as IL-10 and TGF-β leads to more infiltration and proliferation of NK cells and CTLs as well as inhibition of tumor-promoting cells including TAMs, CAFs and Tregs. These immunoregulatory effects of curcumin lead to the release of dead signals such as FasL and TNF-α for cancers. Upregulation of Fas, TNFR and TRAIL because of elevated ROS production by cancer cells can facilitate apoptosis pathways following treatment with curcumin. Curcumin blocks the phosphorylation of another tumor suppressor protein, RB (Retinoblastoma), which plays a significant role in the cell cycle process. Curcumin induces both TP53-dependent and -independent apoptosis of cancer cells by upregulating pro-apoptotic molecules such as BAX, BIM, and PUMA and by downregulating anti-apoptotic molecules like BCL2, BCL-XL, and Survivin. Consequently, the caspase activity gets enhanced and proceeds to apoptosis. Besides, curcumin stimulates lysosomal proteases, phosphatases, and lipase activities, which induce autophagy-mediated cell death. Blocking the angiogenesis process is a vital step to control tumor outgrowth. Curcumin suppresses VEGF receptor (VEGFR1 and VEGFR2) expression, blocks VEGF/VEGFR-mediated signaling pathway, and downregulates angiopoietin expression to confine angiogenesis. In vitro and in vivo studies have indicated that curcumin prevents carcinogenesis by affecting two primary processes: angiogenesis and tumor growth. Turmeric and curcuminoids influence tumor angiogenesis through multiple, interdependent processes: i) action at the level of transcription factors associated with inflammatory processes and early growth response protein which reduces the expression of IL­8 in pancreatic and head and neck cancer cell lines and prevents the induction of VEGF synthesis; ii) inhibition of angiogenesis mediated by NO (nitric oxide) and iii) inhibition of COX­2 and 5­LOX; iv) action at the level of angiogenic factors: VEGF, the primary factor for migration, sprouting, survival and proliferation during angiogenesis, and basic fibroblast growth factor. Because of its anti-apoptotic and antiproliferative efficacy, its ability to interfere with several tumor progression associated signaling pathways, and to modulate tumor-associated miRNA expression, curcumin is regarded as antitumorigenic. In addition, curcumin prevents formation of breast and prostate metastases in vivo. The review by Willenbacher et al. in this issue summarizes some papers that have been published in the field of curcumin’s antitumorigenic effects. Curcumin is also potent against cancer types that are difficult to treat, like melanoma or glioblastoma, as demonstrated by the work of Maiti et al. in this issue. An American phase 2 study reported in 2008. 25 patients had curcumin treatment and 21 had tumors that could be measured. In 2 patients their tumors shrank or remained stable. In some patients their levels of particular immune system chemicals that destroy cancer cells went up. Curcumin also has been studied with regards to the core inflammatory gene signal, NF-kappaB, resulting in a beneficial domino effect throughout the body. One benefit of this domino effect is a direct reduction in the risk of cancer from overweight-induced inflammation. Curcumin has been found to induce cell-cycle arrest and apoptosis by regulating a variety of cell-signaling pathways (3, 41-45). For example, the inhibition of cell proliferation by curcumin has been associated with the Nrf2-dependent downregulation of DNA repair-specific flap endonuclease 1 (Fen1) in breast cancer cells in culture. Curcumin has been shown to induce p53-dependent or -independent apoptosis depending on the cancer cell type. In a panel of cancer cell lines, p53-independent apoptosis induced by curcumin was mediated by the rapid increase of ROS and the activation of MAPK and c-jun kinase (JNK) signaling cascades. Inhibition of NF-κB signaling by curcumin also suppresses proliferation and induces apoptosis in cancer cells.
Effect of Curcumin on Chemoresitance | Curcumin has a proven ability to counter chemoresistance in cancer cells. The ability of curcumin to modulate the regulatory networks governing the balance of cell survival and induction of cell death is well established. Curcumin has been demonstrated to amend the expression of molecules central to chemoresistance including members of the ABC drug efflux transporter family. Curcumin modulates the cancer metabolism and bio-physiological composition of the extracellular milieu culminating in the induction of cell death and retardation in disease progression. Metabolic alterations and suppression of receptor-mediated signaling were suggested to provide chemosensitization of cancer cells by curcumin. The previous investigation on hepatic carcinoma cells demonstrated that curcumin can thwart lactate-induced chemoresistance. Interestingly, curcumin can be exploited to provide health benefits in diabetes mellitus owing to its antioxidant and anti-inflammatory capabilities. In renal tubular epithelial cells, curcumin was also shown to obviate high glucose-induced epithelial-to-mesenchymal transition. High glucose conditions can aggravate the invasion and migration, while curcumin can impede the metastatic events in a variety of malignancies. Antineoplastic potential, metabolic modulatory ability, and chemosensitizing property along with safety investigations provide an edge to curcumin over other phytochemicals. Curcumin has the ability to avert high glucose-induced chemoresistance in cancer cells. Various aspects of the underlying mechanism were also explored. Curcumin mediated the amputation of chemoresistance by repressing the hyperglycolytic behavior of malignant cells via modulated expression of metabolic enzymes (HKII, PFK1, GAPDH, PKM2, LDH, SDH, IDH, and FASN), transporters (GLUT-1, MCT-1, and MCT-4), and their regulators. Along altered constitution of extracellular milieu, these molecular changes culminated into improved drug accumulation, chromatin condensation, and induction of cell death. Molecular alterations in the expression level of transcription factors (p53, HIF-1α, MYC), drug efflux pumps (MDR-1), and their regulators (HCAR-1, mTOR, and STAT3) can be suggested as the underlying molecular mechanism. This investigation contributed to the understanding of the anticancer ability of curcumin through the prevention of chemoresistance in hyperglycemic conditions along with underlying mechanisms. The demonstrated potential of curcumin against high glucose-induced chemoresistance will have implementations in clinical management of malignancies in diabetic patients.
Curcumin as an Anti-Tumor Substance | The anti-tumour activity of curcumin is mediated via anti-inflammatory, apoptosis-inducing, anti-oxidative and anti-angiogenic activities. In colon cancers, the anti-tumour activity of curcumin was mediated via inhibition of COX-2. P53 (apoptosis-inducing in stressful situations) has been shown to have a varied response to curcumin administration; overexpression in human hepatoblastoma, human breast cancer cells and human basal cell carcinoma and downregulation in colorectal carcinoma reveal that it may be tissue-specific. Its anti-angiogenic effect is by inhibition of angiogenic factors like fibroblast growth factor (FGF), ligands of VEGF and angiopoietin 1 and 2 and regulation of cell adhesion molecules like endothelial adhesion molecule-1 (ELAM-1), intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and cell surface proteins that are involved in tumour metastasis. Implementation of curcumin reduces cell mutations caused by exposure to carcinogens and induces the body's anti-tumor responses. Curcumin can promote M1-like tumor microglia activation and increase recruited natural killer cell to cause tumor decimation. Curcumin can inhibit the cancer cell proliferation by inhibit NF-κB, COX-2, CD-31, VEGF, and IL-8, matrix metalloproteinase (MMP)− 9. Turmeric extract or curcumin can inhibit the proliferation of cancer cells such as head and neck cancers,  lung cancer, digestive system cancer, urinary system cancer, and reproductive system cancer in vitro and in vivo. The oral submucosal fibrosis, which is highly associated with oral cancer, is a chronic latent disease that leads to the hardening of the oral mucosa and deep tissues, and extends to the wall of the throat or esophagus, gradually causing difficult or loss of eating, swallowing, and pronunciation. In clinical management of oral mucosal fibrosis, curcumin is evident to treatment can prevent, reduce, and improve oral mucosal fibrosis. Curcumin treatment can increase the levels of vitamins C and E in salivary and serum to enhance organism’s antioxidative values, and decrease the malonaldehyde, 8-hydroxydeoxyguanosine (8-OHdG) to decrease oxidative stress. In clinical application, curcumin is used as an adjuvant or supplement for chemotherapy or nuclear therapy in clinical tumor treatments to reduce postoperative adverse reactions, which still requires clinical verification. Curcumin has multiple potentials due to its numerous antineoplastic mechanisms for cancer therapy. Curcumin, a chemo-sensitizing agent, also enhances the efficacy of several chemotherapeutic agents. According to the study by Chen’s group, among four anticancer chemotherapeutic factors (erlotinib, sorafenib, sunitinib, and doxorubicin), sunitinib combined with curcumin at a molar ratio of 0.46 achieved the most potent synergistic effect in vitro and has been selected to be studied in an animal model. The anti-tumor effects of curcumin or turmeric extract in combination with bevacizumab in HT29 colon tumor-bearing mice have been examined by Yue’s group. When curcumin is combined with bevacizumab therapy, it suppressed tumor growth significantly with no physical side effects. This highly indicates the therapeutic promise of adjuvant application of curcumin for treating cancer, particularly combined with several mAbs. A clinical trial has been executed by Basak et al. with oral cancer patients where APG-157, a botanical drug containing multiple polyphenols, including curcumin has been administrated orally. According to the study, APG-157 was absorbed well and significant trace of curcumin has been found in the blood and in tumor tissues. This trial reported the downregulation of inflammatory markers and Bacteroides species in the saliva and upregulation of the immune T cells in the tumor tissue. Additionally, it reduced inflammation and attracted cytotoxic T cells to the tumor site, signifying its potential usage in combination with immunotherapy drugs. Curcumin alone induced a 49–55% reduction in mean ovarian cancer tumor growth compared with control animals, while the combination of curcumin with docetaxel resulted in a 77% reduction in mean tumor growth compared with the controls. In an animal study, the administration of curcumin decreased the number of lung tumor nodules and inhibited lung metastasis of melanoma. Therefore, it is possible to use curcumin in order to arrest the metastatic growth of tumor cells. 
A study conducted in 2014 revealed that curcumin was able to obstruct tumor growth and metastasis in several animals’ organs including the stomach, colon, and liver.
Effect of Curcumin on Lung Cancer | Cancer stem cell-based treatments with curcumin could be proven as potential processes and targets for tackling lung cancer (Ye et al., 2012). Curcumin also seems to promote tumor progression, reducing the efficiency of docetaxel in lung cancer patients. The therapeutic effect of curcumin has also been exploited in lung cancer. A mechanistic approach was used to study curcumin’s anti-cancer potential, by targeting JAK2/STAT3 and NF-κB signaling pathways, in the A549 lung cancer cell lin. In addition, curcumin, via PI3K/Akt signaling suppression and microRNA-192-5p up-regulation induced apoptosis in non-small cell lung cancer cells with inhibition of cell proliferation. In vivo curcumin lessens the migratory and invasive capabilities of A549 cells and inhibited adiponectin expression thought to be mediated through the NF-κB/MMP pathways and has been proposed as an adjuvant in lung malignancy (Tsai et al., 2015). Curcumin against human non-small cell lung cancer cell line A549, which showed 50% cell viability at a high dose of 10,000 U of interferon (IFN)-alpha (IFNα), was investigated to understand the resistivity of these cells against such a higher concentration of IFNα[64]. On treatment with one-tenth of the IC50 value, the A549 cells showed an increase in p50 (NF-κB1) and p65 (RelA) subunits of NF-κB with respect to time, in addition to an increase in Cox-2 expression. On pretreatment with curcumin, a dose-dependent decrease in these subunits was noticed in Western Blot Analysis and a decrease in Cox-2 expression was also noted. Thus, curcumin showed a remarkable decrease in NF-κB and Cox-2 activity in a dose-dependent manner with a maximum dose of 50 μM in IFNα resistant A549 cell lines and it increased the vulnerability of cells towards the cytotoxic activity of IFNα. Animal study revealed that curcumin administration reduced ultra-histoarchitecture and histoarchitecture abnormalities against benzo[a]pyrene induced lung carcinogenesis in mice (Wang et al. 2016c). In in vitro studies, curcumin treatment is reported to induce miR-98 and suppressed MMP-2 and MMP-9 which leads to inhibition of lung cancer in A549 cell line (Liu et al. 2017). Curcumin downregulated the expression of hTERT, induced cytotoxicity and attenuated proliferation in A549 cell line, and suggested as effective target for lung cancer therapy (Sadeghzadeh et al. 2017). Curcumin treatment reduced CD133-positive cells, reduced the formation tumorsphere, downregulated the expression of lung cancer stem cells markers like Oct4, aldehyde dehydrogenase isoform 1A1, CD133, CD44 and Nanog alongside induced apoptosis and inhibited proliferation of lung cancer cells. In addition, it reduced lung cancer via inhibition of sonic hedgehog and Wnt/b-catenin signaling pathways (Zhu et al. 2017). Curcumin treatment inhibits hepatocyte growth factor induced epithelial-mesenchymal transition and angiogenesis by inhibiting PI3K/Akt/mTOR signal transduction regulated by c-Met in human lung cancer cell line A549 (Jiao et al. 2016). Recent evidence suggest that curcumin treatment effectively prevented lung cancer metastasis and growth by downregulating microRNA (miR)-let 7c and miR-101 mediated expression of enhancer of zeste homolog 2 along with downregulation of Notch1 expression in human lung cancer cell lines (A549 and NCI-H520) (Wu et al. 2016). Curcumin inhibited IL-6-induced proliferation, migration, and invasiveness of human small cell lung cancer (SCLC) cells by reducing JAK/STAT3 phosphorylation (i.e., activation) and downstream genes coding for cyclin B1, survivin, Bcl-XL, MMPs, intercellular adhesion molecule 1 (ICAM-1), and vascular endothelial growth factor (VEGF). The therapeutic efficiency of curcumin in lung cancer is exhibited by the suppression of COX-2, EGFR, NF-­κB, and PI3K/Akt signaling pathway. An interesting study by Jeeyun Lee et al. investigated if interferon (IFN)-α stimulation activates an NF-κB in lung cancer cells, and if curcumin annuls IFN-α dependent NF-κB activation and subsequently NF-κB-regulated gene's (cyclooxygenase-2's) expression. They reported that the aforementioned hypothesis was correct in the case of A549 lung cancer cells and curcumin effectively down-regulate COX-2 expression through IFN-α-dependent activation of NF-κB. G Radhakrishna Pillai et al. reported that curcumin IC50 of 50 μM is required to induce in vitro apoptosis in A549 cells [50]. Lichuan Wu et al. highlighted the fact that curcumin could inhibit cell proliferation, colony formation, and tumorspheres in lung cancer cell line NCI-H460. The underlying mechanisms of curcumin-induced tumorspheres suppression are mainly due to the inhibition of the JAK2/STAT3 signaling pathway. Furong Liu et al. showed that curcumin exerts a cytotoxic effect on NSCLC A549 cells by inhibiting the PI3K/Akt/mTOR pathway to promote apoptosis and autophagy. It indicates that PI3K/Akt/mTOR signal transduction pathway is a key pathway involved in the role of curcumin in lung cancer. One of the studies showed the effect of curcumin on erlotinib-resistant non-small cell lung cancer (NSCLC) cells.  The combination of erlotinib and curcumin reduced tumor growth remarkably in vivo in erlotinib-resistant NSCLC cells. Ping Chen et al. provided the evidence that gefitinib-resistant NSCLC cells growth could be inhibited by downregulating Sp1/EGFR activity and the receptor tyrosine kinase pathways with the use of curcumin and gefitinib together. They also validated that curcumin could be utilized, in the treatment of NSCLC with wild-type KRAS and EGFR mutation, as a sensitizer of EGFR-tyrosine kinase inhibitors (EGFR-TKIs).
Effect of Curcumin on Breast Cancer | Curcumin against resistant breast cancer have resulted in promising results. The maximum tolerable dose of curcumin was found to be 8 g/day.  During the pathogenesis of cancer, multiple signaling pathways are involved and curcumin represents a potential candidate for the regulation of these signaling pathways. Among these, pro-inflammatory transcription factor (NF-κB) is involved in breast cancer cell proliferation. Curcumin down-regulates the NF-κB signaling pathway, thus, affecting the cell proliferation and invasion contributing to breast cancer treatment. In another breast cancer model, curcumin induced autophagy through down-regulation of Akt protein, posing a significant management strategy for breast cancer. These findings suggest the therapeutic potential of curcumin following multiple signaling pathways. Adriamycin resistant MCF-7ADR and Tumor Necrosis Factor resistant BT-20TNF breast cancer cell lines showed 15% (± 6%) and 8% cell viability respectively against curcumin at a dose of 1 μg/ml (2.7 μM). The same study claimed that curcumin exhibited the growth inhibitory effect on estrogen-dependent MCF-7 and T-47D as well as estrogen-independent SK-BR3 cell lines at lower concentrations, and arrested the majority of cells in the G2/M phase and inhibition of ornithine decarboxylase (ODC) activity. A comparative study of the effect of curcumin on human mammary epithelial (MCF-10A) and MDR breast carcinoma (MCF-7/TH) cell lines reported that the IC50 value of curcumin against MCF-10A was 3.5 times higher than that of MCF-7/TH although cytometric analysis showed equal accumulation of curcumin in both cell lines and it is well complemented with the apoptosis studies where 40 µM (24 hr) concentration of curcumin led 1.8% of MCF-10A cells into apoptosis while 46.6% of MDR, MCF-7/TH went into apoptosis under similar conditions, which in terms of considering the collateral damages is a significant observation. In an investigation undertaken by Meiyanto et al., doxorubicin-resistant breast cancer cell lines MCF-7/Dox cells with over-expression of HER2 were tested against doxorubicin (IC50 = 7) and curcumin (IC50 = 80 ± 2.39) separately and in combination. The MTT Assay showed that curcumin at half of its IC50 concentration in combination with doxorubicin at half of its IC50 concentration, decreased the percentage cell viability of MCF-7/Dox cell lines by almost 80%, and this synergistic action of combinatorial treatment-induced cell death, evident through the accumulation of more cells in sub-G1 and G1 phase as compared to the percentage of cells when they were treated separately by doxorubicin and curcumin. Efficacy of curcumin against resistant breast cancer cell lines was demonstrated through SRB assay on MCF-7, antiestrogen-resistant MCF-7/LCC2 and MCF-7/LCC9 cell lines, which revealed IC50 values of curcumin to be 9.7, 12.2 µM and 11.34 µM respectively against these cancer cell lines and colony formation for each cell line was suppressed by curcumin at a concentration of 30 µM. These activities of curcumin were attributed to lowering of anti-apoptotic expressions and inhibition of NF-κB and Akt/mTOR pathway. The photosensitization of cancer cells by curcumin towards photodynamic therapy (PDT) has been covered by Muniyandi et al. and apoptosis is the mode of action in majority of the works cited in the review. The adriamycin resistant breast cancer cell line MCF-7/ADR was found to be equally affected as MCF-7 cells (Cell viability 50%) on 45 minutes preincubation with curcumin (7.5 μM) followed by irradiation with blue light (450 nm, 100 mW/cm2) for 5 min and subsequent 24 h incubation. Clinical trial study recommended that, administration of curcumin (6 g/day for seven consecutive days in every 3 weeks) in combination with docetaxel to be safe, effective and well tolerated for advanced and metastatic breast cancer (Bayet-Robert et al. 2010). In vitro models revealed that curcumin treatment is known to induce cytotoxicity through apoptosis induction and inhibit the viability of MCF-7 cells via caspase-3 and 9 activations. It reduced the expression of miR-21 by upregulating the PTEN/Akt signaling in breast cancer cells (Wang et al. 2017). Experimental evidence suggested that curcumin administration downregulate the expression of estrogen receptor-alfa (ER-a) and tumor suppressor protein exerting antiproliferative effects in T-47D human breast cancer cells (Hallman et al. 2017). Besides, curcumin treatment reduced hypermethylation of glutathione S-transferase (GST) pi 1 (Kumar, Sharma, and Rathi 2017) and deleted in liver cancer 1 (DLC1) (Liu et al. 2017), downregulated the Sp1 and DNA methyltransferase 1 expressions, resulting in inhibition of proliferation of human breast cancer cells (Liu et al. 2017). A recent study revealed that curcumin treatment downregulated the expression of Fibronectin, Twist1 Vimentin, AXL, Slug, b-catenin, N-cadherin and E-cadherin thereby inhibited the migration and invasion of cancer in breast cancer cell lines (Gallardo and Calaf 2016). Curcumin inhibits NF-jB signaling resulting in inhibition of cell growth and invasion in MDA-MB-231 human breast cancer cell line (Yodkeeree et al. 2010). Further, curcumin arrested the cell cycle at the late S and G2M phase alongside induced ROS mediated apoptosis, accumulated p16/Rb and P53/p21 in breast cancer cells (Calaf et al. 2011; Wang et al. 2016d). In breast cancer cells, curcumin prevented EMT-associated morphological changes induced by lipopolysaccharide (LPS) while upregulating E-cadherin and downregulating vimentin. It was further shown that curcumin inhibited NF-κB/Snail signaling involved in LPS-induced EMT. In another study, curcumin increased the expression of the small non-coding RNA miR181b, which then downregulated proinflammatory cytokines, CXCL1 and CXCL2, as well as MMPs, thereby reducing the metastatic potential of breast cancer cells. Compelling evidence has demonstrated the benefits of curcumin combination therapy as compared to monotherapy in breast cancer. An in vitro investigation reveals that the co-administration of curcumin and 4-hydroxytamoxifen (4-OHT), a metabolite of tamoxifen, could restore the sensitivity of 4-OHT of HR-positive MCF-7 cells through the downregulation of cyclin D1 and upregulation of p21. Compared to either curcumin or 4-OHT alone, combined treatment also remarkably activated pro-apoptotic protein Bcl-xL and suppressed the Bcl-2 proteins, thereby further enhancing the apoptotic activities. The phenomenon was reversed with the combined treatment of curcumin and 4-OHT in MDA-MB-231 cells, mediating cell death and preventing the metastatic behavior of breast cancer cells, respectively. Co-treatment of curcumin (10 μg/mL) and trastuzumab (10 μg/mL) significantly reduced cell proliferation and induced G2/M arrest in HER2-overexpressed BT-474 and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) breast cancer cells, compared to trastuzumab alone. Further in vivo study revealed that BT-474 xenograft mice models had the smallest tumor volume after 4 weeks of curcumin (45 mg/kg) and trastuzumab (4 mg/kg) co-treatment. Curcumin also serves as a potential adjuvant with other chemotherapeutic agents in augmenting anticancer effects. The combined treatment of curcumin and paclitaxel significantly suppressed the paclitaxel-mediated NF-κB expression and its regulatory genes COX-2, matrix metallopeptidase 9 (MMP-9), VEGF, and intercellular adhesion molecule 1 (ICAM-1), thus promoting the anti-proliferative and anti-metastatic behavior in breast cancer cells. Interestingly, further experiments proved that curcumin and paclitaxel curbed the metastasis of MDA-MB-435 breast cancer cells to lung tissues in xenograft mice models. More importantly, this combination of curcumin (ranging from 25–225 mg/kg) and paclitaxel (5 mg/kg) was found to be safe and induced no toxicity effects in mice models. Hindered by drug efflux and chemoresistance, doxorubicin was explored in combination with curcumin in breast cancer treatment.  This has successfully augmented the cytotoxicity effect on breast cancer cells Another study illustrated that curcumin inhibited the doxorubicin-induced EMT via the suppression of Akt, β-catenin and glycogen synthase kinase 3 β (GSK3β) protein expression, emphasizing the importance of the combined treatment of curcumin and doxorubicin in inhibiting the metastasis of breast cancer cells. Apart from the combination with chemotherapeutic agents, the combined treatment of curcumin with other natural compounds has also been investigated in breast cancer. Flow cytometry cell death analysis showed that the co-treatment of curcumin (5 μM) and berberine (25 μM) synergistically exerted apoptosis and autophagy cell death to MDA-MB-231 and MCF7 breast cancer cells. Moreover, curcumin (1.5 μM) sensitized the AU565 breast cancer cells treated with quercetin (4 μM) and optiberry (2 μg/mL) to decrease lapatinib-mediated HER2 overexpression via the downregulation of HER2/Akt signalling pathways. Another study reported the benefits of curcumin (200 mg/kg) and epigallocatechin gallate (EGCG) (25 mg/kg) in lowering the tumor burden of xenograft models via the reduction in phosphorylated Akt, EGFR and vascular endothelial growth factor receptor-1 (VEGFR-1) expression, highlighting the enhanced anticancer potential of this treatment regimen. Curcumin is believed to show its impact on cell growth and invasion of breast cancer partially through the down-regulation of NF-κB signaling pathways. Curcumin induces p53-dependent apoptosis and also causes cell cycle arrest in MCF-7 breast cancer cells. In curcumin-treated MCF-7 cells, proapoptotic protein B-cell lymphoma-2 (Bcl-2)-associated X protein (BAX) was found in a high concentration and it indicates curcumin's p53-dependent as well as p53-independent antiproliferative effects. Xiao-Dong Sun et al. identified that curcumin could inhibit the phosphorylation of extracellular regulated protein kinase (ERK1/2) in MDA-MB-231 cells. ERK1/2 is a major signaling molecule in the downstream pathway of EGFR. This is how curcumin inhibits cell proliferation and induces cell apoptosis, by inhibiting the EGFR pathway in vitro in MDA-MB-231 cells. Yunus Akkoç et al. reported that in metastatic MCF-7 breast cancer cells, overexpression of B-cell lymphoma-2 (Bcl-2) is a constraining factor for curcumin-induced apoptosis. The overexpression of Bcl-2 blocks curcumin-induced autophagy through its inhibitory interaction with Beclin-1 in MCF-7 cells. They found that pre-treatment with LY294002, a PI3K inhibitor, enhanced curcumin-induced autophagy and apoptosis by modifying Bcl-2 expression and subsequent autophagosome formation in MCF-7 breast cancer cells. In vivo effect of curcumin and its derivative (2E,6E)-2,6-bis(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC) had been checked on 4T1 (triple-negative breast cancer cell line) breast cancer cells challenged mice. A study showed that curcumin and BHMC treated mice had low tumor burden, mitotic cells, lung metastasis as well as regeneration capacity compared to the untreated mice.
Effect of Curcumin on Prostate Cancer

A randomized, double-blind, controlled study evaluated the effects of soy isoflavones and curcumin on serum PSA levels in men. The authors of this study concluded that curcumin presumably synergizes with isoflavones to suppress PSA production. Curcumin against resistant prostate cancer, the induction of apoptosis has been one of the modes of action of curcumin. PI3/Akt pathway, which promotes cell growth, proliferation, and survival, is inhibited by curcumin. Mechanistic studies, carried out at subtoxic concentrations of curcumin in LNCap cells showed that pretreatment with curcumin sensitized the cells towards tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through inhibition of the NF-κB pathway of cell survival. Castration-resistant prostate cancer cell (CRPC) line C4-2B, showed a promising response to chemo-sensitization towards remarkably low concentration dose of 10nM docetaxel on pretreatment with a combination of 5 μM curcumin and 5 μM nelfinavir, commendably without much adverse effect on primary prostate epithelial cells. The molecular study revealed an increase in pro-apoptotic markers caused by endoplasmic reticulum (ER) stress and decrease in expressions associated with PI3K/AKT survival pathway like phosphorylated-AKT. A summary of in vitro activities of curcumin against various cancer cell lines has been compiled in Table 1. In a pilot phase II study, curcumin (6000 mg per day for 7 consecutive days) along with docetaxel and prednisone showed therapeutic potential against castration-resistant prostate cancer with good patient acceptability and tolerability (Mahammedi et al. 2016). In vitro models revealed that, curcumin treatment downregulated PGK1 via upregulation of miR-143 alongside increased the expression of FOXD3, resulting in inhibition of proliferation and migration of prostate cancer cell (Cao et al. 2017). Curcumin treatment is known to induce transferrin receptor protein 1 (TfR1) and iron regulatory protein 1 (IRP1) expression which leads to induced autophagy and apoptosis in castration-resistant prostate cancer cells (Yang et al. 2017a). It has been reported that curcumin treatment inhibited MT1-MMP and MMP-2 expressions in DU145 cells thus reduced the metastasis and survival of prostate cancer cells mediated by Notch-1 signaling cascade (Yang et al. 2017b). Curcumin treatment induced the arrest of G0/G1 cell cycle phase alongside inhibited the regulatory proteins cyclin D1 and CDK-2. Besides, it upregulated the expression of p21, p27 and p53 while downregulated Bcl-2 expression. Further, curcumin treatment is known to activate caspase (3, 8 and 9) (Sha et al. 2016) while decreased Akt, MMP (2 and 9), Bcl- 2, Bcl-XL and tumor volume in prostate cancer (Jordan et al. 2016). Curcumin treatment is reported to increase HDAC (1, 4 and 8), apoptosis, production of ROS and Nrf- 2 expression, while decrease VEGF, HIF1-a, GSK-3b, Akt, prostate-specific antigen (PSA) level, PSA mRNA expression, HAT activity and cellular proliferation in LNCaP cell lines. The available in vitro studies have shown that curcumin is able to inhibit viability, proliferation, survival, migration/invasion, and adhesion of various human prostate cancer cells. Curcumin inhibited both androgen-sensitive and insensitive prostate cancer cells by targeting a number of signaling cascades responsible for regulating cellular function. The antiproliferative, antisurvival, and antimigratory effects of curcumin in prostate cancer cells may be due to the inhibition of the Akt/mTOR, Ras/MAPK signaling pathways, decreased NF-κB activation, enhanced proapoptoptic caspase and PARP cleavage, and the inhibition of members of the antiapoptotic Bcl-2 family of proteins. Curcumin was also able to induce cell-cycle arrest and enhance autophagy in various prostate cancer cell lines. The available in vivo studies have shown that curcumin administration is able to inhibit the growth/volume, formation, development, proliferation, and angiogenesis of prostate cancer tumors while promoting apoptosis. These effects were observed in mice xenografted with both androgen-sensitive and insensitive prostate cancer cells. Curcumin’s inhibition of prostate tumor growth and progression may be due to its inhibition of Akt expression/activation, decreased NF-κB activation, inhibition of the anti-apoptotic proteins Bcl-2 and Bcl-xL, increased expression of the proapoptotic proteins Bax and Bak, and enhanced PARP and caspase expression. These findings from in vivo studies are in agreement with those from the in vitro studies. The downregulation of cell proliferation, paired with the enhanced activity of programmed cell death both in vitro and in vivo, render curcumin an ideal candidate for the development of novel anticancer pharmaceutical agents providing fewer detrimental effects due to its low toxicity. Androgen­dependent LNCaP prostate cancer cells were injected subcutaneously into mice fed with a 2% curcumin containing diet for up to 6 weeks. Curcumin significantly increased the extent of apoptosis, as measured by an in situ cell death assay, and caused a reduction in cell proliferation, as measured by a BrdU incorporation assay. Multiple studies have been done to evaluate the anticancer effects of curcumin on androgen-sensitive as well as androgen-resistant prostate cancer cell lines. T Dorai et al., 2000, reported that curcumin can reduce the proliferation rate to 20-30% compared to untreated LNCaP cells (androgen sensitive prostate cancer cell-line).  Asok Mukhopadhyay et al. suggested that curcumin can cause tumor necrosis factor (TNF)-induced apoptosis by suppressing NF-κB activation in the prostate cancer cell. Similarly, curcumin also affects multiple other proteins and pathways, such as c-Jun/activator protein 1 (AP-1), cyclin D1, CDK-4, phosphatidylinositol 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR)/E-twenty six proto-oncogene 2 (ETS2) pathway to reduce proliferation, cell growth in androgen-sensitive prostate cancer cell lines. Studies have also shown the anticancer properties of curcumin on the androgen-insensitive prostate cancer cell lines. Curcumin-treated DU-145 prostate cancer cells showed reduced expression of NF-κB in paired with less proliferation and increased apoptosis. Curcumin additionally downregulated the expression of nuclear transcription factor activator protein-1 (AP-1), composed of c-Fos and c-JUN. Many studies have analyzed the effects of curcumin treatment in vivo on the mice xenografted with various human prostate cancer cells. Thambi Dorai et al., 2001, studied the effect of curcumin on athymic nude mice implanted with LNCap cells. It showed a significant increase in apoptosis and reduction in proliferation of LNCaP cells demonstrated by the increased pycnotic brown staining nuclei in situ.
Effect of Curcumin on Colorectal Cancer


Curcumin has demonstrated potential against colorectal cancer  in numerous clinical trials.  Curcumin could be used to avoid colorectal cancer (CRC) in diabetics with type 2 diabetes by lowering leptin blood levels and increasing adiponectin levels. In a  dose-escalation study that explored the pharmacology of curcumin in humans, 15 patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses of between 0.45 and 3.6 g/day for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g of curcumin caused 62% and 57% decrease in inducible prostaglandin E2 production in blood samples taken 1 h after the dose was administered on days 1 and 29, respectively. A daily oral dose of 3.6 g of curcumin was recommended for the phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. In another study, patients were given curcumin capsules at three different doses (3.6, 1.8, and 0.45 g/day) for 7 days . The recoveries of curcumin in normal and malignant colorectal tissues of patients receiving 3.6 g of curcumin were 12.7 ± 5.7 and 7.7 ± 1.8 nmol/g, respectively. In addition, two metabolites of curcumin, curcumin sulfate and curcumin glucuronide, were identified in the tissue samples. Trace levels of curcumin were found in the peripheral circulation. The levels of M1G were also decreased by curcumin treatment in malignant colorectal tissue. The study concluded that a daily dose of 3.6 g of curcumin is pharmacologically efficacious in colorectal cancer patients. Curcumin against resistant colorectal cancer studies on human colorectal cancer cell line HCT116 and its isogenic 5-fluorouracil (5-FU) resistant cell line HCT116R in a 3D model showed that curcumin potentiated the anti-proliferative activity of 5-FU against these cell lines through apoptosis and inhibition of formation of colonies, with suppression of NF-κB pathway. This synergistic combination increased the percentage of apoptotic cells by 56% in HCT116R cell lines. The molecular role of curcumin in apoptosis has already been shown in another report where it intensified the downregulation of anti-apoptotic BclxL and cell division favoring cyclin D1 protein caused by 5-FU in HCT116 and HCT116+ch3 (Complemented with chromosome 3) cell lines and inhibiting activation of IkBα kinase and its phosphorylation. Chemo-sensitization of drug-resistant cancer cell lines by curcumin, towards a particular chemotherapeutic agent, has been reported in one more investigation involving oxaliplatin sensitive human colorectal adenocarcinoma HT29 Cells and its oxaliplatin resistant derived sub-line HTOXAR3 cells, which showed that combination of curcumin and oxaliplatin almost reversed the oxaliplatin resistance. Clinically, curcumin administration (3 g/day orally for one month) converted advanced colon cancer derived regulatory T cells to T helper 1 cells via increasing IFN-c production and repression of Foxp3 expression in colon cancer patients (Xu, Yu, and Zhao 2017). In a nonrandomized, open-label clinical trial, oral curcumin (2 g or 4 g per day for 30 days) administration reduced the number of aberrant crypt foci and prevented the colorectal neoplasia (Kunnumakkara et al. 2017; Carroll et al. 2011). In vitro models revealed that treatment with curcumin induced apoptosis, arrested the cell cycle at the G1 phase, decreased the cell population as well as inhibited the proliferation and mutation of COLO 320DM cells (Dasiram et al. 2017). Additionally, curcumin treatment stimulated 50AMP-activated protein kinase, suppressed the phosphorylation of p65 NF-jB, downregulated MMP-9 and urokinase-type plasminogen activator (uPA) expression as well as reduced the binding ability of NF-jB DNA in LoVo and SW480 cells leading to inhibition of colon cancer invasion (Tong et al. 2016). Curcumin treatment downregulated chemokine receptor 4 expression, upregulated naked cuticle homolog 2 expression and suppressed Wnt signaling. In addition, curcumin treatment downregulated vimentin and upregulated E-cadherin expression, which leads to inhibition of proliferation and epithelial mesenchymal transition in SW620 human colon cancer cells (Zhang et al. 2016d). Evidence suggested that curcumin treatment downregulated the expression of p-glycoprotein (Neerati, Sudhakar, and Kanwar 2013) and upregulated PPAR-c protein (Liu et al. 2015), the potential mechanism by which curcumin can be used for the treatment of colon cancer (Neerati, Sudhakar, and Kanwar 2013). In a 30-day study in 44 men with lesions in the colon that sometimes turn cancerous, 4 grams of curcumin per day reduced the number of lesions by 40%. In a nonrandomized, open-label clinical trial in smokers, curcumin reduced the formation of aberrant crypt foci (ACF), the precursor of colorectal polyps.  Curcumin at 4 g/day significantly reduced ACF formation. The reduction in ACF formation by curcumin was associated with a significant fivefold increase in post-treatment plasma curcumin/conjugate levels. Curcumin was well-tolerated at both concentrations. These findings demonstrated the effect of curcumin against ACF formation in smokers. A study published in the International Journal of Cancer found that curcumin compares favorably with oxaliplatin as an antiproliferative agent in colorectal cell lines.  A study showed a profound reduction in the incidence of colorectal carcinoma when curcumin is introduced. In another recent study, curcumin was administered to patients with colorectal cancer after diagnosis and before surgery. Curcumin was given three times a day for 10–30 days. Curcumin administration decreased serum TNF-α level, increased the number of apoptotic cells, and enhanced the expression of p53 in tumor tissue. The authors of this study concluded that curcumin treatment can improve the general health of colorectal cancer patients via the mechanism of increased p53 expression in tumor cells. In summary, the studies discussed in this section suggest curcumin’s safety and efficacy in patients with colorectal cancer.

Effect of Curcumin on Pancreatic Cancer | A single-blind, randomized, placebo-controlled study from India was conducted to evaluate the effects of oral curcumin with piperine on the pain and markers associated with oxidative stress in patients with tropical pancreatitis. Twenty patients with tropical pancreatitis were randomly assigned to receive 500 mg of curcumin with 5 mg of piperine or to receive placebo for 6 weeks, and the effects on the pattern of pain and on red blood cell (RBC) levels of MDA and GSH were assessed. The results indicated a significant reduction in the erythrocyte MDA levels compared with placebo after curcumin therapy, with a significant increase in GSH levels. The authors of this study concluded that oral curcumin with piperine may reverse lipid peroxidation in patients with tropical pancreatitis. Curcumin was found safe and well-tolerated in a phase II clinical trial of patients with advanced pancreatic cancer. Of the 25 patients enrolled in the study, 21 were evaluable for response. Patients were given 8 grams of curcumin per day orally until disease progression, with restaging every 2 months. No toxicities associated with curcumin administration were noted in the patients. A downregulation in the expression of NF–κB, COX-2, and pSTAT3 in peripheral blood mononuclear cells of patients was observed after curcumin intake. There was considerable interpatient variation in plasma curcumin levels, and drug levels peaked at 22 to 41 ng/ml and remained relatively constant over the first 4 weeks. The study concluded that the oral curcumin is well-tolerated and, despite limited absorption, has biological activity in some patients with pancreatic cancer. An open-label phase II trial evaluated the efficacy of curcumin in combination with gemcitabine against advanced pancreatic cancer. Kanai et al. recently evaluated the safety and feasibility of combinations of curcumin and gemcitabine in 21 patients with gemcitabine-resistant pancreatic cancer. Curcumin at 8 g/day in combination with gemcitabine was safe and well-tolerated.
Effect of Curcumin on Bladder Cancer
| In animal model, curcumin suppressed the invasion and growth of bladder cancer via induction of apoptosis and arresting G1/S phase transition in N-methyl-N-nitrosourea induced bladder tumor in rats (Pan et al. 2017). Curcumin treatment suppressed the N-methyl-N-nitrosourea-induced urothelial tumor in rats. In cell lines studies, curcumin treatment is known to downregulate the expression of insulin-like growth factor (IGF)-2 and reduces the IGF1R and IRS-1 phosphorylation in T24 and UMUC2 bladder cancer cells. In this regards curcumin functions through suppression of IGF-2-mediated PI3K/AKT/mTOR signal transduction (Tian et al. 2017). Curcumin treatment reversed the transition of epithelial-mesenchymal cells via reducing ERK5/AP-1 signaling pathway in SV-40 human urothelial cells which might be the potential drug candidate for prevention of bladder cancer (Liu et al. 2017). In human bladder cancer cell lines, curcumin treatment exert multiple effects like inhibition of MMP-2/9, generation of ROS, upregulated the expression of HO-1, increased the hypomethylation of the miR-203, upregulated the expression of miR-203, inhibited Aurora A promoter activity, downregulated histone H3 activation, induced G2/M phase cell cycle arrest, decreased the expression of cyclin D1 and COX-2, decreased VEGF level, decreased c-myc, decreased Bcl-2 expression, downregulated Survivin protein, upregulated the expression of p53 and Bax, induced fragmentation of DNA, downregulated cyclin A expression and decreased NF-kB expression thereby inhibited the cancer cell invasion, viability of cancerous cells and growth (Imran et al. 2016; Saini et al. 2011).
Effect of Curcumin on Blood Cancer (Multiple Myeloma and Leukemia), Lymphoma, and other Hematological Malignancies

Curcumin against resistant leukemia showed inhibition in growth and clonogenicity to curcumin treatment in dose and time-dependent manner. Golombick et al. conducted a single-blind, crossover pilot study to determine the effects of curcumin on plasma cells and osteoclasts in patients with MGUS. Curcumin decreased the paraprotein load in the ten patients with paraprotein >20 g/L, and five of these ten had a 12% to 30% reduction in paraprotein levels while receiving curcumin therapy. In addition, 27% of patients receiving curcumin had a >25% decrease in urinary N-telopeptide of type I collagen. The study suggested the therapeutic potential of curcumin against MGUS. Vadhan-Raj et al. evaluated the safety, tolerability, and clinical efficacy of curcumin in 29 patients with asymptomatic, relapsed, or plateau phase multiple myeloma. Curcumin was given either alone (orally at 2, 4, 6, 8, or 12 g/day in two divided doses) or in combination with piperine (10 mg in two divided doses) for 12 weeks. Curcumin and piperine were well-tolerated, with no significant adverse events. Furthermore, oral administration of curcumin was associated with significant downregulation in the constitutive activation of NF–κB and STAT3, and it suppressed COX-2 expression in most of the patients. These observations suggest the potential of curcumin against multiple myeloma. In another study, curcumin showed an IC50 value of 35.7 µM against KG1a 23.5 µM against Kasumi-1 on 96 hr exposure and completely stopped colony formation at 20 µM concentration. The mechanistic investigations reflected the role of curcumin in activation of Caspase-3, down-regulation of Bcl-2 mRNA expression and reduction in mitochondrial membrane potential in addition to remarkable morphological changes like cell shrinking and nuclear condensation, which are characteristics of apoptosis. Another drug-resistant leukemia cell line HL60 responded to curcumin with 50% growth inhibition at 30 µM concentration. Cell cycle studies in this experiment established apoptosis as the mechanism of action of curcumin and arrest of the cell cycle in the S-phase was also reported in the same study. Clinically, curcumin administration (5 g for 6 weeks) possessed potent chemosensitizing effect in chronic myeloid leukemia patients, where the patients receiving both curcumin and imatinib exhibited better prognosis with decreased NO levels as compare to the patients receiving imatinib alone (Ghalaut et al. 2012). In animal study, curcumin treatment significantly decreased tumor growth in the chronic myeloid leukemia xenograft mice via release of exosomes enriched miR-21 in plasma (Taverna et al. 2015). In cell line studies, curcumin treatment upregulated apoptosis inducing factor, caspase-3, cleaved PARP-1 while downregulated Bcl-2 resulting in induction of apoptosis in lymphoblastic leukemia cells (Mishra, Singh, and Narayan 2016). Curcumin incubation (10 lM, for 6 days) increased the level of ROS, induced genomic instability, mediated reversal of p15 promoter methylation and induced apoptosis in Raji cells (Sharma et al. 2014). Curcumin treatment (40 mmol/L, for 48h) downregulated the protein expression of nuclear NF- jB P65 as well and its translocation alongside inhibited proliferation of acute myeloid leukemia in KG1a and Kasumi-1 cells (Rao et al. 2015). Also, curcumin treatment (25 lM, for 24–48 h) arrested cell cycle in the S-phase, increased the number of annexin V-FITC(þ)/PI(-) cells and inhibited the proliferation of SHI-1 cells. In addition, curcumin upregulated FasL and downregulated NF-jB, ERK, Bcl-2, MMP-2 and MMP-9 expressions. Further, curcumin induced the activation of MAPK, p38, caspase-3 and JNK resulted in inhibition of SHI-1 cell invasion (Zhu et al. 2016). Curcumin treatment downregulated the expression of VEGF and decreased the phosphorylation of AKT. Curcumin mediated increased miR-196b levels caused downregulation of Bcr-Abl expression in chronic myelogenous leukemia cells (Taverna et al. 2015). Curcumin incubation downregulated Mcl-1 expression and associated with apoptosis in human myeloma cell lines (Gomez-Bougie et al. 2015). Curcumin treatment simultaneously inhibited RAF/MEK/ERK and AKT/mTOR pathway activation resulting in induction of apoptosis and inhibition of proliferation in human leukemia THP-1 cells (Guo et al. 2014). Curcumin incubation increased the generation of intracellular ROS, depletion of intracellular GSH, and activation of caspase enzyme. Chu-Wen Yang et al. investigated the effect and mode of action of curcumin on monocytic leukemia THP-1 cells, derived from human acute monocytic leukemia. The authors demonstrated that curcumin-induced THP-1 cell apoptosis through the activation of c-Jun NH2-terminal kinase/extracellular signal-regulated kinase/activator protein 1 (JNK/ERK/AP1) pathways. Yi-Rong Chen et al. reported that curcumin affects the mitogen-activated protein kinase kinase kinase 1/JNK  pathway by interfering with the signaling molecules like AP-1 and NF-κB as a possible mechanism of action. They speculated that curcumin may affect the JNK pathway by interfering with the signaling molecules at the same level or proximally upstream of the MAPK kinase kinases (MAPKKKs) level. Yaowu Zhang et al. showed curcumin can induce apoptosis in osteosarcoma MG63 cells through the mitochondrial pathway. They reported that the effects of curcumin-induced apoptosis in osteosarcoma cells were associated with caspase-3 activation and reduced the levels of Bcl-2 expression. Jia Rao et al. reported a similar function of curcumin in AML cells. They showed that curcumin down-regulates Bcl-2 and induces apoptosis in daunorubicin (DNR)-insensitive CD34+ AML cell lines and primary CD34+ AML cells. Seong-Su Han et al. reported that curcumin inhibited the proliferation of BKS-2, an immature B cell lymphoma, more effectively than that of normal B lymphocytes and caused the apoptosis of BKS-2 cells in a dose- and time-dependent manner. The authors concluded that curcumin downregulated the expression of survival genes early growth response 1 (EGR-1), cellular myelocytomatosis (c-myc), and Bcl-extra large (Bcl-XL) as well as the tumor suppressor gene p53 in B cells as its possible mechanism of action. Shilpa Kuttikrishnan et al. investigated the anticancer potential of curcumin in acute lymphoblastic leukemia. The authors concluded that curcumin suppresses B-pre-ALL cells' growth and proliferation by inactivation of the PI3K/Akt signaling pathway. Guo-Hua Zhu et al. reported that curcumin significantly induces apoptosis but also partially suppresses invasion in SHI-1 cells (acute monocytic leukemia cell line) in vitro. Their results from polymerase chain reaction (PCR) and western blotting showed that curcumin increased the FasL mRNA level; inhibited Bcl-2, NF-κB, and ERK expression; and activated p38 MAPKs, JNKs, and caspase-3. Zai-Xin Li et al. studied how curcumin affects the proliferation of the Raji cells of Burkitt's lymphoma. Their biochemical studies showed that cell apoptosis increases through upregulation of Bid (BH3-interacting domain death agonist), cytochrome C, and BAX, while oncogene c-Myc was downregulated after curcumin treatment. Taken together, their results suggested that mitochondrial damage induction was the main mechanism of action of curcumin which led to apoptosis of the Raji cells. In vivo effects of curcumin in the xenograft mouse model showed its effective inhibition of tumor growth. All in all, these results were suggestive of curcumin's growth suppressing effect on Burkitt's lymphoma cells both in vivo and in vitro system.
Effect of Curcumin on Cervical Cancer | Curcumin administration (12,000 mg/day for 3 months) reduced the risk of cervical cancer and is found to be safe and well tolerated chemotherapeutic in phase I clinical trial (Cheng et al. 2001). In animal model, curcumin suppressed nuclear b-catenin, decreased oncogenic miRNA-21 and abrogated E6/E7 HPV expression in orthotopic mouse model of cervical cancer (Zaman et al. 2016). Curcumin administration (1000 or 1500 mg/kg, for 30 days) significantly downregulated the expression of VEGF, COX-2, EGF-R and inhibited angiogenesis and tumor growth in cervical cancer xenografts model of nude mice (Yoysungnoen-Chintana, Bhattarakosol, and Patumraj 2014). In cell line studies, curcumin treatment (13 mM) upregulated the expression of early-onset breast cancer 1, O6- methylguanine-DNA methyltransferase, mediator of DNA damage checkpoint 1, p-H2A.XSer140 and p-p53 as well as induced translocation of p-H2A.XSer140 and p-p53 from cytosol to nuclei, resulting in chromatin condensation and induction of DNA damage in HeLa human cervical cancer cells (Shang et al. 2016a). Curcumin activated ATF6, PERK, IRE-1aand elevated the levels of ROS intracellularly as well as induced apoptosis and inhibited the proliferation of cervical cancer cells (ME180, C33A, HeLa and CaSki) (Kim et al. 2016a). Curcumin counteracts estradiol induced proliferation of cervical cancer via induction of apoptosis in cervical cancer cells (Singh and Singh 2011). Incubation with curcumin (20 mM, for 72 h) reversed the hypermethylation and reactivation of the RARb2 gene in cervical cancer cell lines (Jha et al. 2010). Curcumin (50 or 100 mM, 24 h) dose dependently reduced the phosphorylation of ERK, increased the activity of caspase 3 and caspase 9, upregulated AIF, Bax, cytochrome while downregulated Bcl-XL, Bcl-2 in cervical cancer cells. Curcumin treatment downregulated the expression of cyclin D1, iNOS and COX-2 in HeLa, SiHa and Ca Ski cells, and acts as an anti-proliferative agent (Singh and Singh 2009).
Effect of Curcumin on Thyroid Cancer | In cell line studies, curcumin treatment upregulated E-cadherin while downregulated vimentin and MMPs expressions along with reduced metastasis, cell spreading and cell migration in human papillary thyroid carcinoma cells. Curcumin suppressed TGF-b1 mediated transcription, activation and secretion of matrix metalloproteinases. It also inhibited TGF-b1 induced Smad2 and Smad3 phosphorylation in human papillary thyroid carcinoma BCPAP cells (Zhang et al. 2016a). Curcumin treatment induced DNA damage in thyroid carcinoma BCPAP cells via upregulation of H2A.X phosphorylation at Ser139 and ATM-mediated activation of Chk2-Cdc25C-Cdc2 pathway. Moreover, curcumin induced caspase mediated apoptosis in BCPAP cells (Zhang et al. 2016b). Curcumin downregulated the expression of HIF-1aand its binding to hypoxia response element in K1 papillary thyroid cancer cells. In addition, curcumin upregulated the expression of E-cadherin, inhibited the activity of MMP-9 (Zhang et al. 2013a) and weakened K1 cells migration resulting in anti-metastatic effect (Tan et al. 2015). Curcumin treatment reduced the phosphorylation of PI3K and Akt pathway, and downregulated the expression of MMP-1/7 and COX-2 leading to inhibition of cell migration, growth and invasion of thyroid cancer cells (FTC133) (Xu, Qin, and Liu 2014). Curcumin instigate the production of ROS, reduce mitochondrial membrane potential and altered intracellular calcium concentration thereby mediate apoptotic induction in papillary thyroid cancer cell line K1 (Song et al. 2012).
Effect of Curcumin on Skin Cancer | Curcumin decreased the phosphorylation of IRS-1, ILGF-1 receptor, Akt, 4EBP1 and S6K in the mouse keratinocyte cells alongside exerted significant anticancer activity against 7,12-dimethylbenz(a)anthracene (DMBA)-tetradecanoyl phorbol-13-acetate induced skin cancer in mice (Kim et al. 2014). In in vitro studies, curcumin treatment is reported to upregulate mmu-miR-205-5p expression, block proliferating cell nuclear antigen, downregulate Bcl-2 expression and sup- press JAK-2/STAT3 pathway which in turn induction of apoptosis and inhibition of proliferation and invasion (Lelli, Pedone, and Sahebkar 2017). Curcumin treatment arrested the G2/M phase of cell cycle as well as induced autophagy in human melanoma cells (A375 and C8161). In addition, curcumin reduced the activation of P70S6K, and downregulated AKT and mTOR expressions which might offer plausible target in the treatment of human melanoma (Zhao et al. 2016a). In another study, curcumin decreased the invasion of squamous cell carcinoma by suppressing STAT3 signaling pathway in A431 cells (Wu, Lu, and Cui 2015). Curcumin induced the opening of mitochondrial permeability transition pore and melanoma cell death in WM-115 melanoma cells (Qiu et al. 2014). Curcumin inhibited NF-jB pro-survival pathway, upregulated the p53 tumor suppressor protein and downregulated Bcl-2 expression resulting in apoptosis and reversal of skin cancer (Chinembiri et al. 2014).
Effect of Curcumin on Brain Cancer | Curcumin was shown to have inhibitory effects on telomerase and induced telomere shortening and apoptosis in brain tumor cells. Curcumin induced growth inhibition and cell cycle arrest at G2/M in medulloblastoma and glioblastoma cells. In various types of cancers, curcumin was shown to selectively target cells that express telomerase enzyme making these cells more vulnerable to curcumin-induced cytotoxicity of cancer cells. Importantly, the above-mentioned study revealed that the complex and diverse action of curcumin, and its efficacy could depend on the cell types used. The long-term studies on brain tumor cells highlighted the use of curcumin as an adjuvant for cancer therapy. Telomere shortening drives renal cell senescence and leads to renal aging. Khaw and co-workers have demonstrated that curcumin suppresses telomerase activity in brain tumor cells which is associated with reduction in hTERT levels. Treatment with curcumin induces a significant telomere shortening in brain tumor cells suggesting its potential clinical application as telomerase inhibitor and use of curcumin in adjuvant cancer therapy. By contrast, in normal cells curcumin improves viability by acting on telomerase when the cells have been stimulated with toxic molecules. A study conducted on SK-N-SH cells treated with curcumin improved cell viability. Normally, hTERT was inhibited by Aβ1–42; shortened telomere could not restore length, and then, there were plenty of apoptotic cells. Treatment with curcumin could bind to Aβ1–42 and antagonize neurotoxicity; thus, the expression of hTERT was upregulated, shortened telomere restored length and the numbers of cells were increased. Long-term studies on brain tumor cells underscore the use of curcumin in adjuvant cancer therapy. Curcumin against brain cancer in vivo model of Human glioma U-87 cells in athymic mice on intraperitoneal dose of curcumin (120 mg/kg/day) showed less than 50% decrease in median tumor volume in subcutaneous xenograft while in the orthotopic model, the average life span of group receiving similar dose increased by 12% as compared to the control group. In Female SCID mice xenograft model, human primary medulloblastoma cells (DAOY) were subcutaneously injected and after 30 days, the animals were given oral gavage of curcumin (1 mg/kg) dissolved in corn oil. The tumor growth inhibition in curcumin treated group was significantly noticeable as compared to the control group. The group of Smo/Smo transgenic medulloblastoma mice receiving oral dose of curcumin was reported to have a median survival time of 192 days as compared to the control group, which had a median survival time of 144 days. This observation is in agreement with earlier claims of ability of curcumin to cross Blood Brain Barrier. Mechanistic insights in xenografted human medulloblastom D425 cells in athymic mice showed overexpression of p65 subunit of NF-κB and the curcumin treated group showed tumor growth inhibition which can be partially attributed to down regulation of p65 subunit. In another in vivo investigation, human glioblastoma U87-MG cells-inoculated nude mice were administered with 100 mg/kg per day of curcumin in DMSO in Phosphate Buffer Saline through intra-tumoral injections. After seven days, significant decrease in tumor size was observed in curcumin treated group. Microscopic examination post Acridine Orange staining showed increased acidic vesicular organelles in curcumin treated cells with intact nuclei, pointing towards curcumin-induced autophagy being responsible for cell deaths.
Effect of Curcumin on Medulloblastoma and Neuroblastoma

Medulloblastoma is the common malignant brain tumor in pediatrics. In animal model, curcumin inhibited tumor growth and increased the survival rate in Smo/Smo transgenic medulloblastoma mice (Lee et al. 2011). In cell line studies, curcumin treatment arrested G2/M phase of cell-cycle, activated GSK-3band suppressed Wnt/b-catenin path- way resulting in inhibition of proliferation in DAOY medul- loblastoma cell line (He et al. 2014). Curcumin treatment upregulated the PTEN gene expression and downregulated the expression of E2F1, CDK2 and cyclin E1 gene resulting in growth arrest at G2/M phase in medulloblastoma cells. In addition, curcumin treatment increased caspase-3/7 activity, overexpressed Bax while downregulated Bcl-2, Bcl-Xl and surviving expression, which leads induced apoptosis of human medulloblastoma cells (Bangaru et al. 2010). Curcumin treatment inhibits telomerase activity and gene expression of hTERT resulting in telomere shortening in medulloblastoma cell lines (A172, KNS60, U251MG and ONS76) (Khaw et al. 2013). Curcumin phosphorylates Cdc27, a component of the anaphase promoting complex/ cyclosome, which is known to ubiquitinate securing and cyclin B, resulting in proteolysis and apoptosis of DAOY medulloblastoma cell (Lee and Langhans 2012). Further, it was reported that, curcumin treatment induced apoptosis and cell cycle arrest possibly through downregulation his- tone deacetylase 4 and enhanced tubulin acetylation. Curcumin treatment inhibited the sonic hedgehog-glioma associated oncogene-1 pathway via downregulating the protein expression of sonic hedgehog ligand, and its most important downstream targets glioma associated oncogene-1 and patched-1 receptor. Furthermore, curcumin reduced the levels of b-catenin, N-myc, C-myc, cyclin D1 and induced apoptosis in DAOY medulloblastoma cells (Elamin et al. 2010).
Effect of Curcumin on Ovarian Cancer | Curcumin exhibits the important anti-cancer activity in ovarian cancer via the pro-apoptotic function. Curcumin inhibited ovarian cancer cell proliferation and promoted apoptosis, and first confirmed it was associated with the regulatory network of circ-PLEKHM3/miR-320a/SMG1. Liu et al. reported that curcumin could constrain ovarian cancer cell proliferation and facilitate apoptosis by inhibiting autophagy and AKT/mTOR/p70S6 pathway. Yen et al. suggested that curcumin could suppress ovarian cancer cell colony formation via blocking the Wnt/β-catenin pathway. These reports indicated the anti-cancer property of curcumin in ovarian cancer treatment. In the past research, curcumin had been found to improve the radiosensitization of nasopharyngeal carcinoma through regulating the circRNA network. Xu et al. suggested that curcumin could suppress non-small cell lung cancer progression by regulating circ-PRKCA. Circ-PLEKHM3 was downregulated in ovarian cancer, and its expression could be promoted by curcumin. Function analysis showed that circ-PLEKHM3 overexpression could aggravate curcumin function by suppressing cell proliferation, triggering apoptosis and reducing tumorigenesis in ovarian cancer. These data revealed that curcumin might regulate ovarian cancer progression by promoting circ-PLEKHM3. In addition, the anti-cancer role of circ-PLEKHM3 was confirmed in study, which was consistent with the previous study. A previous report displayed the circ-PLEKHM3 acted as miR-9 sponge to regulate ovarian cancer progression. MiR-320a mimic reversed the regulation of circ-PLEKHM3 on curcumin-mediated ovarian cancer cell proliferation and apoptosis, further confirming that circ-PLEKHM3 sponged miR-320a to participate in ovarian cancer progression. The study also validated the carcinogenic role of miR-320a in ovarian cancer, which was consistent with previous reports. These data indicated the importance of circ-PLEKHM3/miR-320a axis for curcumin in ovarian cancer development. Curcumin could up-regulate SMG1 expression via modulating circ-PLEKHM3/miR-320a axis. Curcumin could suppress proliferation and promote apoptosis in ovarian cancer, possibly via regulating circ-PLEKHM3/miR-320a/SMG1 axis. This research might propose a novel mechanism for understanding the function of curcumin in ovarian cancer.
Effect of Curcumin on Liver Cancer | Yu and his colleagues evaluated the role of curcumin in inhibiting the human hepatoma SMMC-7721 cells significantly by promoting apoptosis via modulation of Bax/bcl-2 (Yu et al., 2011). Apoptosis was associated with increases in p53 levels as well as its DNA-binding ability, along with protein expression of Bax. Phosphorylation of CDC27 (cell division cycle 27) is the main mechanism of anticancer efficacy of curcumin by obstructing cell growth and proliferation in an apoptotic pathway, leading to the death of the cells (Lee and Langhans, 2012). According to Li and his colleagues, in human hepatoma cell lines such as HepG2 and HCCLM3, suppression of miR-21 improved anticancer action of curcumin like cell growth suppression, apoptosis via upregulated target gene, and TIMP3 expression, and the mechanism may refer to TGF-β1/smad3 signaling pathway inhibition (Li J. et al., 2020). Curcumin inhibits cancer through modulating several signaling pathways and molecular targets, including TGF-β1/smad3, IGF, PI3K/Akt, Wnt/β-catenin, and vascular endothelial growth fact (VEGF) (Figure 7) (Mohebbati et al., 2017).
Effect of Curcumin on Other Cancer | Curcumin treatment significantly inhibited gastric carcinoma. Curcumin therapy of Burkitt’s lymphoma cell lines in combination with ionizing radiation shows that it boosts lymphoma cells’ susceptibility to ionizing radiation-induced apoptosis and improves cell cycle arrest at the G2/M phase. Curcumin and L-ASP show synergism in patients with blood and bone marrow malignancy (Jiang et al., 2015). Curcumin also hinders the cellular growth of uterine leiomyosarcoma and reduces the spread of castrate-resistant disease and human leiomyosarcoma cells via modulating the AKT-mammalian target of rapamycin pathway for inhibition (Wong et al., 2011). Curcumin extract’s potential in decreasing tumors induced chemically was investigated. It was documented that curcumin is useful in reducing papilloma development throughout carcinogenesis and progression. Dietary curcumin can reduce the number of papilloma that promoted skin tumor, which was explored by Limtrakul et al. (2001) as ras-p21 and fos-p62 oncogene expression was decreased dose-dependently by curcumin.  In addition, curcumin prevents the proliferation of uterine leiomyosarcoma via induction of apoptosis, autophagy, ERK 1/2 activity and fragmentation of DNA in gastric carcinoma cells (Imran et al. 2016). Curcumin treatment suppressed JAK-STAT signaling thus reducing tumor cell growth in ovarian (OVCA 420 and OVCA 429) and endometrial (RL95-2 and Ishikawa) cancer cell lines (Saydmohammed, Joseph, and Syed 2010). Curcumin down-regulated the expression of IL-6, IL-11 and NF-kB which leads to induce apoptosis of fibrosarcoma cells resulting in anticancer activity against bone cancer (Kondo et al. 2001; Kwak et al. 2006). Curcumin induced cell cycle arrest in G2/ M phase, apoptosis and cytotoxicity in squamous carcinoma cells as well as reduced tumor volume in head and neck cancer (Borges et al. 2017). Curcumin treatment reversed the migration and proliferation of hepatic carcinoma by downregulating the expression of HIF-1a. In addition, curcumin reduced the level of MMP-2 and MMP-9 as well as decreased the phosphorylation of p38, which is associated with suppression of cancer invasion and migration in hepatic carcinoma. Additionally, curcumin treatment exhibited anti-proliferative effect in MHCC97H liver cancer cells through generation of ROS, apoptosis and activating toll like receptor -4/MyD-88 pathway (Imran et al. 2016; Liang et al. 2014). Curcumin treatment significantly upregulated the expression of p21/CIP1 and p27/KIP1 CDK, and downregulated the expression of cyclin D1 resulting in decreased proliferation of pancreatic cancer cells. Apart from this, curcumin induced apoptosis via downregulating the ratio of Bcl-2/Bax and increasing the activation of caspase-9/3 in pancreatic cancer cells. Curcumin treatment inhibited PI3K/ Akt pathway and induced forkhead box O1 in Panc-1 pancreatic cancer cells leading to apoptosis (Zhao et al. 2015). Curcumin suppressed the oral tumor volume, numbers of dysplasic lesions, papillomas and squamous cell carcinoma (Imran et al. 2016). Interestingly, curcumin treatment has potential for many cancer types like esophagus cancer, testicular cancer, sarcoma and lymphoma (Kunnumakkara et al. 2017). Curcumin has been reported to have pharmacological efficiency towards multiple other cancer types like gastric, colorectal, liver, and osteosarcoma. Xiang Zhou et al. reported that curcumin, in combination with oxaliplatin and 5-fluorouracil (5-FU), exhibited synergistic inhibitory effect in xenograft gastric tumor (BGC-823 cancer cells) via downregulation of Bcl-2 and cleavage of caspase-3 and PARP through upregulation of BAX [81]. Gizem Calibasi-Kocal et al. reported the dose-dependent chemopreventive role of curcumin in HCT-116 and LoVo cells (human colon cancer cell lines) possibly through inhibition of NF-κB and/or activation of caspase-3 and caspase-9. Biqiong Ren et al. demonstrated the antiproliferative role of curcumin on liver cancer and reported its mechanism of action through inhibition of the heat shock protein 70-toll like receptor 4 (HSP70-TLR4) signaling pathway. Duk Su Lee DS et al. demonstrated curcumin-induced p53 upregulation, cell cycle arrest at gap-1/synthesis (G1/S) and G2/S phase, and caspase-3 activation in human osteosarcoma cells. Curcumin has been reported to possess antiproliferative activity towards fibrosarcoma, a rare malignant tumor of the fibrous connective tissue around the bones. MR Guimarães et al. reported that curcumin was able to inhibit cytokine gene expression in diseased periodontal tissue. They discovered curcumin-induced inactivation of IL-6, and IL-11 in a dose-dependent manner.
 
 
How may Curcumin work against Rheumatoid arthritis and Osteoarthritis?

The potential of curcumin against arthritis was first reported in 1980 in a short-term, double-blind, crossover study involving 18 young patients with rheumatoid arthritis. In this study, curcumin’s efficacy was compared with that of the prescription drug phenylbutazone. Patients were randomly assigned to receive either curcumin (1.2 g/day) or phenylbutazone (0.3 g/day) for 2 weeks. Curcumin was well-tolerated, had no adverse effects, and exerted an anti-rheumatic activity identical to that of phenylbutazone as shown by improvement in joint swelling, morning stiffness, and walking time. Curcumin can reduce joint inflammation and alleviate pain symptoms, mainly due to its anti-inflammatory and cartilaginous protective effects. In primary cultured chondrocytes, curcumin inhibited the mRNA expression of pro-inflammatory mediators IL-1β and TNF-α, MMPs 1.3 and 13, and ADAMTS5, and upregulated the chondroprotective transcriptional regulator Cbp/p300 interacting transactivator with ED-rich tail 2. Curcumin reduces the synthesis of inflammatory mediators, such as TNF-α, IL-17, IL-1β, transforming growth factor-β (TGF-β), and cyclooxygenase-2 and reduces the cartilage and synovial inflammation of rat models of arthritis induced by lipopolysaccharide, Collagen II and Monoiodoacetic acid. Curcumin exerts an anti-inflammatory effect by inhibiting TLR4 pathway and its downstream NF-κB signaling pathway. Activation of NF-κB pathway not only down-regulates pro-inflammatory factors, but also inhibits the expression of matrix degrading enzymes. Curcumin inhibited IL-1β-induced MMP-1 and MMP-3 production by inhibiting AP-1 and NF-κB signaling Pathway activation. Arthritis is an inflammatory autoimmune disease characterized by chronic inflammation of the synovial joint that can lead to severe joint injury. IL-10 plays an important role in the development of rheumatoid arthritis. Curcumin has anti-inflammatory effect and can regulate TLR-4 receptor and its downstream pathway.65 Curcumin can down-regulate the levels of TNF-α, IL-1β, IL-6, IL-12, IL-15, and IL-8 in macrophages, and up-regulate the level of IL-10. Curcumin effectively alleviates MSU-induced inflammatory response by inhibiting TLR4/NF-κB signaling pathway and NLRP3 inflammasome activity. Curcumin is a natural anti-inflammatory drug. Numerous preclinical studies have demonstrated its beneficial effect on arthritis. Clinical trials focused on the treatment of knee osteoarthritis. In a clinical trial of turmeric extract in the treatment of knee osteoarthritis, turmeric extract inhibited inflammation and improved clinical symptoms, as well as reduced IL-1β and oxidative stress. Turmeric extract was more effective than placebo for knee pain. Motahar Heidari-Beni et al produced an herbal formulation consisting of turmeric extract, black pepper and ginger. In patients with knee osteoarthritis, this compound raises prostaglandin E2 (PGE2) levels similar to naproxen. In a randomized, pilot study, 45 patients diagnosed with arthritis were randomized into three groups with patients receiving curcumin (500 mg) and diclofenac sodium (50 mg) alone or their combination. Results show that curcumin administration showed the significantly improvement in overall Disease Activity Score and American College of Rheumatology compare with diclofenac sodium. Clinical trials of curcumin in the treatment of arthritis have produced promising results.  Currently curcumin-containing dietary supplements are widely used for joint health.
In another recent study, curcumin alone (0.5 g) and in combination with diclofenac sodium (0.05 g) was found to be safe and effective in 45 patients with rheumatoid arthritis. Furthermore, the level of CRP was suppressed in these patients after curcumin administration. Several studies have shown the anti-arthritic effects of curcumin in humans with osteoarthritis and rheumatoid arthritis (RA). In a randomized double-blind placebo-controlled trial, 40 subjects with mild-to-moderate degree knee osteoarthritis were randomly assigned to receive either curcuminoid (500 mg/day in three divided doses; n = 19) with 5 mg piperine added to each 500-mg dose or a matched placebo (n = 21) for six weeks. There were significantly greater reductions in the visual analog scale (VAS) (p < 0.001), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores (p = 0.001), and Lequesne’s pain functional index (LPFI) (p = 0.013) scores in the treatment group compared with the placebo group.  This suggests that curcumin may offer an alternative to NSAIDS for patients with osteoarthritis seeking treatment but experiencing negative side effects. This was supported by results from a pilot study showing that a dose of 2 grams of curcumin had an analgesic effect in subjects with acute pain but without a diagnosis of osteoarthritis . At this dose, the activity was higher than that associated with 500 mg of acetaminophen, while a lower dose (1.5 g, 300 mg of curcumin) gave only transient and often inadequate relief of pain, indicative of suboptimal therapeutic plasma concentrations.  This supports the use of 2 g (higher than needed for inflammation) curcumin for relief of pain as a potential alternative to NSAIDS. Regardless of the mechanism by which curcumin elicits its effects, it does appear to be beneficial to several aspects of osteoarthritis , as suggested by a recent systematic review and meta-analysis that concluded: “This systematic review and meta-analysis provided scientific evidence that 8–12 weeks of standardized turmeric extracts (typically 1000 mg/day of curcumin) treatment can reduce arthritis symptoms (mainly pain and inflammation-related symptoms) and result in similar improvements in the symptoms as ibuprofen and diclofenac sodium. Therefore, turmeric extracts and curcumin can be recommended for alleviating the symptoms of arthritis, especially osteoarthritis”. A recent study out of Japan evaluated its relationship with the inflammatory cytokine known to be involved in in the
rheumatoid arthritis process. Scientists discovered that curcumin “significantly reduced” these inflammatory markers. In fact its anti-inflammatory qualities are so strong a 2007 study compared curcumin and cortisone and found they were equal in potency. A few studies have found that curcumin can reduce pain from rheumatoid arthritis or osteoarthritis, sometimes as much as anti-inflammatory drugs. An Iranian clinical trial in Phytotherapy Research in 2014 found that curcumin taken for six weeks, improved symptoms of knee osteoarthritis, compared to a placebo. Most pharmaceutical anti-inflammatories are contraindicated to use over the long-term, but turmeric is not only safe but beneficial for your overall wellbeing. Curcumin's anti-inflammatory properties also make it a strong candidate for treating inflammatory diseases such as osteoarthritis. A 2014 study in the Clinical Interventions in Aging found that curcumin extracts "were as effective as ibuprofen for the treatment of knee osteoarthritis." All current drugs approved for arthritis have anti-inflammatory activity. Anti-TNF (tumor necrosis factor) therapy has been approved for this disease. Curcumin has been shown to both suppress the TNF production, block the action of TNF, and have activity against arthritis.
When inflammation is reduced, the added benefit is pain relief. A double-blind, crossover study showed that Curcumin may be  effective in relieving pain and improvements in morning stiffness, walking time, and joint swelling. A preliminary intervention trial that compared curcumin with a nonsteroidal anti-inflammatory drug (NSAID) in 18 patients with rheumatoid arthritis (RA) found that improvements in morning stiffness, walking time, and joint swelling after two weeks of curcumin supplementation (1.2 g/day) were comparable to those experienced after two weeks of phenylbutazone (NSAID) therapy (300 mg/day). In a more recent randomized, open-label study in 45 RA patients, supplementation with a mixture of all three major curcuminoids (0.5 g/day for eight weeks) was found to be as effective as diclofenac (NSAID; 50 mg/day) in reducing measures of disease activity, tenderness, and swelling joints. Several studies have shown curcumin’s ability to reduce pain, stiffness, and swelling in joints afflicted by arthritis. The Arthritis Foundation suggests that those with arthritis who wish to seek relief take capsules of curcumin powder, between 400 mg to 600 mg, three times a day. Given that curcumin is a potent anti-inflammatory compound, it makes sense that it may help with arthritis. Several studies show this to be true. In a study in people with rheumatoid arthritis, curcumin was even more effective than an anti-inflammatory drug (42). Many other studies have looked at the effects of curcumin on arthritis and noted improvements in various symptoms.  An in vitro and ex vivo study found that curcumin has anti-platelet and prostacyclin modulating effects compared to aspirin, indicating it may have value in patients prone to vascular thrombosis and requiring anti-arthritis therapy. In a randomized, pilot study, curcumin administration (500 mg, b.i.d., p.o., for 8 weeks) reduced Disease Activity Score in rheumatoid arthritis without any adverse events. In addition, the effect of curcumin was better than the patients receiving diclofenac sodium (Chandran and Goel 2012). In animal model, curcumin administration (100 mg/kg orally for two weeks) showed anti-arthritic activity by augmenting the generation of somatostatin in the small intestine of Freund’s complete adjuvant induced arthritic rats (Yang et al. 2015). Curcumin (50 mg/kg, i.p.) attenuated the severity and progression of collagen induced arthritis in DBA/1 J mice by decreasing the production of B cell-activating factor belonging to the TNF family in spleen cells and serum as well as reduction of serum IL-6 and IFNc(Huang et al. 2013). It reduced the pannus formation process that produced through articular cartilage of collagen induced arthritic rats (Kamarudin et al. 2012). In in vitro studies, curcumin treatment (2.5–10 mmol for 14 days) inhibited the osteoclastogenic potential of peripheral blood mononuclear cells obtained from patients with rheumatoid arthritis by decreasing stimulation of ERK 1/2, c-Jun N-terminal kinase, p38 and downregulating nuclear factor of activated T cells (NFATc1), receptor activator of NF-jB and c-Fos expression, and reduce bone deterioration during rheumatoid arthritis (Shang et al. 2016b). Curcumin treatment efficiently blocked phorbol 12-myristate 13 acetate and IL-1b-induced upregulation of IL-6 expression in MH7A cells and Fibroblast-like synoviocytes. In addition, it inhibited NF-jB activation, induced ERK1/2 dephosphorylation, exerted strong anti-inflammatory activity and induced apoptosis in fibroblast-like synoviocytes, which might use as a natural remedy for the management of rheumatoid arthritis (Kloesch et al. 2013). Mechanistically, curcumin blocks certain cytokines and enzymes that lead to inflammation, and this sheds light on the possibility of curcumin for the treatment of rheumatoid arthritis. Osteoarthritis is the most common type of arthritis, which is characterized by pain, tenderness, bone spurs, stiffness, and loss of function in the joints (Farzaei et al. 2015). In a randomized, double-blind, placebo-controlled prospective study, chronic administration of curcumin (180 mg/day, p.o., for 8 weeks) significantly reduced knee pain in osteoarthritic patients as compared to the placebo group (Nakagawa et al. 2014). Curcumin treatment showed protection against osteoarthritis by inhibiting the release of inflammasome NLRP3, followed by downregulation of IL-1b, TNF-a and cleaved caspase-1 in surgical mouse osteoarthritis model (Sun et al. 2017). Mechanistically, curcumin reduced MMP-2, MCP-1, L-selectin, advanced oxidation protein product levels, suppressed the release of proteoglycans, expression of cyclooxygenase, prostaglandin E2 and inflammatory cytokines while increased CD47 levels in chondrocytes (Liu et al. 2016; Chin 2016).
 
How may Curcumin work against Gastrointestinal and Inflammatory bowel disease such as Crohn's disease, Ulcerative Colitis, Irritable bowel syndrome, gastritis, dyspepsia, gastric and peptic ulcers?
Six hundred milligrams of curcumin five times a day for 12 weeks to individuals with peptic ulcers could prevent ulcer development. Abdominal pain along with other symptoms has greatly decreased with curcumin within 1–2 weeks. Kim et al. (2005) found that orally administered ethanolic C. longa extract decreased stomach acid, gastric juice secretion, and ulcer initiation in male rats by inhibiting H2 histamine receptors, which is similar to the effects of ranitidine. Similarly, the antiulcer action of C. longa ethanolic extract was seen as it lowers ulcer index in addition to stomach acidity significantly. C. longa extract also suppressed hypothermic-restraint stress depletion of stomach wall mucus and diminished the severity of necrotizing agent-induced lesions. Curcumin significantly protects against severe colitis by inhibiting activation of NLRP3 inflammasomes and production of IL-1β, resulting in improved weight loss, reduced disease activity index and increased colon length. Curcumin can inhibit the production of pro-inflammatory factors which is beneficial to improve intestinal inflammation in patients with IBD. Curcumin can effectively induce and maintain symptom relief in patients with ulcerative colitis, reduce inflammatory markers and improve the quality of life of patients. Curcumin is derived from natural products, with high safety, has the capacity for anti-inflammatory, antioxidant, and regulating autophagy and gut microbiota. Curcumin is a safe and effective adjuvant agent in the treatment of IBD. In patients with IBD, curcumin has a beneficial effect on clinical symptoms, endoscopic relief, reduction of oxidative stress or inflammatory markers. Alternatively, curcumin can also play a beneficial role in a more common intestinal disease. Irritable bowel syndrome is a functional bowel disorder that classically presents with symptoms of abdominal pain, bloating, and altered bowel habits of diarrhea or constipation. The Irritable Bowel Syndrome- symptom severity score (IBS-SSS) was used to evaluate the effect of curcumin on patients with IBS. Curcumin can effectively improve IBS-SSS, abdominal pain and other symptoms, and improve the quality of life of patients. Research suggest that the beneficial effects of curcumin on IBS may be due to its anti-inflammatory effect. Because of its scientifically evidenced characteristics to interfere with a variety of signal transduction pathways, transcription factors, and cellular processes, curcumin can potentially be applied in the treatment of many diseases (inflammatory disorders in particular). In this context, curcumin has been used to treat gastrointestinal diseases such as indigestion, flatulence diarrhea, and even gastric and duodenal ulcers. Kwiecien and colleagues summarize in their review curcumin’s protective effects against esophageal and gastric disorders. In addition, curcumin is potentially efficacious against intestinal inflammatory diseases. Burge and colleagues discuss the beneficial effects of curcumin on the microbiome, its antimicrobial properties, changes in cytokine profiles, and alterations to immune cell maturation and differentiation. The combination of all these molecular actions makes curcumin a promising candidate to treat intestinal inflammatory diseases like necrotizing enterocolitis, Crohn’s disease, and ulcerative colitis. Crohn’s disease is a pro-inflammatory disease. All current drugs approved for this disease have anti-inflammatory activity. Anti-TNF therapy has been approved for this disease. Curcumin has been shown to both suppress the TNF production and the TNF action. Several clinical trials suggest that curcumin can help people with this inflammatory bowel disease. Clinical Gastroenterology and Hepatology featured a study in 2015 which found that in people with mild to moderate ulcerative colitis who took standard medication (mesalamine), the addition of a high-dose curcumin supplement helped half of them achieve remission after four weeks; none of those given a placebo benefited. Curcumin taken orally has been shown to have activity against inflammatory bowel disease. Study results suggest that Curcumin could have a protective role in ulcerative colitis via regulation of oxidant/anti-oxidant balance and modulation of the release of some inflammatory endocoids, namely TNF-alpha and NO. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial.  The development of DSS-induced colitis was significantly attenuated by curcumin. Inhibition of p38 MAPK signaling by curcumin could explain the reduced COX-2 and iNOS immunosignals and the nitrite production in colonic mucosa, reducing the development of chronic experimental colitis. In addition, Curcumin seems promising with regards to remission in patients with quiescent Ulcerative Colitis. Preliminary evidence suggests that curcumin might be useful as an add-on therapy to control disease activity. One multicenter, randomized, double-blind, placebo-controlled study has examined the efficacy of curcumin enema (2 g/day) in the prevention of relapse in 82 patients with quiescent UC . Six-month treatment with curcumin significantly reduced measures of disease activity and severity and resulted in a lower relapse rate than with placebo in subjects on standard-of-care medication (sulfasalazine or mesalamine). In another randomized controlled trial in active UC patients treated with mesalamine, the percentage of patients in clinical remission was significantly higher after a one-month treatment with oral curcumin (3 g/day) than with placebo. Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial. Another study conducted in the UK revealed that those with IBS who took two capsules of turmeric every day over the course of eight weeks experienced less abdominal pain and had more consistent bowel movements. A recent study from the American Gastroenterological Association suggests that curcumin may help ease ulcerative colitis, a form of inflammatory bowel disease that causes ulcers in the digestive tract. Turmeric has been known for a long time to help with digestive problems. For example, it helps very well with bad digestion of fats. But even if you suffer from irritable bowel syndrome or Crohn’s disease, turmeric can mean a great deal to you. This is partly because it prevents inflammation in the intestinal wall. Curcumin can also be a solution for people with a stomach ulcer. Curcumin has a significant role in cases of gastric ulcers. An open, phase II trial was performed on 25 patients with endoscopically diagnosed gastric ulcer. Participants were provided 600 mg powdered turmeric, five times daily. After 4 weeks, ulcers had completely healed in 48% patients. The success rate increased over time, with 76% being ulcer free after 12 weeks of treatment. No significant adverse reactions or blood abnormalities were noted. In a clinical study, five patients with a stomach ulcer were given five times 600 mg of curcumin every day for 12 weeks. Almost half of them had no stomach ulcers after four weeks, and by the end of the study, the gastric ulcer had disappeared by 76%. In a multi-centered, double-blind, placebo-controlled trial, curcumin treatment (1 g after breakfast and 1 g after the evening meal with mesalamine or sulfasalazine for 6 months) appeared to be a safe and promising drug candidate for maintaining remission in ulcerative colitis patients (Hanai et al. 2006). Holt et al. (2005) carried out a pilot study to see how curcumin therapy affected IBD patients who had earlier received standard UC or CD therapy. Curcumin with standard treatment exerts more beneficial effects than placebo plus conventional UC treatment in maintaining recovery, according to Hanai et al. (2006). Bundy et al. (2004) examined that abdominal pain or discomfort score was lowered significantly by 22% and 25% in the one- and two-tablet group volunteers, respectively, and revealed the role of C. longa on IBS pathology. In animal study, curcumin administration reversed inflammation of the colonic mucosa, restored colonic length, and reduced colonic weight and colonic damage. In addition, curcumin increased the number of T regulator (Treg) cells while suppressed the secretion of IL (2, 6, 12 and 17) and TNF-a. Curcumin is known to downregulate the expression of co-stimulatory molecules CD254 [RANKL], CD54 [ICAM-1], CD205, CD256 [RANK], TLR4 and CD252[OX40 L] against 2, 4, 6-trinitrobenzene sulfonic acid induced colitis in mice (Zhao et al. 2016b). In a recent experimental study, curcumin administration demonstrated therapeutic potential through downregulation of colonic TNF-a, myeloperoxidase (MPO), p-38MAPK and p-p38MAPK expressions in mouse murine ulcerative colitis model (Khoury et al. 2015). Curcumin treatment is known to reduce interferon (IFN)-c, COX-1, COX-2, TNF-a, NF-jB and iNOS expression. Further, it was reported that curcumin treatment reduces inflammation of colon due to inhibition of chemokinesis and neutrophil chemotaxis (Wan et al. 2014). Moreover, curcumin mitigated inflammatory bowel disease via influencing MAPK, ERK pathways, increasing antioxidants, inducing free radical scavenging and MPO inhibition (Baliga et al. 2012). Mechanistically, curcumin treatment reduced ulcerative colitis by inhibiting neutrophil chemotaxis, suppressing the secretion of inflammatory cytokines and inducing antioxidant effects. In a pilot study, administration of curcumin (350 mg, t.i.d. for 1 month followed by 350 mg q.i.d. for another 2 month) reduced the inflammatory response in Crohn’s disease condition. In addition, it reduced the erythrocyte sedimentation rates and Crohn’s Disease Activity Index in patients (Holt, Katz, and Kirshoff 2005). Oral administration of curcumin (40 mg/kg, for 21 days) reversed the visceral nociceptive response to graded intensity of colorectal distension and pellet output associated with chronic acute combined stress mediated depressive and anxiety like behaviors in rats. Mechanistically, curcumin treatment increased the levels of serotonin, BDNF and pCREB in the hippocampus, while these levels were reduced in the colonic of chronic acute combined stressed rats (Yu et al. 2015). The 5-HT1A receptor is known to be involved in the mode of action of curcumin for the management of visceral hypersensitivity in rats with irritable bowel syndrome. In addition, curcumin administration causes remarkable decrease in visceromotor response to colorectal distension in rats (Farzaei et al. 2016b). Adjunctive therapy of curcumin (500 mg/day for 4 weeks) with anti-helicobacter regimen ameliorated the symptoms of dyspepsia in peptic ulcer patients (Khonche et al. 2016). In animal study, curcumin administration reduced the restraint stress and water immersion stress-induced gastric lesions by increasing gastric blood flow and attenuating pentagastrin or histamine-stimulated secretion of gastric acid. In addition, the expression levels of iNOS, COX-2 and TNF-awas significantly downregulated in gastric mucosa of curcumin administered rats exposed to restraint stress and water immersion stress, resulting in gastroprotective effect (Czekaj et al. 2016). Curcumin (10, 50 or 100 mg/kg orally for three days) dose dependently reduced LPO and gastric ulcer area and restored GPx, CAT and SOD levels in gastric mucosa of naproxen treated rats (Kim et al. 2016b). Curcumin treatment reversed stress mediated gastric ulceration in rats by reducing the hemorrhage of gastric mucosa, increasing gastric pH values and attenuating ulcer index which is associated with downregulation of histone H3 acetylation at H þ , K þ -ATPase promoter gene (He et al. 2015a). Curcumin treatment decreased pepsin activity, total acid output and ulcer index alongside reduced MDA level, ameliorated mucin, CAT, NO and SOD in gastric mucosa of indomethacin-induced ulcer in rats (Morsy and El-Moselhy 2013). Additionally, curcumin ameliorated indomethacin-induced gastric ulcer by inducing angiogenesis and collagenization of gastric tissue via upregulation of TGF-b, MMP-2, membrane type 1-MMP and VEGF expressions in ulcerated tissues (Sharma et al. 2012). The biological mechanism of curcumin to combat peptic ulcer is mainly due to its antioxidant and anti-inflammatory activities. The gastroprotective effect is also due to inhibition of acid release, amelioration of blood flow, angiogenesis and collagenization of gastric tissue (Sharma et al. 2012; Yadav et al. 2013).  Clinically, curcumin administration (40 mg orally, three times a day, for four weeks) reduced the production of IL-1b, IL-8, COX-2 and TNF-ain gastric mucosa, and attenuated inflammation in gastritis patients infected with H. pylori bacteria (Koosirirat et al. 2010). In a randomized clinical trial, administration of curcumin (700 mg orally, three times a day, for 4 weeks) reduced the level of MDA, DNA oxidative damage, endoscopic and chronic inflammation scores and glutathione peroxides in gastritis patients (Judaki et al. 2017). In animal model, curcumin treatment downregulated the expression of chemokines such as CXCL1, CCL5, CXCL10, CXCL11, CCL20 and Chemokine (C-C motif) ligand 25 in stomach of mice bearing Helicobacter pylori induced gastric inflammation. In addition, curcumin decreased secretion of IL-1b, IL-6 and TNF-aduring H. pylori infection. Further, curcumin supplementation reduced the macromolecular leakage, MyD88 expression and NF-jB activation in gastric cells (Santos et al. 2015). Study suggested that antimicrobial activity of curcumin against H. pylori is responsible for the management of gastritis in mice (De et al. 2009). The biological effect of dietary polyphenol curcumin to reduce chronic gastritis is mainly due to its antioxidant, anti-inflammatory and anti-bacterial activities (Yadav et al. 2013), therefore, it can be recommended as a novel drug for management of gastritis. One open-label study evaluated the efficacy of curcumin in five patients with ulcerative proctitis and in five patients with Crohn disease.  Significant decrease in symptoms as well as in inflammatory indices (erythrocyte sedimentation rate and CRP) were observed in all patients with proctitis This study suggests the efficacy of curcumin against IBD. Another study evaluated the efficacy of curcumin as maintenance therapy in 89 patients with quiescent ulcerative colitis. The relapse rates were 4.65% in the curcumin-treated group and 20.51% in the placebo group. In another recent study, ingestion of oral curcumin at 500 mg/day along with prednisone was associated with clinical and endoscopic remission in a 60-year-old woman with a 17-year history of left-sided ulcerative colitis and enteropathic arthropathy (34). The patient had been examined for persistently active colitis in December 2009. Both a clinical and endoscopic evaluation confirmed the diagnosis. Previously, multiple mesalamine preparations, sulfasalazine, and steroid enemas had not been effective, and the patient had required multiple courses of steroids for disease exacerbation. She refused azathioprine/6-mercaptopurine and anti-TNF treatment because of possible adverse effects. In addition to 40 mg of prednisone, 500 mg of curcumin per day was given to the patient. After receiving curcumin and prednisone treatment for 1 year, the patient’s bowel movements had gone to two per day without blood, she was no longer taking steroids, and she was feeling well. She remained in clinical remission at further clinical evaluations in April, July, and December 2010. A colonoscopy performed in September 2010 showed no ulceration and biopsies consistent with chronic inactive ulcerative colitis (34). Thus, based on this case study, curcumin represents a viable treatment alternative or adjunctive therapy in the management of chronic ulcerative colitis. A recent study assessed the effect of curcumin on the levels of p38 mitogen-activated protein kinase (p38 MAPK), IL-1β, IL-10, and matrix metalloproteinase-3 (MMP-3) in the gut of children and adults with IBD. Results indicated suppression in p38 MAPK activation, reduction in IL-1β, and enhancement in IL-10 levels in curcumin-treated mucosal biopsies. Furthermore, dose-dependent suppression of MMP-3 in colonic myofibroblasts was observed after curcumin treatment. Another study conducted with eight healthy participants reported that turmeric has the potential to increase bowel motility and to activate hydrogen-producing bacterial flora in the colon.
 
How may Curcumin work against metabolic diseases such as polycystic ovary syndrome, metabolic syndrome, and obesity?
Effect of Curcumin on Metabolic Syndrome | The role of curcumin in reducing oxidative stress and inflammation has far-reaching implications when it comes to overall metabolic health. The idea that curcumin can attenuate systemic inflammation has implications for metabolic syndrome (MetS), which includes insulin resistance, hyperglycemia, hypertension, low high-density lipoprotein cholesterol (HDL-C), elevated low-density lipoprotein cholesterol (LDL-C), elevated triglyceride levels, and obesity, especially visceral obesity. Curcumin has been shown to attenuate several aspects of metabolic syndrome by improving insulin sensitivity, suppressing adipogenesis, and reducing elevated blood pressure, inflammation, and oxidative stress. In addition, there is evidence that curcuminoids modulate the expression of genes and the activity of enzymes involved in lipoprotein metabolism that lead to a reduction in plasma triglycerides and cholesterol and elevate HDL-C concentrations. Curcumin has been shown to have a role in decreasing angiogenesis and adipogenesis by suppressing CCAAT/enhancer-binding protein alpha and PPAR expression and by lowering cholesterol levels. Moreover, curcumin has the ability to upregulate the gene expression of pancreatic glucose transporter 2 (GLUT2), GLUT3, and GLUT4, thus stimulating insulin secretion. In a randomized double-blind placebo-controlled trial with a parallel-group design, 117 subjects with metabolic syndrome received either 1 g curcumin plus 10 mg piperine to increase absorption or a placebo. Analysis revealed significant reductions in serum concentrations of TNF-α, IL-6, transforming growth factor beta (TGF-b), and monocyte chemoattractant protein-1 ( MCP-1) following curcumin piperine supplementation. The results of this study suggest that curcumin piperine supplementation significantly decreases serum concentrations of pro-inflammatory cytokines in subjects with metabolic syndrome. In addition, the study looked at the cholesterol-lowering properties and found that curcuminoids were more effective than the placebo in reducing serum LDL-C, non-HDL-C, total cholesterol, triglycerides, and lipoprotein a (Lp(a)), in addition to elevating HDL-C concentrations. The effects of curcuminoids on triglycerides, non-HDL-C, total cholesterol, and Lp(a) remained significant after adjustment for baseline values of lipids and body mass index. From the same study, the authors also reported markers of oxidative stress. There was a significant improvement in serum SOD activities (p < 0.001) and reduced MDA (p < 0.001) and C-reactive protein (CRP) (p < 0.001) concentrations in the group receiving the curcumin with piperine compared to the placebo group. Quantitative data synthesis revealed a significant effect of curcuminoids vs. placebo in reducing circulating CRP concentrations. The authors concluded that short-term supplementation with a curcuminoid-piperine combination significantly improves oxidative and inflammatory status in patients with metabolic syndrome. Curcuminoids with piperine could therefore be regarded as natural, safe, and effective CRP-lowering agents. Inflammatory cytokines were also measured in the above study. Mean serum IL-1β (p = 0.042), IL-4 (p = 0.008), and vascular endothelial growth factor (VEGF) (p = 0.01) were found to be significantly reduced by curcumin piperine therapy. The authors suggest that the findings indicate that curcumin piperine may exert immunomodulatory effects via altering the circulating concentrations of IL-1β, IL-4, and VEGF. In a randomized double-blind placebo-controlled crossover trial, 36 obese adults received either 1 g curcumin and 10 mg piperine or a placebo for 30 days followed by a two-week washout period, after which they received the other treatment. A significant reduction in serum triglyceride concentrations was observed.
Effect of Curcumin on Obesity | Obesity is Inflammatory Disease. Studies have suggested that properties in curcumin may have a positive effect on blood sugar and blood pressure and may also promote weight loss and prevent obesity. Scientists led by Dr David Fairlie from the University of Queensland, Australia, have found abnormal amounts of an inflammatory protein called PAR2 in the fat tissues of overweight and obese rats and humans. PAR2 is also increased on the surfaces of human immune cells by common fatty acids in the diet. When obese rats on a diet high in sugar and fat were given a new oral drug that binds to PAR2, the inflammation-causing properties of this protein were blocked, as were other effects of the high-fat and high-sugar diet, including obesity itself. In the prevention and treatment of obesity and metabolic syndrome, Curcumin has been reported to modulate numerous targets that have been linked to obesity and insulin resistance. 1) Curcumin has been shown to downregulate the expression of TNF in various tissues. 2) Curcumin can suppress NF-κB activation induced by a wide variety of inflammatory agents through inhibition of degradation of IκBα. 3) Curcumin can inhibit the activation of IKK linked to the activation of NF-κB, and this leads to the suppression of expression of inflammatory biomarkers such as cyclooxygenase-2 (COX-2) and vascular endothelial growth factor. 4) Curcumin has been shown to downregulate the expression of various NF-κB-regulated proinflammatory adipocytokines including chemokines (such as MCP-1, MCP-4, and eotaxin)  and interleukins (IL-1, IL-6, and IL-8). Curcumin also suppressed the expression of plasminogen activator inhibitor type-1 through the inhibition of the transcription factor early growth response (Egr)-1 gene product that has been closely linked with insulin resistance and obesity. 5) Curcumin has been reported to mimic most antidiabetic drugs in that it activates PPAR-γ in hepatic stellate cells. 6) Curcumin has been shown to downregulate activation of c-Jun NH2 terminal kinase. 7) Curcumin has been shown to inhibit the Wnt/β-catenin pathway, which is closely linked to obesity. Later studies have indicated that Curcumin inhibits Wnt pathway signaling through downregulation of the transcription coactivator p300. Another potential mechanism by which Curcumin could inhibit β-catenin signaling is through inhibition of glycogen synthase kinase (GSK)-3β, which directly causes the phosphorylation of β-catenin. Curcumin was found to inhibit GSK-3β with as little as 66 nM IC50 (
32). 8) Curcumin has been shown to induce the expression of hemeoxygenase (HO)-1 through the activation of Nrf2 in pancreatic cells and thus mediate the survival of these cells. 9) Curcumin downregulates the secretion of insulin-like growth factor-1 but induces the expression of insulin-like growth factor binding protein-3. 10) Curcumin interrupts leptin signaling by reducing phosphorylation levels of the leptin receptor (Ob-R) and its downstream targets. 11) Curcumin suppresses gene expression of Ob-R in HSCs. 12) Curcumin has been reported to increase the expression of adiponectin, which negatively controls obesity. A study conducted by researchers at Tufts University found that curcumin, the predominant polyphenol in turmeric, suppressed the growth of fat tissue in mice and cell models and ultimately reduce weight gain. Two groups of mice were fed high-fat diets—one supplemented with 500 mg of curcumin per kilogram of weight. The curcumin group did not gain weight as the high-fat-only group.  Clinically, chronic administration of curcuminoids (comprising curcumin, bisdemethoxycurcumin and demethoxycurcumin) significantly decreased serum pro-oxidant-antioxidant balance, oxidative stress burden (Sahebkar et al. 2013), serum triglycerides (Mohammadi et al. 2013), VEGF, IL-1band IL-4 in obese patients (Ganjali et al. 2014). In animal study, curcumin treatment reduced the level of triglyceride and LDL-cholesterol along- side increased HDL-cholesterol, which is known to ameliorate lipoprotein metabolism. Curcumin administration (0.05% w/w of diet) markedly decreased the plasma level of free fatty acid and triglyceride in the hamsters fed with high-fat diet (10% coconut oil and 0.2% cholesterol w/w) (Ganjali et al. 2017). Curcumin administration (200 mg/kg, dissolved in 0.1% carboxy methyl cellulose, for 10 weeks) significantly decreased body weight, adipose weight, liver weight, plasma levels of triacylglycerol, lipid ratios, hepatic fat accumulation while increased HDL in fructose-fed rats (Maithilikarpagaselvi et al. 2016). Curcumin administration alone (80 mg/kg/day, p.o., for 12 weeks) significantly down-regulated the hepatic expression of sterol regulatory element-binding proteins-1, sterol regulatory element-binding proteins-2, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, mevalonate kinase, 24-dehydrocholesterol reductase, 7-dehydrocholesterol reductase, lanosterol synthase, sterol- C4-methyl oxidase-like (Sc4mol), squalene synthase, proprotein convertase subtilisin/kexin type 9, LDL-receptor, acetyl- coenzyme A carboxylase-1, ATP citrate lyase, acyl-CoA syn- thetase, fatty acid synthase, fatty acid desaturase-1, fatty acid desaturase-2, stearoyl-coenzyme A desaturase-1, glycerol-3- phosphate acyltransferase, glucose-6-phosphatase and phos- phoenolpyruvate carboxykinase-1 in high fat diet-induced obese mice. In addition, curcumin administration upregulated the hepatic phosphorylation of IRS-1, IRS-2 and Akt at serine 473 resulting in reversal of obesity in mice (Ding et al. 2016). Curcumin administration (200 mg/kg body weight) with high fat diet for 10 weeks significantly decreased the hepatic ERK and p38 signaling pathway activation as well as reduced body weight in rats (Maithili Karpaga Selvi et al. 2015). Curcumin (1 g/kg) along with high fat diet containing 60% of total calories from fat (5.1 kcal/g diet) administration for 16 weeks significantly decreased hepatic lipids levels, lipid peroxidation. Curcumin (100 or 400 mg/kg) along with high fat diet for 8 weeks effectively reduced serum fetuin-A levels and hepatic triglycerides level in obese rats. Curcumin is known to inhibit NF-jB activation and macrophage infiltration in adipose tissue. In addition, curcumin downregulated the expression of the plasminogen activator inhibitor type-1, TNF-aand MCP-1 while upregulated the expression of adiponectin in adipocytes (Bradford 2013). In in vitro assay, curcumin downregulated the expression of axin, GSK-3b, CK1-a, AP-2 (mature adipocyte marker) and upregulated the expression of Fz2 (Wnt direct receptor), Wnt10b, LRP5 (Wnt co-receptor), c-Myc and cyclin D1 in 3T3-L1 cells. In addition, curcumin inhibited the phosphorylation of MAPK, JNK, p38 and ERK thereby rescue the differentiation of 3T3-L1 cells into adipocytes (Ahn et al. 2010). Curcumin treatment inhibited mitotic clonal expansion process and downregulated the expression of PPAR-c, kruppel-like factor 5 and C/EBParesulting in reduced adipocyte differentiation (Kim et al. 2011). Mechanistically, curcumin administration inhibits NF-jB activation and macrophage infiltration, reduces the expression of  plasminogen activator inhibitor type-1, MCP-1, TNFa, very low density lipoprotein (VLDL), cytokines and leptin alongside induced HO-1, fatty acid oxidation, APO-A1 and adiponectin level. In addition, curcumin treatment reduces the incidence of obesity and its associated risk factors, mainly due to its antioxidant and anti-inflammatory activities (Alappat and Awad 2010).
Effect of Curcumin on Polycystic Ovary Syndrome (PCOS) | The latest systematic review and meta-analysis of randomized-control trials investigated a significant improvement in fasting glucose, fasting insulin, the homeostasis model assessment measuring insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI) in women with PCOS who took curcumin in comparison with a placebo group.  Jamilian et al. found that administration of curcumin for 12 weeks in women with PCOS had beneficial effects on glycemic control, among other things. The researchers reported that reduced fasting glucose (p = 0.002) significantly increased insulin sensitivity (p = 0.02), and positive alterations in serum lipids (i.e., a decrease in total cholesterol (p = 0.001) and LDL cholesterol (p = 0.001) and an increase in HDL cholesterol levels (p = 0.01)) in comparison to patients taking a placebo; in addition, curcumin supplements decreased the weight of women suffering from PCOS. Other researchers who have looked at the effects of curcumin on glycemic status, lipid profile, and high-sensitivity C-reactive protein (hs-CRP) levels in overweight/obese women with PCOS found that serum insulin, QUICKI (p < 0.05), and HOMA-IR (p = 0.067) were significantly improved in the group treated with curcumin. In contrast, the differences in lipid parameters and hs-CRP levels were not statistically significant in the curcumin-treated group. Curcumin may stimulate insulin-mediated glucose uptake through the phosphatidylinositol 3-kinsase (PI3K)/Akt pathway, which, in turn, upregulates glucose transporter 4 (GLUT4) in the adipocyte and skeletal muscle, leading to an increase in glucose levels. Additionally, curcumin may also enhance GLUT4 and glucose uptake in adipocytes. Curcumin has been shown to inhibit liver gluconeogenesis through modulation of 5’AMP-activated protein kinase (AMPK), thus reducing blood glucose levels. Moreover, the lipid-lowering potential of curcumin may be a consequence of curcumin’s ability to decrease the circulatory levels of lipid peroxides and total serum cholesterol (TC), or to increase the levels of high-density lipoprotein (HDL). There are some potential mechanisms that may be responsible for the beneficial influence of curcumin on lipid profile; for example, curcumin may suppress the expression of Niemen-Pick C1-like (NPC1) protein in the intestine, which mediates the cholesterol absorption of hepatocytes. Curcumin also ameliorates dyslipidemia and activates the lipid metabolism pathway, which elevates lipoprotein lipase activity to decrease triglyceride levels. The hypothesis about the beneficial impact of curcumin supplementation on women with PCOS is because curcumin may support the improvement in complications of PCOS by regulating gene expression—that is, by increasing the gene expression of superoxide dismutase (SOD) and glutathione peroxidase enzymes (GPx)—and cellular signaling. One of the first studies on the effects of curcumin on postprandial glucose and insulin response, which was conducted in 2010 by Wickenberg et al. showed the possible effects of curcumin on postprandial insulin levels. Curcumin is generally assumed to improve the body’s antioxidant enzymes by impacting related gene expression in patients with PCOS. In a randomized and double-blinded clinical trial involving 67 overweight or obese female patients with PCOS, the effects of curcumin on gene expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) (p = 0.011) and silent information regulator 1 (SIRT1) were reported. SIRT1 contributes to the deacetylation of the PGC-1α gene, thereby increasing the rate of thermogenesis and oxidation of lipids, and is also an NAD+-dependent histone deacetylase in the pathway of insulin secretion [15]. These results would seem to suggest that curcumin may improve hormonal profiles in patients with PCOS due to its support of ovarian function by reducing inflammation and oxidative stress. Interestingly, Sohrevardi et al. reported that the hormonal parameter of total testosterone levels and the biochemical parameters of triglycerides, HDL, and total cholesterol were significantly improved in the group taking curcumin together with metformin after three months in comparison to the group treated with only metformin. The anti-inflammatory properties of curcumin may mitigate hyperandrogenism due to its possible role in glucose and lipid metabolism. Moreover, curcumin has the ability to lower circulating tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) concentration. Proinflammatory cytokines such as TNF-α have been found to be significantly higher in PCOS patients [25]. Moreover, curcumin may exert anti-diabetic effects by increasing the gene expression of PPAR-γ, which has a pleiotropic impact on glucose homeostasis and insulin sensitivity and controls gene expression in lipid and glucose metabolism. Heshmati et al. [28] reported not only reduced glucose and insulin plasma levels, but also significantly reduced serum dehydroepiandrosterone (DHEA) levels (−26.53 μg/dL; p = 0.035) in patients with PCOS who took curcumin supplements for 12 weeks in doses of 1500 mg per day in comparison to the placebo patients. To date, there are few studies that have assessed the influence of curcumin on the sex hormones in women with PCOS. Regarding proinflammatory cytokines, Mohammadi et al. [31] investigated the therapeutic effects of curcumin on TNF-α, IL-6, and C-reactive protein (CRP) in rats with PCOS. The difference between the curcumin-treated group and the non-curcumin-treated rats with PCOS was significant. The results showed decreased IL-6 and CRP, and interestingly, they observed decreased expression of tumor necrosis factor alpha (TNF-α) in the granulosa layer and follicular fluid of follicles and ovarian cysts in the PCOS group treated with curcumin.
 
How may Curcumin work against liver diseaseS such as Non-alcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD), cirrhosis, and hepatitis?
Effect of Curcumin on Non-Alcoholic Fatty Liver Disease (NAFLD) or Metabolic-Associated Fatty Liver Disease (MAFLD) | Curcumin and related phenolics have been linked with the inhibition of lipid peroxidation, free radical formation (e.g., neutralization of superoxide, peroxyl, and hydroxyl radicals (ROSs), nitric oxide, and peroxynitrite (RNS)) and DNA damage. Despite obesity and hyperlipidemia, it is also known that patients with type 2 diabetes have a high prevalence of NAFLD (up to 70%). The above diseases share multiple cardiometabolic risk factors and proinflammatory pathways. Różański et al. analyzed databases and publications that have described the effects of using curcumin supplementation on biochemical parameters in MAFLD. They concluded that curcumin may have therapeutic potential in MAFLD patients. Jalali et al. included nine relevant randomized controlled trials (RCTs) in their meta-analysis in order to study the effects of curcumin supplements on metabolic markers and anthropometric parameters in patients with NAFLD. As shown in Table 3, the study reported a significant decrease not only in alanine transaminase (ALT) (p = 0.049) and aspartate transaminase (AST) (p = 0.032) activity, but also in serum total cholesterol (TC), LDL, FBS (p = 0.027), HOMA-IR (p = 0.031), serum insulin, and waist circumference (WC). After a meta-regression analysis of the duration and a dosage-based analysis, a significant change in BMI was indicated, and a subgroup analysis (age-based and TC-based) also indicated a significant decrease in TG. The study investigated changes in two-month and three-month supplementation with curcumin. The authors concluded that the use of curcumin in the analyzed studies had a beneficial effect on both metabolic and anthropometric parameters in patients with NAFLD. Curcumin administration (60 mg/kg for 4 weeks) inhibited the bio- synthesis of unsaturated fatty acids and fatty acids synthesis in ethanol treated mice. In addition, ethanol induced hepatic steatosis was reversed by curcumin treatment (Guo et al. 2017). Animal studies have shown that curcumin administration reduced the ethanol-induced increase in MDA content, decreases the levels of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and increases the GSH levels. In addition, it is known to reduce fatty liver, oxidative stress, inflammation and necrosis (Nabavi et al. 2014; Nanji et al. 1999; Ghorbani, Hajizadeh, and Hekmatdoost 2016). Non-alcoholic fatty liver disease is an umbrella term for a variety of pathological conditions including steatosis, fibrosis, cirrhosis and steatohepatitis, caused by accumulation of fat in the liver. It is closely correlated with metabolic syndrome, obesity, overweight and type 2 diabetes in pediatric and adult individuals (Nabavi et al. 2014). In randomized placebo-controlled trial, curcumin administration (70 mg/day for two months) significantly reduced the liver fat content, triglycerides, LDL-cholesterol, serum levels of total cholesterol, body mass index, ALT, AST, glycated hemoglobin and glucose in patients with nonalcoholic fatty liver disease as compared to placebo group (Rahmani et al. 2016). Additionally, curcumin upregulated the expression of adiponectin precursor and reduced its methylation in experimental model of fatty liver disease (Park et al. 2016). In methionine and choline feed deficient mouse model, curcumin administration inhibited the activation of NF-kB and reduced the inflammatory recruitment in steatohepatitis (Leclercq et al. 2004). Curcumin administration downregulated the intrahepatic expression of procollagen type I, CD11b, tissue inhibitor of metalloprotease (TIMP)-1, monocyte chemoattractant protein-1 and a-smooth muscle-actin in methionine and choline feed deficient mouse model of steatohepatitis alongside reduced the oxidative stress in cultured stellate cells (Vizzutti et al. 2010).  Curcumin administration reduced the serum hepatic markers viz., AST, ALT and MDA thereby attenuated lipopolysaccharide/d-galactosamine induced liver damage in rats. In the same study, curcumin administration reduced the NF-jB activation and TNF-a level in liver and serum. Furthermore, curcumin upregulated Nrf-2-dependent antioxidant defense genes like quinone (NQO-1), NAD(P)H dehydrogenase, glutamate-cysteine ligase and heme oxygenase-1 which is responsible for the hepatoprotective activity (Xie et al. 2017). Curcumin administration ameliorated the barrier integrity of intestine, reduced ectopic fat deposition in liver and modulated the gut microbiota which in turn reversed hepatic steatosis in high fat diet fed rats (Feng et al. 2017). Curcumin administration elicited hepatoprotective effect via reversal of reduced GPx, CAT and SOD levels in tartrazine induced liver injury. In addition, it reduced the intracellular vacuolization, dilation of central vein and sinusoids as well as necrosis in hepatotoxic rats (El-Desoky et al. 2017). Recent experimental evidence suggests that curcumin administration reduced Gr1hi monocytes infiltration in liver, downregulated the expression of MCP-1, TNF-aand TGF-b1 in mouse model of CCl 4 induced liver fibrosis (Huang et al. 2016b).
Effect of Curcumin on Cirrhosis |  It was reported that curcumin administration prevents bile duct ligation induced cirrhosis in rats via inhibition of oxidative stress and downregulation of TGF-b(Reyes-Gordillo et al. 2008). Curcumin administration ameliorated the functional properties of hepatocytes and downregulated the expression of NF-jB and iNOS in liver of biliary duct ligated rats (Barta et al. 2015). 
Effect of Curcumin on Hepatotoxic Ailments | Curcumin is said to increase apoptosis in injured hepatocytes while also reducing inflammatory effects, hepatic fibrogenesis, and substantially liver injury. The hepatoprotective attribute of curcumin might be due to direct free radical scavenging mechanisms, boosting glutathione levels, and assisting in liver detoxification. Curcumin has hepatoprotective activity similar to that of silymarin. From studies, it can be concluded that curcumin  has hepatoprotective potential in various including carbon tetrachloride (CCl4), acetaminophen (paracetamol) and galactosamine. This hepatoprotective effect is mainly a observed due to the antioxidant activity of curcumin along with its ability to decrease the formation of proinflammatory cytokines. Administration of curcumin is resulted in decrease of liver injury. Aflatoxin-induced biliary hyperplasia, lipid alterations, and necrosis were likewise cured by curcumin. Sodium curcuminate is a salt of curcumin that has choleretic effects, boosting biliary excretion of bile salts, cholesterol, bilirubin, and bile solubility, thus helping to prevent and treat cholelithiasis. This could be related to the antioxidant capacity of curcumin’s phenolic groups. Tacrine is well-known for its hepatotoxic and T-cell-destructive properties. Curcumin was over ten times more efficient than standard therapy, ascorbic acid, in research involving human hepatocytes cells that had been disrupted by tacrine (Song et al., 2001).
Effect of Curcumin on Hepatitis | A recent in vitro study demonstrated that curcumin treatment time and dose dependently reduce the expressions of hepatitis B virus surface antigen and e-antigen in hepatitis B virus transfected HepG2.2.15 cell line. In addition, curcumin inhibited replication of hepatitis B virus gene via down-regulation of cccDNA-bound histone acetylation (Wei et al. 2017). Study revealed that curcumin treatment inhibits hepatitis B virus via downregulation of the metabolic coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a). It has been reported that combination of nucleotide/nucleoside analog with curcumin can synergistically reduce the replication of hepatitis B virus (Nabavi et al. 2014; Mouler Rechtman et al. 2010). It was reported that co-incubation of hepatitis C virus with curcumin and its derivatives potently inhibits the entry of all major hepatitis C virus genotypes. Curcumin affects the membrane fluidity resulting in impairment of viral binding and fusion thereby inhibits cell-to-cell transmission in human liver cells (Colpitts et al. 2014). Co-administration of curcumin and IFN-a profoundly inhibited hepatitis C virus replication in Huh7 cells and found to be effective against hepatitis C virus infections (Kim et al. 2010). Moreover, curcumin exhibited anti-HCV activity by inducing HO-1 and modulating ERK and NF-jB activities in Huh7.5 cells expressing the hepatitis C virus genotype 1 b subgenomic replicon (Chen et al. 2012). Mechanistically, curcumin shows hepatoprotective action due to its antioxidant effects and inhibitory activity against NF-jB that is known to regulate different pro-fibrotic and pro-inflammatory cytokines. Additionally, curcumin supple- mentation reduced liver marker enzymes, cholesterol levels and replication of hepatitis B and C viruses (Nabavi et al. 2014).
 
How may Curcumin work as an antimicrobial, Antibacterial, Antiviral, antiparasitic, and Antifungal?
Curcumin has antiviral potential (von Rhein et al., 2016) even for HIV; inhibiting HIV-1 LTR promoter directed gene expression with no effect on cell viability (Ashraf, 2018). Curcumin had moderate effectiveness towards Plasmodium falciparum and Leishmania organisms. The ethanol extracts exhibit anti-Entamoeba histolytica activity while curcumin has anti-P. falciparum and anti-Leishmania effect in vitro. Curcumin seems to have its antiviral activity for Epstein–Barr virus and HIV (Taher et al., 2003). An extract of C. longa in both aqueous and ethanol is used in aquaculture as a treatment for bacterial infections (Sahu et al., 2005). Curcumin exerts anti-parasitic action against African trypanosomes, has schistosomicidal activities against Schistosoma mansoni adult worms, and has anti-malarial in addition to nematocidal effects. Curcumin has shown a wide range of antiviral activity against different viral models. Similar to these reports, our findings indicated that curcumin inhibits SARS-CoV-2 D614G strain which contains the most widespread amino acid change (D614G in the spike protein) carried by more than 99% of the prevalent variants since the beginning of 2020. According to previous reports, curcumin exhibited moderate selectivity for pre-infection and post-infection treatment strategies. Contrarily, low selectivity was obtained for pre–post infection treatment and co-treatment strategies. Curcumin inhibited SARS-CoV-2 D614G strain by pre-infection treatment of Vero E6 cells. This effect has also been observed with other enveloped viruses such as Influenza, Dengue, Zika, Chikungunya, Japanese encephalitis, Pseudorabies, and Vesicular stomatitis virus, showing that curcumin treatment affects the early stages of the replicative cycle, such as viral attachment, internalization, fusion, or decapsidation. With regard to SARS-CoV-2, spike protein binds to its human receptor ACE2 (angiotensin-converting enzyme 2) through its receptor-binding domain. Previous studies have reported a favorable binding affinity of curcumin to the spike protein and its cell receptor, ACE2 (angiotensin-converting enzyme). According to the above, it could be suggested that curcumin prevents the recognition of the target cell and subsequent SARS-CoV-2 entry by direct interaction with cell factors or viral proteins. This effect could be related to our results obtained by co-treatment which suggest a possible virucidal activity of curcumin against SARS-CoV-2 D614G strain. It has been demonstrated that curcumin as a plant derivative has a wide range of antiviral activity against a variety of viruses including parainfluenza virus type 3 (PIV-3), feline infectious peritonitis virus (FIPV), vesicular stomatitis virus (VSV), herpes simplex virus (HSV), flock house virus (FHV), and respiratory syncytial virus (RSV) assessed by MTT test showed the potent antiviral activity of curcumin and its bioconjugates against different viral pathogens for further studies. Curcumin showed the anti-influenza activity against influenza viruses PR8, H1N1, and H6N1. The results showed more than 90% reduction in virus yield in cell culture using 30 μM of curcumin. In H1N1 and also H6N1 subtypes, the inhibition of haemagglutinin interaction reflected the direct effect of curcumin on infectivity of viral particles and this has proved by time of drug addiction experiment. Additionally, unlike amantadine, viruses developed no resistance to curcumin.  There are several studies illustrate that curcumin can impede viral replication and prevent injuries caused by several virus infectious diseases in particular, for RNA virus infections. In vitro and in vivo results have shown that curcumin effectively moderates infections and symptoms caused by the hepatitis virus, respiratory syncytial virus (RSV), Human Immunodeficiency Virus (HIV/AIDS),  Zika virus, Chikungunya virus, Epstein Barr virus, papilloma virus (HPV), enterovirus (enterovirus), Japanese encephalitis virus, influenza virus, dengue virus, and coronavirus (such as SARS-COVID 19) In recent studies that have calculated and simulated molecular docking models for viral infections, the results showed that the curcumin molecule can directly interact with proteins of Ebola virus, influenza virus, AIDS Viruses, dengue virus, and human papillomavirus (HPV), etc. The combination of curcumin with viral coat proteins, virus-specific enzymes, or RNA polymerase can affect and abolish virus replication, infection, and damage to cells. Current research results show that turmeric can inhibit SARS and COVID 19 infections via molecular binding, and currently curcumin is also applied in clinical trial on COVID 19 infection. Antimicrobial activities for curcumin and rhizome extract of C. longa against different bacteria, viruses, fungi, and parasites have been reported. The promising results for antimicrobial activity of curcumin made it a good candidate to enhance the inhibitory effect of existing antimicrobial agents. Curcumin has shown antibacterial activity effectively against Staphylococcus aureus, Salmonella paratyphi, Trichophyton gypseum, and Mycobacterium tuberculosis. The antibacterial activity of the aqueous extracts from turmeric is believed to be due to the anionic constituents like nitrate, sulphates, chlorides, and thiocyanate. Antibacterial activity of curcumin was also studied in endodontic bacteria Streptococcus mutans, Actinomyces viscosus, Lactobacillus casei, Porphyromonas gingivalis, Prevotella intermedia, and Enterococcus faecalis, and a significant inhibition of bacterial growth was observed. Many studies have revealed that curcumin and turmeric extracts inhibit the growth of microorganisms. Curcumin has antibacterial effects on both gram-positive and -negative bacteria, such as: Staphylococcus aureus, Streptococcus pneumoniae, Salmonella, Escherichia coli, Helicobacter pylori, etc., which often cause human infectious diseases. In preclinical and clinical studies for sepsis treatment, i.e. systemic bacterial infections, curcumin can act on PI3K/AKT, NFκB, TNF-α and TGF-β1 pathways to attenuate the toxicity of LPS on sepsis and curcumin also exerts the protective role in the lungs, liver, and kidneys while reducing the sequelae of tissue fibrosis after sepsis.  Curcumin is very effective against several pathogenic Gram +ve bacteria such as Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus species that cause many infections such as skin problems, pneumonia, meningitis, and urinary tract infection. The study of curcumin against 14 strains of Candida including 4 ATCC strains and 10 clinical isolates showed that curcumin is a potent fungicide compound against Candida species with MIC values range from 250 to 2000 μg/mL. In another study, anti-Candida activity of curcumin was demonstrated against 38 different strains of Candida. A recent study revealed that, curcumin exhibited in vitro antibacterial activity against most prevalent organisms like Enterococcus faecalis, Prevotella intermedia, Porphyromonas gingivalis, Actinomyces viscosus, Lactobacillus casei, Streptococcus mutans and Aggregatibacter actinomycetemcomitans (Mandroli and Bhat 2013). Moreover, curcumin demonstrated its effectiveness against Bacillus subtilis, Mycobacterium tuberculosis, Escherichia coli, Helicobacter pylori, Staphylococcus intermedius, Sarcina lutea, Sarcina lutea and Neiserria gonorrhoeae (Tyagi et al. 2015; Marathe et al. 2011). Curcumin treatment reduced growth of gut microbiota like Bifidobacterium, E. faecalis, Bifidobacterium. pseudocatenulatum G4, Bifidobacterium. longum BB536,E. coli K-12, Lactobacillus acidophilus and Lactobacillus casei thereby inducing the susceptibility to infectious disease (Marathe et al. 2011). Curcumin inhibited the growth of both Gram-negative and Gram-positive bacteria. Curcumin effectively reduced the infectious disease caused by various species of Staphylococcus aureus (Tong et al. 2015;Teowetal.2016). Mechanistically, curcumin interfere with quorum sensing, virulence and biofilm initiation, and inhibits bacterial cell by suppressing its dynamic assembly. Curcumin demonstrated its effectiveness against parasites like Trypanosoma, Plasmodium and Giardia. In parasites culture, curcumin treatment induced DNA damage via its prooxidant activity and inhibited histone acetyltransferases in Plasmodium falciparum resulted in cytotoxicity, which can be targeted for treatment of malaria (Cui, Miao, and Cui 2007), revealing its therapeutic potential against cerebral malaria as adjunctive therapy (Mimche, Taramelli, and Vivas 2011). Curcumin induced DNA damage and apoptosis and effectively inhibited the growth of Giardia lamblia (Perez-Arriaga et al. 2006). Moreover, curcumin administration mediates anti-parasitic activity against Trypanosoma, a parasite which is responsible for sleeping sickness and Chagas disease (Marathe et al. 2011). The biological effect of curcumin to reduce these infections is mainly due to its pro-oxidant and apoptotic activities, therefore, it can be recommended as a novel drug for management of giardia, trypanosoma and plasmodium infections. Curcumin treatment upregulated the transcription of chitin synthase-1, chitin synthase-3 and PKC in Sporothrix schenckii thus reduced virulence in infected mice (Huang et al. 2016a). Curcumin induced photodynamic inactivation of the fungus Candida albicans in murine model of oral candidiasis (Dovigo et al. 2013). Also, curcumin exhibited therapeutic potential against oropharyngeal candidiasis in a mouse model (Karaman et al. 2011). In fungal cell cultures, curcumin inhibited the growth of wide range of pathogenic fungus that includes Aspergillus clavatus, Aspergillus terreus, Aspergillus tamarii, Aspergillus fumigatus, Aspergillus flavus IMI190443,  Aspergillus nomius ATCC 15546, Aspergillus fumigatus ATCC 16913, Paracoccidioides brasiliensis B339, Paracoccidioides brasiliensis MG04, Paracoccidioides brasiliensis 17, Paracoccidioides brasiliensis 608, Paracoccidioides brasiliensis Pb18, Paracoccidioides brasiliensis Pb01, Paracoccidioides brasiliensis MG05, Sporothrix schenckii ATCC 10212, Cryptococcus neoformans ATCC 32608, Candida dubliniensis (Cd28), Candida dubliniensis (Cd22), Candida glabrata ATCC 2001, Candida parapsilosis ATCC 20019, Candida krusei ATCC 20298, Candida tropicalis ATCC 750 and Candida albicans ATCC 18804 (Martins et al. 2008). Curcumin (500 mg/L) also exhibited antifungal effects against Phytophthora infestans, Pu. Recondite and Rhizoctonia solani (Kim, Choi, and Lee 2003). Curcumin demonstrated fungicidal activity against the clinical isolates of Candida species like Candida tropicalis, Candida kefyr, Candida krusei, Candida guilliermondii, Candida glabrata, Candida parapsilosis and Candida albicans at MIC value of 32–128 mg/mL (Zorofchian Moghadamtousi et al. 2014). The suggested anti-fungal mechanisms of curcumin includes the leakage of intracellular component through the flappy membrane, disruption of fungal plasma membrane, generation of oxidative stress, induction of early apoptosis, inhibition hyphae development, upregulation of chitin synthase and PKC etc. (Lee and Lee 2014; Sharma et al. 2010). These evidences on the mechanistic action of curcumin could be employed in improving the treatment strategies for fungal infections. A recent study has shown that the anti-inflammatory and anti-oxidant effects conferred by curcumin protect from human cytomegalovirus infection in Balb/c mice (Lv et al. 2014). Among various phytochemicals evaluated for antiviral activity against norovirus, curcumin exhibited most potent anti-noroviral effects. In a cell culture infection model, curcumin exposure for 3 days was found to reduce norovirus infectivity by 91%. Thus, curcumin might be a promising anti-noroviral candidate to prevent foodborne illness (Yang et al. 2016).  Curcumin demonstrated promising anti-influenza activity against influenza viruses PR8, H1N1 and H6N1 by interfering with viral hemagglutination activity (Chen et al. 2010; Dao et al. 2012; Ou et al. 2013). In dengue infected BHK-21 cells, curcumin administration reduced the number of plaques produced, intracellular accumulation of viral proteins and increased the level of Lys48 ubiquitin-conjugated proteins in dengue virus (Padilla-S et al. 2014). In in vitro assays, curcumin demonstrated potent antiviral effect against Human enterovirus 71 (EV71). Curcumin inhibited viral RNA synthesis and expression of viral protein, thereby decreasing production of viral progeny (Qin et al. 2014). Proteomics analysis indicated that curcumin (15–240 lM) pretreatment exert antiviral activity by downregulating heat shock cognate 71 and inhibited the replication of viral hemorrhagic septicemia virus (Jeong et al. 2015). On the other hand, curcumin exhibited remarkable antiviral effects against herpes simplex virus type 1 (HSV-1) by blocking the recruitment of RNA polymerase II and expression of viral immediate-early genes (Kutluay et al. 2008). In another study, curcumin and its metallo derivatives, viz. gallium-curcumin and Cu-curcumin also exhibited remarkable anti-HSV-1 activity in vitro (Zandi et al. 2010). Moreover, curcumin administration conferred significant protection against intra-vaginal HSV-2 infection (Bourne et al. 1999). Curcumin inhibited both HIV-1 (IC 50 -100mM) and HIV-2 protease (IC 50 -250mM) thereby suppressed the replication of viral genes and prevent multiplicity of HIV (Sui et al. 1993). Curcumin mediated inhibition of HIV protease and integrase (IC 50 40 mM) resulted in anti-retroviral activity (Mazumder et al. 1997; Mazumder et al. 1995). Curcumin induced anti-HIV activity can be attributed to degradation of Tat via proteosomal pathway and inhibition of Tat protein acetylation by p300/CREB-binding protein thereby sup- pressed HIV-1 multiplication (Ali and Banerjea 2016; Balasubramanyam et al. 2004). Curcumin demonstrated strong anti-HPV activity in cervical and oral cancer cells through downregulation of HPV oncogene expression (E6 and E7) of highly oncogenic HPV, HPV-16 and HPV-18 (Divya and Pillai 2006; Mishra and Das 2015; Prusty and Das 2005). Curcumin downregulated the transcription factor, AP-1 in HeLa cells which is critical for transcription of HPV-16 and HPV-18 (Prusty and Das 2005). Curcumin mediated downregulation of viral oncogenes is attributed to its ability to modulate apoptosis and prevent NFkB and AP- 1 translocation thereby suppressing the transcription of HPVs (Divya and Pillai 2006; Prusty and Das 2005). Curcumin exhibited potent antiviral effect against coxsackie virus by inhibiting viral replication, RNA expression and protein synthesis via ubiquitin-proteasome system mediated protein modification or degradation (Si et al. 2005; Si et al. 2007). Mechanistically, curcumin treatment downregulated JunD protein, reduced production of infective viral particles, downregulated genomic transcription and translation, inhibited viral oncoproteins E6 and E7 expressions, suppressed the Akt/sterol regulatory element-binding proteins (SREBP)- 1 pathway, increased p53 level, inhibited hemagglutination, inhibited proteases, integrase and Tat protein acetylation (Zorofchian Moghadamtousi et al. 2014; Mazumder et al. 1995; Balasubramanyam et al. 2004; Dutta, Ghosh, and Basu 2009). The extensive research on antiviral activities of curcumin against different viral pathogens nominates this compound as a potent antiviral drug candidate.
Effect of Curcumin on COVID-19 | Curcumin, a natural compound with anti-inflammatory effect, could as an adjuvant drug in COVID-19 treatment. Curcumin has been revealed to be linked to the viral S1 protein, which is required for SARS-CoV-2 entry in an in silico approach; thus, it may inhibit cytokine storm in the severe stage of COVID-19 (Pawitan, 2020).  Curcumin can inhibit SARS-CoV replication. Several studies suggest that curcumin can inhibit SARS-CoV-2 replication. Evidence has already emerged regarding the action of curcumin in SARS-associated corona virus (SARS CO-V) by directly interacting with viral proteins, disrupting the viral envelope, inhibiting viral proteases and modulating NFKB, Nrf2 and high mobility group box 1(HMGB1) pathways in vitro. SARS-CoV-2 (COVID-19) has nearly 79% resemblance to SARS CO-V and hence the postulation. Curcumin can block the interaction between the spike glycoprotein and angiotensin-converting enzyme 2 (ACE2) and inhibit the Nsp15 protein, therefore blocking replication of the virus or inhibiting viral protease. These observations were supported by a study by Han et al. who demonstrated that curcumin strongly inhibited TGEV proliferation and viral protein expression in a dose and time-dependent manner, and treatment with curcumin caused a reduction in both viral particles (IC50 of 8.6 μM) and protein levels in porcine kidney cells. This study suggested that curcumin may inhibit the adsorption of TGEV or that it possesses excellent virucidal activity.  Compared to the placebo group, curcumin could reduce the frequency of Th17 cells, Treg and their related inflammatory factors in both mild and severe COVID‐19 patients. In addition to anti-inflammatory effect, curcumin can also play an antiviral role by inhibiting SARS-CoV-2 entry into cells and inhibiting viral proliferation. Curcumin has a variety of pharmacological effects and high safety, which makes it an adjunctive drug for the treatment of COVID-19. In a clinical trial, orally administered curcumin with piperine as adjuvant therapy in COVID-19 treatment could substantially reduce morbidity and mortality, and improve clinical symptoms.  Curcumin effectively neutralized SARS-CoV-2 at subtoxic concentrations in Vero E6 and human Calu-3 cells. Furthermore, curcumin treatment significantly reduced SARS-CoV-2 RNA levels in cell culture supernatants. This data uncovers curcumin as a promising compound for complementary COVID-19 treatment. Curcumin concentrations contained in turmeric root or capsules used as nutritional supplements completely neutralized SARS-CoV-2 in vitro. Due to the antiviral as well as anti-inflammatory effect of curcumin, the compound might have a positive effect on COVID-19 progression. Curcumin potently neutralizes SARS-CoV-2 in vitro at low subtoxic concentrations. The good safety profile of curcumin and its immunomodulatory as well as the antiviral effect make curcumin a promising candidate for complementary treatment of COVID-19.
 
How may Curcumin work against depression, major depressive disorder, and anxiety?

Curcumin has a wide range of characteristics that are important to depression pathogenesis. The extract prevented the decrease in serotonin, noradrenalin, and dopamine concentrations while increasing serotonin turnover, cortisol levels, and serum corticotrophin-releasing factor levels (Xia et al., 2007). The consequences of orally administered curcumin seem on behavior under chronic stress or depression condition in the rat model. Curcumin administration showed a similar impact to imipramine, a known antidepressant drug, and it has been indicated by various authors to be a feasible alternative source in depression condition (Mohammed et al., 2019; Qi et al., 2020). Curcumin has anti-inflammatory, antioxidant and neurotrophic properties, suggesting it has strong potential for relieving depression. Curcumin’s anti-inflammatory effect is one reason for its improvement in depression. In addition to its anti-inflammatory properties, curcumin also inhibits the release of monoamine oxidase, serotonin and dopamine, and regulates the hypothalamus pituitary adrenal axis, neurotrophic factors, and hippocampal neurogenesis and neuroplasticity. Administration of curcumin decrease mRNA expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α, through down-regulation IL-1β/NF-κB signaling,105 inhibit the NLRP3 inflammasome activation. Curcumin improves IL-1β-induced neuronal apoptosis by inhibiting the P38 pathway In a meta-analysis of nine clinical trials, curcumin may improve symptoms of depression and anxiety in patients with depression. In randomized double-blind, placebo-controlled trial, adjuvant curcumin (doses increased from 500 mg/day to 1500 mg/day) showed a significant difference between curcumin and placebo at weeks 12 and 16. The core issue of depression has been identified as inflammation, and curcumin has been found to be comparable to prescription antidepressant drugs. In one  study published in Phytotherapy Research, scientists studied 60 patients with serious depression over a six-week trial and found that turmeric was as effective at treating depression as Prozac.  This randomized control trial took 60 volunteers diagnosed with major depressive disorder and compared the effect of curcumin to fluoxetine (Prozac). Researchers discovered that the principal curcuminoid in turmeric is not only as effective as Prozac in managing depression, but it doesn’t carry with it all the dangerous side effects as anti-depressive drugs do. One-third of the participants in the study were given 20 mg of fluoxetine (which is sold under the prescription names Prozac and Sarafem), one-third were given 1,000 mg of curcumin (the active ingredient in turmeric), and one one-third were given a combination of both.  "Curcumin, an active ingredient of Curcuma longa (Zingiberaceae), has shown potential antidepressant-like activity in animal studies,” the researchers wrote. “The objectives of this trial were to compare the efficacy and safety of curcumin with fluoxetine in patients with Major Depressive Disorder (MDD).” They concluded that curcumin was “well tolerated” by all the patients. All three groups showed approximately equal improvement in their depression, whether they were taking the turmeric, the antidepressant or a combination of both.“This study provides first clinical evidence that curcumin may be used as an effective and safe modality for treatment in patients with MDD without concurrent suicidal ideation or other psychotic disorders. Curcumin, a natural compound derived from the herb Curcuma longa, exhibits a wide range of pharmacological properties and thus has been considered as a potent antidepressant drug. Curcumin may exhibit multiple antidepressant activities: (a) modulating the neurotransmitter levels including DA, NE, 5‐HIAA and inhibiting the expression of monoamine oxidase enzymes; (b) reducing the inflammatory response by regulating the production of pro‐inflammatory markers; (c) repairing neurodegeneration and enhancing neurogenesis and neuronal plasticity typically increased BDNF levels; (d) improving the activities of antioxidant enzymes; (e) decreasing the nitric oxide levels; (f) regulating mitochondrial disturbances; and (g) moderating hypothalamus‐pituitary‐adrenal (HPA) disturbances. The multiple mechanisms of curcumin provide a unique advantage in the medication of depression, especially in the term of adverse effects. A new study, published online ahead of print in the Journal of Affective Disorders, finds that the spice curcumin, a derivative of turmeric, may be an effective treatment for depression. The study was a randomized, placebo-controlled trial (the gold standard methodology for medication studies). The researchers found that curcumin was better than a placebo treatment, and those with atypical depression were far more likely to improve. The use of curcumin appeared especially effective for those with atypical depression. Atypical depression, despite its name, is relatively common (around 40% of MDD cases). The “atypical” moniker refers to its particular features: excessive sleep, weight gain, mood improvement in response to positive events, heavy, immovable feelings in the limbs, and interpersonal rejection sensitivity. Atypical depression is considered to have a more chronic course, with worse outcomes overall, so the potential for a viable treatment with fewer side effects than current medications provides hope for an improved prognosis. Previous studies have shown evidence that curcumin could be an effective treatment for depression and found minimal side effects. This study adds to the literature by comparing several doses of curcumin as well as a curcumin/saffron combination treatment. A study published in Brain Research examined the effects of curcumin administration to laboratory rats after exposure to a chronic stress protocol. Researchers found that curcumin supplementation had a beneficial effect on reducing stress-related symptoms of depression. A study in Psychopharmacology showed curcumin increased serotonin production and had an antidepressant effect on laboratory mice exposed to several lab tests. In a six-week, randomized, single-blinded, placebo-controlled study in 60 MDD patients, supplemental curcumin (~880 mg/day of curcuminoids) alone yielded a similar response rate to the antidepressant, fluoxetine (a serotonin reuptake inhibitor [Prozac]; 20 mg/day) in terms of depressive symptoms. A 2009 review published in Scientific World Journal hypothesizes that curcumin from turmeric may provide benefits for depression by assisting with the regulation of brain neurotransmitters like dopamine and serotonin and inhibiting the monoamine oxidase enzyme, which plays a role in breaking down these neurotransmitters.  The neurotransmitters are also what Prozac treats, helping serotonin be used effectively by the brain.  Major depressive disorder (MDD) is a neuropsychiatric disorder associated with abnormal neurotransmission; it is primarily treated with drugs that improve the bioavailability of neurotransmitters like serotonin, noradrenaline, and dopamine in the brain. Characteristics of MDD also include alterations in the hypothalamus-pituitary-adrenal axis, increased neuroinflammation, defective neurogenesis, and neuronal death. A few clinical studies have examined the effect of curcumin alone or with conventional antidepressant drugs in MDD patients. A recent meta-analysis of six randomized controlled trials found that supplementation with curcumin significantly reduced depression symptoms. Moreover, in a randomized controlled study in 100 participants taking escitalopram (a serotonin reuptake inhibitor [Lexapro]; 5 to 15 mg/week), supplemental curcumin (1,000 mg/day) for six weeks increased the antidepressant effect of the medication. Curcumin also induced a reduction in plasma concentrations of inflammatory markers and an increase in plasma concentrations of brain-derived neurotrophic factor compared to placebo (antidepressant drug alone). A study involving 56 people with major depressive disorder revealed that 500 mg of curcumin taken twice a day for eight weeks could ease mood-related symptoms.  In a controlled trial, 60 people with depression were randomized into three groups. One group took Prozac, another group one gram of curcumin and the third group both Prozac and curcumin. After 6 weeks, curcumin had led to improvements that were similar to Prozac. The group that took both Prozac and curcumin fared best. According to this small study, curcumin is as effective as an antidepressant. Depression is also linked to reduced levels of brain-derived neurotrophic factor (BDNF) and a shrinking hippocampus, a brain area with a role in learning and memory. Curcumin boosts BDNF levels, potentially reversing some of these changes. There is also some evidence that curcumin can boost the brain neurotransmitters serotonin and dopamine. A study published in the journal Acta Poloniae Pharmaceutica found that curcumin compared favorably to both drugs in reducing depressive behavior in an animal model. Depression and anxiety are different neurological disorders, but depressive patients often experience symptoms like anxiety disorder, such as irritability, nervousness, and problems in concentrating and sleeping. Depression and anxiety disorders have its own pathophysiology as well as behavioral and emotional symptoms. In a double blind, cross-over clinical trial, curcumin administration (1 g/day for 30 days) significantly reduced anxiety like behavior. Chronic curcumin administration (500 mg, twice daily for eight weeks) is associated with elevated urinary level of substance P and thromboxane B2 as compared to the placebo group. In addition, curcumin administration ameliorated the plasma endothelin-1 and leptin which is associated with greater reductions in IDS-SR30, a major depressive episode (Lopresti et al. 2015). In a randomized, double-blind, placebo-controlled trial, curcumin treatment (500 mg twice daily) for 4 to 8 week provides partial improvement in people with major depressive disorder (Lopresti et al. 2014). A recent meta-analysis data suggest that, curcumin supplementation appears to be efficacious, safe and well-tolerated anti-depressant and anxiolytic in patients (Ng et al. 2017). In animal study, curcumin treatment is reported to attenuate depressive phenotype during chronically stressed condition via several mechanisms viz., reduction in adrenal gland to body weight ratio, reduction in serum corticosterone level, reduction in adrenal cortex thickness as well as upregulation of BDNF and COX-2 expression and reduction in (pCREB/ CREB) levels in brain. Curcumin administration increased the level of synaptophysin and BDNF in amygdala alongside reduced depressive like behavior in chronically stressed rats (Zhang et al. 2014). Curcumin treatment is known to inhibit the release of glutamate in synaptosome and induce activation of GluN2B N-methyl-D-aspartate receptor (NMDAR) subunits resulting in antidepressant like action (Zhang et al. 2013c; Lin et al.). Curcumin administration significantly reduced anxiety like effect in ovariectomized (Morrone et al. 2016) and stressed rats (Haider et al. 2015). The general mechanism of action of curcumin treatment includes, inhibition of brain monoamine oxidase (MAO)-A/ B activity, modulation of serotonin receptor, amelioration of brain dopamine, serotonin and noradrenaline levels, increase the neurotrophic factor, enhance neuronal growth, increase neuroprotection, reduce neuroinflammation, apoptosis and oxidative stress (Lopresti 2017; Choi et al. 2017).

 
How may Curcumin work as an antioxidant?
The chemical structure of curcumin gives it a powerful antioxidant capacity, which is 2.75 times that of vitamin C and 1.6 times that of vitamin E.  Curcumin can help the body rid itself of hydroxyl radicals, singlet oxygen, superoxide radicals, nitrogen dioxide, and NO. Curcumin pretreatment was proven to reduce ischemia-induced mutations in the heart (Dikshit et al.). The efficiency of curcumin on endothelial heme oxygenase-1 (inducible stress protein) employing bovine aortic endothelial cells was discovered in an in vitro investigation that resulted in increased cellular resistance to oxidative stress. Curcumin can also help Caenorhabditis elegans live longer by lowering intracellular ROS and lipofuscin levels during aging (Liao et al., 2011). Previous research into the potential of C. longa to sustain hippocampal cells of male Wistar rats from lead-induced damage and reduces lipid peroxidation caused by toxic heavy metals. Resveratrol and curcumin alleviate and synergistically repair oxidative stress to the tissues by enhancing antioxidant response through free radical scavenging (Al-Basher et al., 2020). In one of the earlier studies, the anti-inflammatory and antioxidant capability of curcumin was detected to be synergistically enhanced with quercetin, and a synergistic protective effect was also demonstrated in diazinon-induced rats (Abdel-Diam et al., 2019). The anti-inflammatory impact of berberine and curcumin may decrease oxidative stress, liver inflammation, and lipid metabolism (Feng et al., 2018), and the berberine combination also reduced inflammatory and oxidative stress responses in the cortex and hippocampus of rats (Lin et al., 2020). Antioxidant and anti-inflammatory properties are the two primary mechanisms that explain the majority of the effects of curcumin on the various conditions. The anti-oxidative action of curcumin is mediated through inhibition of stress-induced elevated levels of 8-hydroxydeoxyguanosine and 8-nitroguanine, regulating the activity of mitochondrial respiratory complexes and upregulation of Nrf2 (nuclear factor erythroid-derived 2-related factor 2) that induces haemoxygenase-1 (HO-1) The anti-oxidant activity of curcumin is predominantly due to the hydroxyl group. Curcumin (5,10,20 and 30 µM) stimulates the expression of Nrf2 in a concentration- and time-dependent manner, which in turn increases HO-1 expression and HO-1 activity, which is a redox-sensitive inducible protein that protects from various forms of stress in cultured renal epithelial cells from rats. It stimulates ARE (antioxidant responsive elements) binding activity in NRK cells from rat kidney. Sreejayan et al. showed that curcumin at a dose of 25 µM reduced nitrite production from incubated solution of sodium nitroprusside in phosphate-buffered saline. The scavenging of nitric oxide (NO) by curcumin was concentration-dependent (50% at 20.4 and 100% at 50 µM). Curcumin was shown not to interact with nitrite detection assay or directly interact with nitrite. All forms of curcumin—demethoxy curcumin, bisdemethoxy curcumin and diacetyl curcumin—had NO scavenging property irrespective of the methoxy or the phenolic group.Curcumin has also been shown to improve systemic markers of oxidative stress. There is evidence that it can increase serum activities of antioxidants such as superoxide dismutase (SOD). A recent systematic review and meta-analysis of randomized control data related to the efficacy of supplementation with purified curcuminoids on oxidative stress parameters—indicated a significant effect of curcuminoids supplementation on all investigated parameters of oxidative stress including plasma activities of SOD and catalase, as well as serum concentrations of glutathione peroxidase (GSH) and lipid peroxides. It is noteworthy to point out that all of the studies included in the meta-analysis utilized some sort of formulation to overcome bioavailability challenges, and four out of the six used piperine. Curcumin’s effect on free radicals is carried out by several different mechanisms. It can scavenge different forms of free radicals, such as reactive oxygen and nitrogen species (ROS and RNS, respectively); it can modulate the activity of GSH, catalase, and SOD enzymes active in the neutralization of free radicals; also, it can inhibit ROS-generating enzymes such as lipoxygenase/cyclooxygenase and xanthine hydrogenase/oxidase. In addition, curcumin is a lipophilic compound, which makes it an efficient scavenger of peroxyl radicals, therefore, like vitamin E, curcumin is also considered as a chain-breaking antioxidant. Curcumin can be served as a free radical scavenger in the body and also promotes the endogenous antioxidant glutathione (GSH) synthesis to protect cells or tissues from free radical injury. In vitro cell and animal experiments also show that curcumin can enhance the activity of superoxidase dismutase (SOD) and increase GSH levels in cells and serum as well. In preclinical studies and clinical trial, when the body organs or tissues become ischemia due to the temporary interruption of blood circulation, such as stroke, myocardial infarction, surgery, or transplantation, etc.. After restoring blood flow, those ischemic reperfusion tissues often produce excessive free radicals and cause oxidative stress and injury. Administration of curcumin can scavenge free radicals; thereby, reducing the damage of free radicals to tissue cells, which also reduces damage caused by excessive inflammation of tissues. Remarkably, investigating the role of natural substances such as curcumin or derivatives with high antioxidant potential that counteract oxidative stress seems to be an effective preventive measure against free radical-linked aging. Due to its chemical structure, curcumin has proved to be an excellent scavenger of ROS and reactive nitrogen species and is able to attenuate or prevent the exercise-induced oxidative stress and inflammation, by modulation of GSH, catalase, and SOD enzymes and inhibiting of ROS-generating enzymes such as lipoxygenase / cyclooxygenase and xanthine hydrogenase/oxidase. This has strengthened our conviction that curcumin is the golden nutraceutical with proven potential in preventing/delaying the onset of age-related diseases. Curcumin displays potent biological and pharmacological effects on renal health. Aging is an independent risk factor increasing the likelihood of developing cardiovascular diseases which is due primarily to the arteries remodeling and the development of vascular endothelial dysfunction. Another promising anti-aging potential of curcumin supplementation was shown in healthy middle-aged older men and postmenopausal women. Indeed, 12 weeks curcumin administration has improved resistance artery endothelial function by increasing NO bioavailability and reducing vascular oxidative stress. This suggests the critical role of curcumin to maintain health vascular endothelium with aging, a fundamental element in the prevention of atherosclerosis and arterial diseases. Another study provides additional support about the role of curcumin associated with aging in patients at risk of cardiovascular diseases through reducing serum LDL-cholesterol and triglyceride levels. Determining the long-term benefits of curcumin in patients with cardiovascular diseases or at risk to develop cardiovascular disorders seems like a promising research avenue. The accelerated aging induced by oxidative stress results in sex-specific differences in longevity and susceptibility to age-related neurodegeneration. In a previous research, curcumin was shown to prolong lifespan of fruit fly model (Drosophila melanogaster) through enhancing SOD activity. These findings were corroborated by other data where curcumin induced sex-specific in vivo responses to oxidative stress. This includes protection from hydrogen peroxide and alterations in behavior of Drosophila melanogaster. This may rely on gene expression and support the anti-aging role of curcumin in gender-dependent manner. Curcumin belongs to the class of hormetic agents that stabilize Nrf2 and enhance expression of HO-1. Curcumin triggers Nrf2 pathway, which has a pivotal role in activating antioxidant enzymes, such as thioredoxin reductase, Hsp70, sirtuins. Furthermore, another study finding reported that curcumin increased the activity of several antioxidant enzymes including protein thiol, non-protein thiol, GPx, and SOD in dogs fed with curcumin on day 30 compared with control dogs. In addition, curcumin consumption stimulated the antioxidant capacity in the serum of dogs and consequently reducing ROS levels. Curcumin improved animal health, with particular emphasis on the stimulation of the antioxidant system and evidence of an anti-inflammatory effect. This suggested that curcumin exerts beneficial effect on both growth, health and consequently slowing down aging. Curcumin supplementation accompanied with regular physical exercise could potentially slowing down aging and/or preventing oxidative stress-induced age-related functional and structural changes and the age-related disorders. Collectively, these findings reinforce the antioxidant potential of curcumin on organ health function in the context of aging. Further investigations are warranted to unravel the exact molecular targets and signaling pathways responsible for the antioxidant effects of curcumin in different human populations.
 
How may Curcumin work against retinal diseases such as uveitis, Diabetic retinopathy, and Age-related macular degeneration?

Effect of Curcumin on Uveitis | Curcumin administration attenuated the degenerative and inflammatory conditions associated with eye like uveitis.  Corticosteroids are normally used for treatment of uveitis. However, the adverse effects associated with these drugs limit their use. One study evaluated the efficacy of curcumin against chronic anterior uveitis. Curcumin was administered orally to patients with chronic anterior uveitis at a dose of 375 mg three times a day for 12 weeks.  All patients who received curcumin alone exhibited improvement, the group receiving anti-tubercular therapy along with curcumin had a response rate of 86%. Furthermore, follow-up of all patients for the next 3 years found recurrence rates of 55% for the first group and 36% for the second group.  The efficacy of curcumin on recurrences after treatment was comparable to that of corticosteroid therapy. Furthermore, lack of any adverse effects with curcumin was an advantage over corticosteroid therapy. Thus, the study demonstrated the therapeutic role of curcumin and its efficacy against recurrent anterior uveitis.
Effect of Curcumin on Diabetic Retinopathy | Retina, because of its high content of polyunsaturated fatty acids (PUFA), high oxygen and glucose uptake is, vulnerable to oxidative stress. Inflammation is another underlying factor in the pathogenesis of diabetic retinopathy . Oxidative stress leads to formation of ROS, which is hypothesized to cause the development of neuropathy, nephropathy, myocardial infarction and retinopathy. Autooxidation of glucose, shift in redox balance, decrease in the concentration of reduced glutathione (GSH–ROS scavenger), vitamin C, Beta carotene and vitamin E and impairment of antioxidant enzymes like superoxide dismutase (SOD), glutathione reductase, glutathione peroxidase and catalase are considered as the possible sources of oxidative stress in diabetes. Retina of diabetic rats shows elevated superoxide and hydrogen peroxide (H2O2) levels along with lipid peroxidation and oxidative damage to DNA because of ROS. The other pathways that lead to diabetic retinopathy are polyol pathway that depletes nicotinamide adenine dinucleotide phosphate (NADPH) essential for regeneration of GSH, advanced glycosylation end product (AGE) and its receptor RAGE that get deposited in the retinal capillary cells leading to more ROS and activation of NFKB and caspase-3-induced apoptosis and damage to cellular constituents, protein kinase C (PKC) pathway, which gets activated by increased ROS and diacylglycerol as a result of hyperglycaemia that increase vessel permeability and blood flow, stimulate neovascularization, endothelial proliferation and apoptosis by regulating the action of vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1) and transforming growth factor-β (TGF-β). ROS also activates hexosamine pathway by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which further activates AGE pathway and the damage thereafter. ROS causes dysfunction of mitochondria, which leads to superoxide production and free radical damage and mutations in mitochondrial DNA that leads to mitochondrial DNA damage in retina in diabetes. Also, ROS-induced damage to mitochondria suppresses antioxidant-mediated effective scavenging of ROS. Exposure of pericytes and endothelial cells shows an increase in caspase-3 activity, oxidative stress and transcription factors that leads to capillary cell death. Photoreceptors, Muller cells, ganglion cells and astrocytes are affected and are involved in the pathogenesis of diabetic retinopathy.
Effect of Curcumin on Age-related Macular Degeneration | Curcumin protected against H2O2-induced cell death in a concentration of 10 µM when pre-treatment time was less than 8–12 h. Curcumin reduced and maintained intracellular ROS levels in age-related macular degeneration-RPE cells at varied concentrations (0.1, 1, 10 µM) for 12 h in H2O2-exposed cells. Treatment with curcumin showed increase of anti-oxidant genes HO-1, SOD2 (superoxide dismutase 2) and GPX1 (glutathione peroxidase 1) and reduces the expression of VEGF, PDGF (platelet-derived growth factor) and IGFBP 2 (insulin-like growth factor binding protein 2) using RTPCR in RPE-age-related macular degeneration cells. Pre-treatment with curcumin inhibited JNK pathway that involves a series of inflammatory pathways leading to cell death in RPE-age-related macular degenerationcells. Thus, curcumin may potentially be an ideal drug in restoring the function in age-related macular degeneration patient-derived RPE cells. Park et al. studied the protective effects of curcumin in A2E-accumulated ARPE-19 cells that were exposed to blue light to induce cytotoxicity. A2E and iso-A2E are main pigments of lipofuscin that accumulate in RPE and cause RPE cell death in age-related macular degeneration.
 
How may Curcumin work as an Anti-inflammatory?

Chronic inflammation may be the engine that drives many of the most feared illnesses of middle and old age. This concept suggests a new and possibly much simpler way of warding off disease. Instead of different treatments for, say, heart disease, Alzheimer's and colon cancer, there might be a single, inflammation-reducing remedy that would prevent all three. Curcumin activity for inflammation after giving oral administration was comparable to that of cortisone or phenylbutazone. Curcumin reduced inflammatory swelling, this effect resulted from inhibiting biosynthesis of inflammatory prostaglandins from arachidonic acid and neutrophil function during inflammatory states. A large number of studies have proved that curcumin has a variety of biological activities, among which anti-inflammatory effect is a significant feature of it. The physiological and pathological mechanisms of inflammatory bowel disease, psoriasis, atherosclerosis, COVID-19 and other research focus diseases are not clear yet, and they are considered to be related to inflammation. The anti-inflammatory effect of curcumin can effectively improve the symptoms of these diseases. The anti-inflammatory property of curcumin is by inhibition of TNF-dependent NFkB (tumour necrosis factor-dependent transcriptional nuclear factor kappa B) and pathways that produce reactive oxygen intermediates. Curcumin downregulates COX-2 (cyclooxygenase-2) that are predominantly seen at the sites of inflammation that mediate pain and inflammatory process. Curcumin is effective against inflammation and edema. Curcumin is acceptable at large doses (12 g/day) in humans, according to phase I clinical studies and has been shown to have medicinal potential against a variety of human ailments, particularly diabetes, cancer, arthritis, cardiovascular disease, Crohn’s disease, and neurological disease.  Curcumin was evaluated for its anti-inflammatory potential in a rat model for the treatment of osteoarthritis. Results suggested that curcumin significantly reduced the expression of cytokine levels in synovial fluid targeting the TLR4/NF-κB signaling pathway. The effect of curcumin on inflammatory indices was evaluated in a randomized control study. Results of the study indicated an outstanding reduction in inflammation through reduction in TNF-α, concluding that curcumin plays a key role in inflammation suppression in hepatic patients with nonalcoholic fatty liver disorders. The findings of another study revealed that curcumin reduced the expression of IL-6, TNF-α, and the NF-κB signaling pathway and reduced the rate of cell apoptosis resulting in the healing of injured kidney cells. Apart from individual therapy, curcumin in combination therapy has shown significant anti-inflammatory action. In this regard, hyperlipidemia-induced inflammation was targeted by the combined delivery of curcumin and rutin in Wistar rats. Results of the study showed an increase in HDL and a decrease in triglyceride level after treatment with curcumin and rutin combined therapy. It is concluded that curcumin has potential in treating inflammation and can be used as a therapeutic medicament. Curcumin inhibits pro-inflammatory enzyme 5-LOX (5-lipoxygenase) that are involved in the biosynthesis of leukotrienes and lipid mediators of inflammation. It also downregulates inflammatory cytokines like TNF, IL-1 (interleukin-1), IL-6, IL-8, iNOS (inducible nitric oxide synthase) and interferon-ϒ. Curcumin at a dose of 360 mg/dose for 3–4 months in humans reduced clinical relapse in those with quiescent inflammatory bowel disease and decreased the use of concomitant medications. This inflammation theory explains how immune-system errors are linked to more illnesses. Medical researchers are becoming increasingly convinced that the most primitive part of the immune system (inflammation), may play a crucial role in some of the most devastating afflictions of modern humans, including heart disease, cancer, diabetes and possibly Alzheimer's. Study findings suggest that in the past, gene variants rose in frequency in the human population to help protect us against viruses, bacteria and other pathogens. But now in our modern world, the environment and exposure to pathogens has changed, and the genetic variants that were originally meant to protect us, now make an autoimmune reaction more likely. These results are consistent with the hygiene hypothesis in which our cleaner environment is thought to contribute to the increasing prevalence of inflammatory diseases.  While short-term inflammation in the body is a necessary component of a functioning system, helping to fight off pathogenic invasion and repairing tissue and muscle damage, chronic inflammation is widely attributed with almost every disease known to the Western world. This includes heart disease, cancer and a whole host of neurological disorders. Curcumin reduces inflammation by lowering histamine levels and by increasing the production of natural cortisone by the adrenal glands. Extensive research over the past 30 years has shown that curcumin plays an important role in the prevention and treatment of various pro-inflammatory chronic diseases including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and malignant diseases. Oral administration of curcumin in instances of acute inflammation was found to be as effective as cortisone or phenylbutazone, and half as effective in cases of chronic inflammation. Its anti-inflammatory properties may be attributed to its ability to inhibit both biosyntheis of inflammatory prostaglandins from arachidonic acid and neutrophil function during inflammatory states. Oxidative stress has been implicated in many chronic diseases, and its pathological processes are closely related to those of inflammation, in that one can be easily induced by another. In fact, it is known that inflammatory cells liberate a number of reactive species at the site of inflammation leading to oxidative stress, which demonstrates the relationship between oxidative stress and inflammation. In addition, a number of reactive oxygen/nitrogen species can initiate an intracellular signaling cascade that enhances pro-inflammatory gene expression. Inflammation has been identified in the development of many chronic diseases and conditions. These diseases include Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, epilepsy, cerebral injury, cardiovascular disease, metabolic syndrome, cancer, allergy, asthma, bronchitis, colitis, arthritis, renal ischemia, psoriasis, diabetes, obesity, depression, fatigue, and acquired immune deficiency syndrome (AIDS). Clinical trials have also shown that curcumin can reduce inflammatory mediators. The regulatory effect of curcumin on immune cells is beneficial to its treatment of inflammatory diseases. Curcumin mainly acts on dendritic cells, T helper 17 cell, T regulatory cell. Curcumin inhibits Th17 differentiation, and regulate Treg/Th17 rebalance is by inhibit the IL‑23/Th17 pathway.29,30 Oxidative stress is closely related to inflammatory processes. Curcumin reduces ROS production due to its effect on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increasing the activity of antioxidant enzymes, and is related to Nrf2-Keap1 pathway. Curcumin reduces inflammation through its antioxidant activity. Curcumin has significant anti-inflammatory effects, and a large number of preclinical or clinical researches have studied its effect on inflammatory diseases, among them, inflammatory bowel disease, arthritis, psoriasis, depression, atherosclerosis and COVID-19 are the focus of research hotspots. Current evidences suggest that curcumin is effective in reducing levels of inflammatory mediators, and that curcumin’s anti-inflammatory properties may have a beneficial effect on these diseases. Tumor necrosis factor α (TNF-α) is a major mediator of inflammation in most diseases, and this effect is regulated by the activation of a transcription factor, nuclear factor (NF)-κB. Whereas TNF-α is said to be the most potent NF-κB activator, the expression of TNF-α is also regulated by NF-κB. In addition to TNF-α, NF-κB is also activated by most inflammatory cytokines; gram-negative bacteria; various disease-causing viruses; environmental pollutants; chemical, physical, mechanical, and psychological stress; high glucose; fatty acids; ultraviolet radiation; cigarette smoke; and other disease-causing factors. Therefore, agents that downregulate NF-κB and NF-κB–regulated gene products have potential efficacy against several of these diseases. Curcumin has been shown to block NF-κB activation increased by several different inflammatory stimuli. Curcumin has also been shown to suppress inflammation through many different mechanisms beyond the scope of this review, thereby supporting its mechanism of action as a potential anti-inflammatory agent. The high concentrations of curcumin contained in turmeric act to target multiple steps in the inflammatory pathway, blocking inflammatory markers at the molecular level and thereby significantly lowering long-term inflammation in your body. Whether we are healing from an injury or an autoimmune disease, inflammation is a common health challenge. Nutritionists, functional medicine GP’s and physiotherapists commonly use curcumin for it’s anti-inflammatory qualities. And it’s no wonder considering six major scientific trials all found curcumin to possess a potent anti-inflammatory action, which is completely non-toxic in nature. Recent findings suggest dietary interventions, including curcumin supplementation, as a strategy to combat inflammaging. Interestingly, the age-modulatory properties and healthful effects of curcumin have been illustrated in different cellular and animal models, including C. elegans, Drosophila, and mice. As it was clearly discussed above, curcumin was found to extend both healthspan and lifespan, mainly blocking the most relevant proinflammatory pathway NF-kB. In addition to the well-documented evidence supporting the numerous biological properties of curcumin in inhibiting NF-κB signaling dependent inflammation. Indeed, curcumin was shown to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and contributes to fuel the inflammaging. Interestingly, the short-term treatment of cells with low concentrations of curcumin decreased the level of secreted pro-inflammatory cytokines such as IL-8 in normal young cells. Moreover, lower doses of curcumin have increased the production of sirtuin, i.e., NAD-dependent deacetylases, and sirtuin 1 reduced inflammation by inhibiting NF-κB signaling. Curcumin inhibits and regulates tissue production and secretions of pro-inflammatory cytokine, such as interleukin-4 (IL-4) tumor necrosis factor alpha (TNF-α). Conversely, curcumin can increase anti-inflammatory cytokine production, such as IL-10 and soluble intercellular adhesion molecule 1 (sCAM-1). In preclinical studies, curcumin can reduce the degree of inflammation of animal skin and prevent or reduce the respiratory tract inflammation caused by viral or bacterial infections. In clinical trials, the curcumin treatment improves pain symptoms caused by osteoarthritis and tissue inflammation and delays the degradation of articular cartilage, which improves the mobility and quality of life in patient. Furthermore, curcumin also recovers the effect of nicotine, acetylcholine, serotonin, barium chloride, and histamine on the reduction of intestinal peristalsis. It is believed that curcumin exerts its effect in dose-dependent and cell-context manner on the protein activity involved SASP. Particularly, increasing evidence suggests that repeated stimulation of innate immune responses over time results in the development of inflammaging. In these settings, both an increased burden of senescent cells during aging and a hyper-stimulation of macrophages over time can play key roles of inflammaging process. Recent reports of randomized controlled trials conducted from 2008–2020 have demonstrated that curcumin was able not only to modulate the antioxidant status but also restore quantity, quality, and functional-metabolic status of immune cells. This lends support to other data showing partial anti-inflammatory, immunotropic and antioxidant activity of turmeric extract in vitro and in vivo. Further implication of curcumin in modulating aging-related inflammation through lowering CRP level in dose-dependent manner in rats’ model was reported. Moreover, MDA and NO levels were increased significantly in animals fed with curcumin. This has strengthened our belief that curcumin slows down the aging process by suppressing age-related inflammatory indices. A study evaluating several pharmaceutical anti-inflammatories found that aspirin and ibuprofen are the least potent, while curcumin is among the most potent anti-inflammatory and anti-proliferative agents available. Inflammation is thought to be one of the major factors in all kinds of diseases, and turmeric contains loads of curcumin, a powerful anti-inflammatory substance. It's been shown to alleviate joint pain, and can even help with heartburn and indigestion. Researchers are also looking at curcumin for its anti-aging properties. Turmeric is safe and non-toxic and has been studied for anti-inflammatory properties, inhibiting various molecules that contribute to inflammation such as lipooxygenase, COX-2, leukotrienes, prostaglandins, nitric oxide, interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12).  One study compared the effectiveness of Curcumin – the active ingredient in turmeric – and a popular non-steroidal anti-inflammatory drug (NSAID) called phenylbutazone. At the end of the six days, those taking the Curcumin and the NSAID enjoyed a significantly better anti-inflammatory response than placebo. Curcumin in inflamed organs (liver, lung, brain and kidneys) reduces the expression levels of NLRP3, IL‐1β, IL‐18 and caspase‐1 and inhibits the inflammasome. Curcumin activated Nrf2 and inhibited NF‐kB. In the liver, curcumin directly targets 3'UTR‐rTXNIP with the help of miR200a and inhibits NLRP3 inflammasome. Curcumin reduces the severity of neurotoxicity by inhibiting the formation of TXNIP/NLRP3 complex associated with ER stress through the regulation of AMPK. Curcumin in LPS‐stimulated mouse macrophages inhibits the activity of NLRP3 inflammasome by inhibiting potassium excretion, mitochondrial instability, ASC oligomerization and speckle formation. In addition to the above, ROS, autophagy, Sirtuin‐2 and acetylated alpha‐tubulin are the targets used by curcumin in inhibiting the inflammasome. In the lungs, curcumin effectively prevented the increasing Notch1. In addition to inflammasome components, curcumin effectively inhibits TLR4 and MyD88 expression and IBB phosphorylation. Curcumin has a regulatory effect on several molecules in the intracellular signal transduction pathways involved in inflammation.

According to Sandur et al. (2007), curcumin, demethoxycurcumin, and bisdemethoxycurcumin are the active compounds in C. longa that inhibit TNF-induced NF-κB activation. Researchers discovered that curcumin has anti-inflammatory properties by inhibiting the pro-inflammatory transcription factor (NF-κB). Curcumin also inhibits the binding of activator protein 1 (AP-1) binding factors, but the Sp1 binding factor remained unaffected. Curcumin inhibits the activation of NF-κB by phorbol ester and hydrogen peroxide, in addition to TNF-α. Furthermore, curcumin suppresses the NF-κB activation pathway after the convergence of multiple stimuli but before human I kappa B alpha phosphorylation.  Curcumin is equally efficacious as cortisone or phenylbutazone when given orally in acute inflammation. Curcumin’s therapeutic effect in sepsis appears to be achieved by activation of peroxisome proliferator-activated receptor gamma (PPAR-γ), which leads to inhibition of pro-inflammatory cytokine along with expression and release of TNF-α (Jacob et al., 2008).  Majority of the benefits seemed to be due to the anti-inflammatory and antioxidant properties of curcumin, while the quercetin in the molecule was negligible. Interestingly, anti-inflammatory effects of curcumin have been shown to encompass the inhibition of MCP-1. Other anti-inflammatory effects involved the downregulation of inflammatory mediators such as COX-2 activity, lipoxygenase, iNOS, MAPK, JAK and inhibition of TNF-α production, IL-1, -2, -6, -8, and -12, macrophage migration inhibitory factor (MIF). A recent study has shown that curcumin not only stimulated the antioxidant system and reduced oxidative reactions in dogs but also reduced leukocyte counts, which suggests mild anti-inflammatory effects achieved in dogs fed with at a dose of 30 mg of curcumin/dog/day, These substantiate previous findings, where it was observed that nursing lambs fed with curcumin had lower total leukocytes, neutrophils, and lymphocytes. A similar effect was reported in rats treated with 50 and 400 mg/kg curcumin, indicating a remarkable improving effect on health and the immune response. This points toward the importance of curcumin in reversing the inflammatory responses and enhancing the immune system performance, both playing a critical role in ameliorating health and consequently slowing down aging (see Figure 2).Curcumin has also been shown to inhibit mediators of the inflammatory response, including cytokines, chemokines, adhesion molecules, growth factors, and enzymes like cyclooxygenase (COX), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). Nuclear factor-kappa B (NF-κB) is a transcription factor that binds DNA and induces the transcription of the COX-2 gene, other pro-inflammatory genes, and genes involved in cell proliferation, adhesion, survival, and differentiation. The anti-inflammatory effects of curcumin result from its ability to inhibit the NF-κB pathway, as well as other pro-inflammatory pathways like the mitogen-activated protein kinase (MAPK)- and the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT)-dependent signaling pathways. Inhibition of dextran sulfate sodium (DSS)-induced colitis by curcumin in mice has been associated with a downregulation of the expression of p38-MAPK and pro-inflammatory cytokine TNF-α and a reduction of myeloperoxidase (MPO) activity, a marker of neutrophil infiltration in intestinal mucosa. Curcumin has also been shown to improve colitis by preventing STAT3 activation and STAT3-dependent induction of cell proliferation in mouse colon. Moreover, curcumin was shown to attenuate the immune response triggered by collagen injections in a mouse model of rheumatoid arthritis, partly by blocking the proliferation of T lymphocytes in mouse splenocytes. In addition, curcumin has been found to reduce the secretion of TNF-α and IL-1β and the production of COX-2-induced prostaglandin G2. In one study, curcumin inhibited the secretion of matrix metalloproteins (MMPs) — responsible for the degradation of the synovial joints — in human fibroblast-like synoviocytes and in human articular chondrocytes. Curcumin has also been found to alleviate neuro-inflammation in a mouse model of traumatic brain injury, reducing macrophage and microglial activation and increasing neuronal survival. A placebo-controlled trial in 40 men who had surgery to repair an inguinal hernia or hydrocele found that oral curcumin supplementation (1.2 g/day) for five days was more effective than placebo in reducing post-surgical edema, tenderness and pain, and was comparable to phenylbutazone therapy (300 mg/day). Scientists now believe that chronic, low-level inflammation plays a major role in almost every chronic, Western disease. This includes heart disease, cancer, metabolic syndrome, Alzheimer's and various degenerative conditions. Therefore, anything that can help fight chronic inflammation is of potential importance in preventing and even treating these diseases. Curcumin is strongly anti-inflammatory. In fact, it’s so powerful that it matches the effectiveness of some anti-inflammatory drugs, without the side effects. It blocks NF-kB, a molecule that travels into the nuclei of your cells and turns on genes related to inflammation. NF-kB is believed to play a major role in many chronic diseases. The key takeaway is that curcumin is a bioactive substance that fights inflammation at the molecular level.  A 1999 study published in the journal Phytotherapy Research found that the primary polyphenol in turmeric, the saffron colored pigment known as curcumin, compared favorably to steroids in the management of chronic anterior uveitis, an inflammatory eye disease. A 2008 study published in Critical Care Medicine found that curcumin compared favorably to the corticosteroid drug dexamethasone in the animal model as an alternative therapy for protecting lung transplantation-associated injury by down-regulating inflammatory genes. An earlier 2003 study published in Cancer Letters found the same drug also compared favorably to dexamethasone in a lung ischaemia-repurfusion injury model. A 2004 study published in the journal Oncogene found that curcumin (as well as resveratrol) were effective alternatives to the drugs aspirin, ibuprofen, sulindac, phenylbutazone, naproxen, indomethacin, diclofenac, dexamethasone, celecoxib, and tamoxifen in exerting anti-inflammatory and anti-proliferative activity against tumor cells. Curcumin down‐regulates the expression of inflammatory enzymes, such as COX2 and iNOS, inhibits the expression of the 5‐LOX pro‐inflammatory enzyme and chemokines and reduces the expression of CRP and inflammatory cytokines of TNF‐α, IL‐6 and IL‐8. Oral curcumin supplementation may potentially play a role in inhibiting the COVID‐19 inflammation along with other drug regimens by affecting these pathways and molecules and due to applying anti‐inflammatory, antioxidant and anti‐apoptotic properties without specific side effects. The spice worked as well as the drug, but without the negative side effects. Because of the crucial role of inflammation in most chronic diseases, the potential of Curcumin has been examined in neoplastic, neurological, cardiovascular, pulmonary and metabolic diseases. The pharmacodynamics and pharmacokinetics of Curcumin have been examined in animals and in humans.  Clinically, chronic curcumin administration (375 mg, t.i.d., p.o., for 6–22 months) reduced the symptoms associated with idiopathic inflammatory orbital pseudo-tumors in patients (Lal et al. 2000). In a study of curcumin’s anti-inflammatory properties, Satoskar et al.  evaluated the effects of this polyphenol on spermatic cord edema and tenderness in 46 men (15–68 years old) who had just undergone surgical repair of an inguinal hernia and/or hydrocele. After surgery, patients were randomly assigned to receive curcumin (400 mg), placebo (250 mg lactose powder), or phenylbutazone (100 mg) three times a day for 6 days. Curcumin proved to be superior by reducing all four measures of inflammation. Curcumin binds to Toll-like receptors (TLRs) and regulates downstream nuclear factor kappa-B (NF-κB), Mitogen-activated protein kinases (MAPK), Activator Protein 1(AP-1) and other signaling pathways. Curcumin can down-regulate NF-κB through acting on Peroxisome proliferator-activated receptor gamma (PPARγ). Curcumin can also play anti-inflammatory effects by regulating The Janus kinase/Signal transducer and activator of transcription (JAK/STAT) inflammatory signaling pathway. Curcumin could directly restrain the assembly of NLRP3 inflammasome, or inhibits the activation of NLRP3 inflammasome by inhibition of NF-κB pathway, which may be one of the mechanisms of curcumin for the treatment of inflammatory diseases. In the studies of inflammatory cells and animals, curcumin decreased levels of pro-inflammatory mediators such as Interleukin-1, Tumor necrosis factor-α (TNF-α), Inducible nitric oxide synthase (iNOS), NO, Regulated upon activation normal T cell expressed and secreted factor(RANTES), Granulocyte colony-stimulating factor (G‐CSF), and Monocyte chemotactic protein‐1 (MCP-1).
 
How may Curcumin work against CARDIOVASCULAR HEART Disease like coronary atherosclerosis, hypertension, stroke, elevated ldl cholesterol and triglyceride levels?
Effect of Curcumin on Cholesterol and Triglyceride Levels | Curcumin's protective effects on the cardiovascular system include lowering cholesterol and triglyceride levels, decreasing susceptibility of low density lipoprotein (LDL) to lipid peroxidation, and inhibiting platelet aggregation. In clinical researches, curcumin is demonstrated to have the antihypertensive effects while lowering blood pressure it can also increase myocardial trophic blood flow. Curcumin increases VLDL cholesterol trans-protein plasma, causing increased levels and mobilization of α-tocopherol from adipose tissue that protects against oxidative stress that occurs during atherosclerosis. It was suggested that oral intake of 500 mg/day curcumin for a week leads to a significant reduction in serum lipid peroxide (33%) and total serum cholesterol (12%) levels while increasing HDL cholesterol (29%). One study evaluated the effects of curcumin in reducing the serum levels of cholesterol and lipid peroxides in ten healthy human volunteers. Curcumin (at 0.5 g/day) administered to the volunteers for 7 days reduced serum lipid peroxides by 33% and total serum cholesterol levels by 11.63%, and increased HDL cholesterol by 29%. Because of these properties, curcumin was suggested to act as a chemopreventive agent against atherosclerosis. Curcumin can reduce the viscosity of blood and thrombosis formation via hindering the synthesis of thromboxane A2 (TXA2) and regulating calcium signals to prevent platelet activation and aggregation. Curcumin may affect bleeding during menstruation and in repair of the endometrium, because it can inhibit platelet aggregation. Therefore, it is not proper to use during menstruation as it may cause excessive menstrual blood volume and prolonged menstruation. In addition, curcumin can inhibit the activation of NF-κB, AKT, and ERK to protect and activate vascular endothelial cell from incapacitation, which reduces arterial sclerosis, thrombosis, and abnormal blood pressure. Clinical studies have shown that curcumin reduces the recurrence rate in patients with coronary artery obstruction disease and who have had installed vascular stents within coronary artery.  Turmeric extract demonstrated decreased susceptibility of LDL to lipid peroxidation in addition to lower plasma cholesterol and triglyceride levels. Higher doses decreased lipid peroxidation of cholesterol and triglyceride levels. Curcumin's effect on cholesterol levels may be due to decreased cholesterol uptake in the intestines and increase conversion of cholesterol to bile acids in the liver. Curcumin may help reverse many steps in the heart disease process. Perhaps the main benefit of curcumin when it comes to heart disease is improving the function of the endothelium, which is the lining of your blood vessels. It’s well known that endothelial dysfunction is a major driver of heart disease and involves an inability of your endothelium to regulate blood pressure, blood clotting and various other factors. Several studies suggest that curcumin leads to improvements in endothelial function. One study found that it’s as effective as exercise while another shows that it works as well as the drug Atorvastatin. In addition, curcumin reduces inflammation and oxidation (as discussed above), which play a role in heart disease as well. One study randomly assigned 121 people, who were undergoing coronary artery bypass surgery, either a placebo or 4 grams of curcumin per day, a few days before and after the surgery. The curcumin group had a 65% decreased risk of experiencing a heart attack in the hospital. A study in Nutrition Research in 2012, postmenopausal women who took curcumin for eight weeks had an improvement in arterial function, comparable to that seen in women who engaged in aerobic exercise. Another study in Phytotherapy Research in 2013 found that curcumin reduced triglycerides, while a study in 2014 found that curcumin significantly reduced LDL (“bad”) cholesterol and triglycerides in people with metabolic syndrome. Curcumin also helps the endothelium (the lining of blood vessels) to function at its optimum level, similar to the effect found during intense exercise.
Effect of Curcumin on Hypertension |  Hypertension is a condition in which the pressure on blood vessels is greater than the normal pressure. A clinical study demonstrated that turmeric (standardized to 22.1 mg of active curcumin) supplementation (3 capsules daily for three months) attenuated hematuria, proteinuria and systolic blood pressure associated with refractory or relapsing nephritis in patients without any adverse events (Khajehdehi et al. 2012). In animal study, curcumin administration downregulated the expression angiotensin I receptor in vascular smooth muscle cells. In addition, curcumin reduced angiotensin II-induced high blood pressure in C57Bl/6J mice associated with downregulated expression of angiotensin I receptor and decreased vasoconstriction in the mesenteric artery (Yao et al. 2016). Further, curcumin administration upregulated eNOS expression, decreased superoxide enzyme level and downregulated p47phox NADPH oxidase expression in vascular tissues, which is known to be responsible for 2kidney-1clip induced hypertension in rats (Boonla et al. 2014). In another study, curcumin treatment increased the expression of eNOS, decreased oxidative stress, restored glutathione redox ratio in aortic tissues along with decrease in plasma protein carbonyls, MDA and urinary nitrate/ nitrite levels in cadmium intoxicated mice resulting in anti- hypertensive effect (Kukongviriyapan et al. 2014). In conclusion, curcumin supplementation effectively reduce hypertension via blocking angiotensin I receptor, reducing circulating angiotensin-converting enzyme, inducing vasodilation and mediating nephroprotection. Stroke, sometimes called a “brain attack”, occurs when blood circulation to a part of the brain is blocked or ruptured. In animal studies, curcumin pre- and post-treatment significantly improved CAT, glutathione peroxidase (GPx) and SOD, while reduced TNF-a, IL-6, MDA and xanthine dehydrogenase levels in forebrain tissue. In addition, curcumin treatment significantly reduced apoptotic index induced by bilateral common carotid artery occlusion/reperfusion in rats (Altinay et al. 2017), increased the numbers of BrdU-positive cells, BrdU/doublecortin-positive cells, activated notch signaling pathway and stimulated neurogenesis during stroke (Liu et al. 2016). Curcumin pretreatment (200 mg/kg, i.p., for 7 days) significantly decreased MDA, NO, TNF-a, IL-1b, caspase-3, while increased SOD and GPx levels in the spinal cord of ischemia-reperfusion injury in rats. Further, curcumin administration reduced oxidative stress, inflammation and apoptosis in spinal cord as well as reversed locomotor deficit in rats (Gokce et al. 2016). Curcumin administration upregulated eukaryotic initiation factor 4 A, adenosylhomocysteinase, isocitrate dehydrogenase, ubiquitin carboxyterminal hydrolase L1, while downregulated pyridoxal phosphate phosphatase expressions in the cerebral cortex of rat (Shah et al. 2016a). Curcumin treatment (50 mg/kg, i.p., for five days) downregulated TNF-a, IL-6, Ac-p53 and Bax, while upregulated Bcl-2 and SIRT1 expression in brain. In addition, curcumin increased mitochondrial cytochrome clevels, mitochondrial complex I activity, mitochondrial membrane potential, while decreased cytosolic cytochrome clevels in brain resulting in reversal of mitochondrial dysfunction in transient middle cerebral artery occlusion/reperfusion stroke model of rat (Miao et al. 2016).
Effect of Curcumin on Atherosclerosis | Curcumin has an anti-atherosclerosis effect, possibly through its anti-inflammatory properties.  Anti-hypercholesterolemic, anti-atherosclerotic (Gao et al., 2019), and protective capabilities against cardiac ischemia and reperfusion (Wang et al., 2018) of curcumin have been proven in preclinical and clinical trials. Curcumin has anti-CVD potential by improving the lipid profile of patients, and it might be administered alone or as a dietary supplement to traditional CV medicines (Qin et al., 2017). Curcumin is also seen in many studies to protect against coronary heart disease (Li H. et al., 2020) and also possesses anticoagulant properties. Curcumin limits the risk of lipid peroxidation, which triggers inflammatory responses that may lead to cardiovascular disease (CVD) and atherosclerosis, due to its ability to scavenge reactive oxygen forms. Moreover, curcumin and statins influence the same mediators of plasma lipid changes. Experimental studies on atherosclerosis concluded that the positive effects of curcumin on atherosclerosis were associated with the dose of curcumin. Additionally, curcumin has the ability to prevent endothelial dysfunction and smooth muscle cell proliferation and migration. These properties of curcumin are responsible for skewing macrophage polarization from M1 to M2, regulating TLR4/MAPK/NF-κB pathways in macrophages (which induce M2 polarization) and secreting interleukins (IL-4 and/or IL-13). Moreover, curcumin may indirectly maintain cell homeostasis by regulating the expression and activity of lipid transporter, which is responsible for cholesterol uptake and efflux. Zhou et al. suggested that curcumin could be used as a therapeutic supplement in atherosclerosis due to its ability to modulate macrophage polarization through the inhibition of the toll-like receptor (TL4)-mediated signaling pathway. This indicates that curcumin is related to anti-inflammatory and atheroprotective effects. Zhang et al. investigated the potential suppression of atherosclerosis development by curcumin in ApoE-knockout mice by inhibiting TLR4 expression in an animal model. Mice were fed a high-fat diet supplemented with curcumin for 16 weeks and compared to a control group (without curcumin supplementation). The results indicated that, in vitro, curcumin at least partially inhibited TLR4 expression, inhibited NF-κB activation in macrophages, and, indeed, influenced the inflammatory reaction. The causal role of curcumin in inhibiting TLR4 expression was also demonstrated by Meng et al. [46], who indicated that its mechanism may be related to the blocking of NADPH-mediated intra-cellular ROS production. Comprehensively, the treatment of atherosclerosis and other cardiovascular diseases with curcumin was shown to be effective in many studies. Curcumin reduces the activation of M1 macrophages. Curcumin regulates the polarization and plasticity of macrophages by affecting TLR4/MAPK/NF-κB pathway, which is beneficial to reduce atherosclerosis. In ApoE−/− mice fed a high-fat diet supplemented with 0.1% curcumin significantly decreased TLR4 expression in atherosclerotic plaques and reduced the development of atherosclerosis. In addition, curcumin supplementation can inhibit the activation of NF-κB in aorta and the levels of IL-1β and TNF-α in aorta and serum.122 Activation of the NF-κB pathway leads to activation of NLRP3 inflammasome. Inhibition of NLRP3 inflammasome improves atherosclerotic lesions in ApoE−/− rats,123 and anti-inflammatory therapy targeting IL-1β reduces the recurrence rate of cardiovascular events. Curcumin can inhibit NF-κB-mediated NLRP3 expression, thereby inhibiting vascular smooth muscle cell migration, and alleviating hypertension, vascular inflammation and vascular remodeling in spontaneously hypertensive rats, which is beneficial to cardiovascular diseases including atherosclerosis.125 In ApoE−/− mice, atorvastatin calcium and curcumin synergistically inhibited adhesion molecules and plasma lipid levels, reducing foam cell formation and inflammatory cytokines secretion by blocking monocyte migration to the intima. Curcumin has significant efficacy in the treatment of atherosclerosis in animal models. Clinical evidence in non-atherosclerotic populations suggests that curcumin can reduce lipid levels and inflammatory responses, as it did in a mouse model. A meta-analysis of 20 randomized controlled trials with 1427 participants suggested a significant decrease in plasma concentrations of triglycerides and an elevation in plasma high-density lipoprotein cholesterol (HDL-C) levels.   In another randomized controlled trial, administration of curcumin for 6 months increased the level of adiponectin in serum, decreased pulse wave velocity and reduced the level of leptin, uric acid, triglyceride, total body fat, visceral fat and insulin resistance alongside lowered the atherogenic risks in type 2 diabetic population (Chuengsamarn et al. 2014). In animal study, curcumin administration reported to possess anti-atherosclerotic activity by downregulating the expression of lipocalin-2 in apolipoprotein E knockout mice (Wan et al. 2016). Curcumin supplementation downregulated monocyte chemotactic protein-1, P-selectin, vascular cell adhesion molecule-1, intracellular adhesion molecule-1 and MMP (1, 2 and 9) expressions, exerting anti-atherosclerotic activity. It oxidized LDL and lowered lipid levels in the serum of hypercholesterolemic rabbits (Um et al. 2014). Another mechanistic study revealed that curcumin supplementation suppresses the expression of CD36 and aP2 in macrophages of atherosclerotic mice (Hasan et al. 2014). In murine macrophage line RAW264.7, curcumin reduced ox-LDL- induced TNF-a, IL-1b, IL-6 production and apoptosis along with upregulation of ATP-binding cassette transporter (ABCA1) and CD36 expressions, thereby inducing lipid disposal and removal. Studies have shown that endothelial dysfunction is a common cause of heart disease, occurring when the endothelium is no longer able to regulate blood pressure, clotting and a number of other factors. Therefore, by improving endothelial function, curcumin lowers your risk of heart disease. In addition to helping out the endothelium, curcumin also reduces inflammation and oxidative damage, two factors that are also common contributors to heart disease. One study on 121 people—all of whom were undergoing coronary artery bypass surgery—found that the group taking 4 grams of curcumin for a few days before and after the surgery were much less likely to experience a heart attack. Other studies have revealed that the anti-inflammatory action of turmeric helps prevent artery disease. Valdez points out that recent studies suggest curcumin can protect the heart from ischemia—an inadequate blood supply to an organ or part of the body, particularly the muscles within the heart. A study published in the journal Drugs in R & D found that a standardized preparation of curcuminoids from Turmeric compared favorably to the drug atorvastatin (trade name Lipitor) on endothelial dysfunction, the underlying pathology of the blood vessels that drives atherosclerosis, in association with reductions in inflammation and oxidative stress in type 2 diabetic patients. Curcumin capsules were found to enhance the functioning of endothelium lining in the heart’s blood vessels. Any abnormality in the endothelial functioning can cause blood pressure or cause blood clotting. This dysregulation then leads to heart disease. Recent research literature on Curcumin supplement intake suggest its treatment potential on par with the drug Atorvastatin or regular moderate exercise. Moreover, the already proven benefits of Curcumin/Turmeric in terms of their anti-inflammation and anti-oxidation properties has a benign influence on the heart as well. Even coronary artery bypass surgery patients were found to have a significant decreased risk of suffering a relapse heart attack upon starting a Curcumin capsule regimen. curcumin administration (4 g/day beginning from 3 days before the surgery and continued up to 5 days after surgery) significantly attenuated myocardial infarction associated with coronary artery bypass grafting via antioxidant and anti-inflammatory effects (Wongcharoen et al. 2012). In animal study, curcumin sup- plementation (10, 20 or 30 mg/kg) significantly reduced oxidative stress, apoptosis and infract size via stimulating janus kinase 2/signal transducer and activator 3 of transcription (JAK2/STAT3) signaling pathway thus protects myocardium in ischemia reperfusion rats (Liu et al. 2017). In another study, curcumin administration (150 mg/kg) downregulated the NF-jB expression, upregulated PPAR-cand Bcl-2 expression, thereby attenuated apoptosis and inflammation in rats with myocardial infarction injury (Lv et al. 2016). Curcumin is reported to protect hypoxia-induced cardiomyocytes apoptosis via downregulation of specific protein 1 (SP1) and upregulation of miR-7a/b expression in mice (Geng et al. 2016). It is known to reduce fibrosis by activating cardiac NAD-dependent deacetylase sirtuin (SIRT)-1 expression during myocardial infarction in mice (Xiao et al. 2016). Curcumin treatment inhibited the activity of MMPs, reduced MDA level, restored extracellular matrix degradation and decreased deposition of collagen in ischemic/ reperfused myocardium of rats. In addition, curcumin supplementation downregulated phospho-Smad2/3 and TGFb1 expression while upregulated mothers against decapentaplegic homolog 7 expression in the infarcted myocardium, which might prove to be effective for the management of heart attack (Wang et al. 2012). In in vitro study, curcumin attenuated apoptosis and induce autophagy by upregulating Bcl-2 and downregulating the expression levels of beclin-1, Bax, SIRT1 and Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) in hypoxia reoxygenation-induced H9c2 myocytes (Huang et al. 2015b). These findings revealed that curcumin reverses myocardial infarction and heart attack via its antioxidant, anti-inflammatory and anti-apoptotic properties.
 
How may Curcumin work against kidney disease?
Kidney disease is a condition in which the kidneys lose the ability to balance fluids and eliminate waste. In animal model, curcumin treatment significantly reduced plasma MPO activity, thiobarbituric acid reactive substances (TBARS) level, superoxide anion generation while increased GSH levels in rat ischemia reperfusion model of acute kidney injury. In addition, curcumin reduced plasma potassium level, plasma uric acid level, microproteinuria and blood urea nitrogen along with induced NMDA receptor antagonism during acute kidney injury resulting in nephroprotective effect (Kaur et al. 2016). Curcumin administration (200 mg/ kg, p.o.) significantly reduced the level of MPO, IL-1b, IL-6, IL-10, TNF-a, MDA and caspase-3 resulting in protective effect against cisplatin induced renal dysfunction in male Wistar albino rats (Topcu-Tarladacalisir, Sapmaz-Metin, and Karaca 2016). Curcumin administration downregulated the expression of NAD(P)H oxidase subunits (p22phox, p47phox and p67phox), cytochrome P450 2E1 (CYP2E1) and nitrotyrosine renal protein. In addition, curcumin decreased inflammatory cytokine like IFNc, IL-1band TNF- a. Besides, the expression of glucose regulated protein 78, MAPKs, p-ERK1/2, p-JNK and C/EBP homologous protein (CHOP) were downregulated. In the same study, curcumin administration reduced apoptosis signaling proteins (cleaved caspase-12 and cleaved caspase-3) in low-dose streptozotocin with high-fat diet induced nonalcoholic steatohepatitis kidney disease in mice (Afrin et al. 2017). Curcumin ameliorated kidney function via reducing plasma adiponectin, plasma sclerostin, plasma cystatin C while increasing renal CAT, SOD, Nrf2, GSH in adenine induced chronic kidney Figure 4. Modulation of growth factor pathways and intracellular signaling components by curcumin in its anticancer effects. Curcumin treatment blocked the effect of Shh-Gli1, Wnt/b-catenin, ATKs and AR pathways as well as its downstream signaling components which lead to reduce cancer incidence, cancer progression, treatment resistance and disease relapse (Ali et al. 2018). Moreover, curcumin administration reduced renal mesangial matrix expansion, reduced renal hypertrophy, downregulated fibronectin and collagen IV expressions, decreased