Canker sore (Recurrent Apthous Stomatitis, RAS) or the painful ulcers onside the mouth or at the base of the gums, and gingivitis, the common gum disease associated with gum bleeding, are among the common oral health care issues afflicting the population today, yet treatment regimens currently available leave much room for improvement. In a recent clinical trial involving 30 canker sore patients and 29 patients with gingivitis, treatment with Curcumin C3 Reduct (two 100 mg chewable tablets/day) over a three week period showed remarkable results. At the end of the study, all canker sore patients were completely cured of their painful ulcerous lesions. The efficacy of C3 Reduct in gingivitis was evaluated by several parameters including gingival index score, bleeding and inflammation. C3 Reduct treatment led to excellent abatement of pain, numbness, ulcer formation, dryness with no staining or allergic symptoms. The results are published as a peer-reviewed paper in Evidenced-Based Complementary and Alternative Medicine: "Efficacy and Safety of Tetrahydrocurcuminoids for the treatment of Canker Sore and Gingivitis".
Background. Tetrahydrocurcuminoids (THCs) are among the major metabolites of curcuminoids with a higher bioavailability and physiological stability and exhibit a broad spectrum of therapeutic activities. )e objective of this study was to evaluate the efficacy of THCs in patients suffering from canker sore and gingivitis designed as an exploratory clinical trial.
Methods. This is an open label prospective pilot clinical trial carried out at two clinical centers: Noble Hospital, Pune, Maharashtra, and Sri Venkateshwara Hospital, Bangalore, Karnataka in India.
Participants were assigned to 21 days of treatment with chewable oral THCs supplement. Patients were instructed to self-administer one chewable tablet containing 100 mg of THCs twice daily for up to 21 days. )is clinical trial was registered at a public Clinical Trial Registry in India (http://www.ctri.nic.in). )irty-one canker sore and twentynine gingivitis patients participated in this study. Body mass index, throat numbness/relief, Visual Analog Scale (VAS) pain score, canker sore lesions, gingival appearance, inflammation and bleeding were assessed before and after treatment, at 14 and 21 days. Vital signs and laboratory parameters were assessed for safety.
Results. THCs treatment significantly reduced the reddening at the site, difficulty in chewing, swallowing, and VAS pain score in the canker sore patients. Further, both single and multiple lesions were completely healed. In gingivitis patients, gingival appearance, bleeding, and inflammation were significantly reduced. No adverse effects were observed during the study.
Conclusion. Overall, the findings of this study show that supplementation of THCs for 21 days reduced the pain and prevented the progression of the disease in patients suffering from canker sore and gingivitis without adverse side effects.
Efficacy and Safety of Tetrahydrocurcuminoids for the Treatment of Canker Sore and Gingivitis, Muhammed Majeed, Shaheen Majeed, and Kalyanam Nagabhushanam, Evidence-Based Complementary and Alternative Medicine, Volume 2020, Article ID 6611877, 10 pages

Brief : Adenosine monophosphate-activated protein kinase (AMPK) is the central regulator of energy homeostasis. AMPK balances nutrient supply with energy demand and stimulates ATP-production under energy depleted conditions; Curcumin C3 Reduct® activates the AMPK and helps to reduce excess glucose and fats, by burning them for energy. Curcumin C3 Reduct® is more potent than curcumin in activating cellular energy balance. First ever EFSA approved tetrahydrocurcuminoids (from Curcuma longa) Regulation number (EU)2022/96
Abstract : Curcumin, the bioactive component of curry spice turmeric, and its related structures possess potent anti-oxidant and anti-inflammatory properties. Several lines of evidence suggest that curcumin may play a beneficial role in animal models of diabetes, both by lowering blood glucose levels and by ameliorating the long-term complications of diabetes. However, current understanding of the mechanism of curcumin action is rudimentary and is limited to its anti-oxidant and anti-inflammatory effects. In this study we examine potential anti-diabetic mechanisms of curcumin, curcumin C3 complex , and tetrahydrocurcuminoids (THC). Curcuminoids did not exert a direct effect on receptor tyrosine kinase activity, 2-deoxy glucose uptake in L6-GLUT4myc cells, or intestinal glucose metabolism measured by DPP4/a-glucosidase inhibitory activity. We demonstrate that curcuminoids effectively suppressed dexamethasone-induced phosphoenol pyruvate carboxy kinase (PEPCK) and glucose6-phosphatase (G6Pase) in H4IIE rat hepatoma and Hep3B human hepatoma cells. Furthermore, curcuminoids increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC) in H4IIE and Hep3B cells with 400 times (curcumin) to 100,000 times (THC) the potency of metformin. These results suggest that AMPK mediated suppression of hepatic gluconeogenesis may be a potential mechanism mediating glucose-lowering effects of curcuminoids.
Keywords: Curcumin Tetrahydrocurcumin PEPCK G6Pase Dexamethasone Gluconeogenesis AMPK ACC
Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells Teayoun Kim, Jessica Davis, Albert J. Zhang, Xiaoming He, Suresh T. Mathews, Elsevier Inc., T. Kim et al. / Biochemical and Biophysical Research Communications 388 (2009) 377–382

Anstracts : The healthful spice turmeric, has traditionally been used in skin care since ancient times in South Asia. Recent scientific research has validated its inherent beneficial effects, both nutritional and topical.
Technological innovation in ingredients enables imparting the goodness of curcuminoids from "curry", (turmeric) into skin, hair and nails without being hampered by the yellow color. Tetrahydrocurcuminoids (a) are patented colorless derivatives of the yellow "bioprotectant" curcuminoids (b) with multifaceted benefits in anti-aging and skin protectant compositions. This article discusses innovative applications of the natural compositions of Curcuminoids and Tetrahydrocurcuminoids, as well as a single component Tetrahydrocurcumin.
Skin ageing and antioxidants : Aging is attributed to the effects of collective damage to connective tissues, that overpowers the body's natural ability to repair them. The perceptible signs of skin aging include discoloration, wrinkles, and texture loss. These effects result from structural and metabolic changes effected by biochemical reactions in the connective tissues, that are accelerated by free radicals. Environmental agents such as UV rays exacerbate the effects of free radical reactions and oxidative stress. These reactions to time and the environment are rooted in the metabolic processes in the body, and the ability of the internal machinery to combat stress and adapt to the environment (1, 2).
About 25 percent of the lipids in the skin surface are unsaturated, and therefore more prone to attack by free radicals... (to be continued)
Currying skin health with multifunctional curcuminoids - Household and Personal Care Today nr. 4/2007, Muhammed Majeed, Lakshmi Prakash. Curcuminoids and Tetra hydro curcuminoids (colorless hydrogenated
derivative of the natural yellow curcuminoids)

The efficacy of C3 Reduct in gingivitis was evaluated by several parameters including gingival index score, bleeding and inflammation. C3 Reduct treatment led to excellent abatement of pain, numbness, ulcer formation, dryness with no staining or allergic symptoms. The results are published as a peer-reviewed paper in Evidenced-Based Complementary and Alternative Medicine: "Efficacy and Safety of Tetrahydrocurcuminoids for the treatment of Canker Sore and Gingivitis" authored by Dr. Muhammed Majeed, Shaheen Majeed, and Dr. Kalyanam Nagabhushanam (Volume 2020, Article ID 6611877).
A previously published independent clinical paper focused on the utility of C3 Reduct in oral leukoplakia which could ultimately progress to oral cancer in certain cases. C3 Reduct was applied as a 2% gel formulation in the affected areas inside the mouth. The researchers concluded that the topically applied gel was extremely effective in alleviating clinical symptoms. Remarkable histological improvement was seen in a subset of patients encouraging future long- term trials. The results, "Efficacy and Safety of Tetrahydrocurcuminoids in the Treatment of Oral Leukoplakia: A Pilot Study" by Yogesh Chhaparwal et al was published in Asian Journal of Pharmaceutical Clinical Research (Vol 11 Issue 12).
Objective: The objective of this study is to evaluate the efficacy and safety of tetrahydrocurcuminoid (THC) in the treatment of oral leukoplakia.Methods: Patients with oral mucosal lesions with clinical features of leukoplakia were selected, and an incisional biopsy of the lesion was performed to confirm the diagnosis. Demographic data, habit history, and complete medical history were documented. Subjects were given 2% THC gel (Sami Labs, Bengaluru) with advice to apply the gel to the affected areas, 5 times daily for 12 weeks. The lesion was examined, and its characteristics were documented in a standard manner at baseline, 3, 6, 9, and 12 weeks.
Results: Of the eight patients, 6 were males with age range from 40 to 70 years (mean age of 56 years). All the patients reported a reduction of burning sensation within 3 weeks of starting treatment and were completely asymptomatic by the end of the study. There was a decrease in the size of the lesion during the follow-up period. Reduction in thickness of the lesion was found in six of eight patients. Histological improvement a stage better was seen in three patients after completion of treatment. However, there was no histological improvement in four patients, and one patient progressed to mild dysplasia from hyperkeratosis without dysplasia.
Conclusion: THD when topically applied in gel form is remarkably effective in alleviating clinical symptoms. The remarkable histological improvement was seen in 3 of 8 patients.
Keywords: Curcumin, Leukoplakia, Efficacy, Oral care
Efficacy and safety of tetrahydrocurcuminoid in the treatment of oral leukoplakia: a pilot study, Yogesh Chhaparwal, Keerthilatha M Pai, M.S. Kamath, Sunitha Carnelio, Shubha Chhaparwal, Asian J Pharm Clin Res, Vol 11, Issue 12, 2018, 194-196

Abstract: The O‐type forkhead domain transcription factor (FOXO) is involved in many biological processes such as aging, the oxidative stress response, and growth regulation. FOXO activity is tightly controlled within cells. In particular, growth factor signaling pathways and the oxidative stress response can both stimulate nuclear translocation of this transcription factor. Here, we show that tetrahydrocurcumin (THC), a curcumin metabolite, regulates the oxidative stress response and aging via FOXO. In NIH3T3 cells, THC induced nuclear accumulation of FOXO4, a member of the FOXO family of transcription factors, by inhibiting phosphorylation of protein kinase B (PKB)/Akt. In Drosophila melanogaster, THC attenuated the oxidative stress response, an effect that was blocked in a foxo mutant background. THC also extended the life span of Drosophila under normal conditions, and loss of either foxo or Sir2 activity eliminated this effect. Based on these results, THC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.
Key words: tetrahydrocurcumin, Drosophila, NIH‐3T3‐FOXO4 cell line, anti‐aging, FOXO, resveratrol
Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor, Lan Xiang, AGING, November 2011, Vol 3 N 11

Abstrat : Polyphenol curcumin, a yellow pigment, derived from the rhizomes of a plant (Curcuma longa Linn) is a natural antioxidant exhibiting a variety of pharmacological activities and therapeutic properties. It has long been used as a traditional medicine and as a preservative and coloring agent in foods. Here, curcumin-converting microorganisms were isolated from human feces, the one exhibiting the highest activity being identified as Escherichia coli. We are thus unique in discovering that E. coli was able to act on curcumin. The curcumin-converting enzyme was purified from E. coli and characterized. The native enzyme had a molecular mass of about 82 kDa and consisted of two identical subunits. The enzyme has a narrow substrate spectrum, preferentially acting on curcumin. The microbial metabolism of curcumin by the purified enzyme was found to comprise a two-step reduction, curcumin being converted NADPH dependently into an intermediate product, dihydrocurcumin, and then the end product, tetrahydrocurcumin. We named this enzyme “NADPH-dependent curcumin/dihydrocurcumin reductase” (CurA). The gene (curA) encoding this enzyme was also identified. A homology search with the BLAST program revealed that a unique enzyme involved in curcumin metabolism belongs to the mediumchain dehydrogenase/reductase superfamily.
Discussion : So far, two phases of curcumin metabolism in the livers and intestines of rats and humans, and plasma of mice, have been reported. Phase I metabolism comprises the reduction of the four double bonds of the heptadiene-3, 5-dione structure: namely, curcumin→DHC→ THC → hexahydrocurcumin → octahydrocurcumin. During phase II, curcumin and its reduced metabolites are conjugated with a monoglucuronide, a monosulfate and a mixed sulfate/glucuronide: namely, conjugated curcumin → conjugated DHC → conjugated THC → conjugated hexahydrocurcumin → conjugated octahydrocurcumin.
Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism Azam Hassaninasab, PNAS April 19, 2011, vol. 108, no. 16, 6615–6620

Abstract : Protective effects of curcumin (U1), one of the major yellow pigments in turmeric and its derivative, tetrahydrocurcumin (THU1), against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage were studied in male ddY mice. Single Fe-NTA treatment (5 mg Fe/kg body intraperitoneally) transiently causes oxidative stress, as shown by the accumulation of lipid peroxidation products and 8-hydroxy-29-deoxyguanosine in the kidney. Mice were fed with a diet containing 0.5 g/100 g U1 or THU1 for 4 wk. THU1 significantly inhibited 2-thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-29-deoxyguanosine formation in the kidney; U1 inhibited only 4-hydroxy-2-nonenal-modified protein formation. To elucidate the mechanisms of protection by U1 and THU1, the pharmacokinetics and radical-scavenging capacities of U1 and THU1 were investigated by HPLC and electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide, respectively. Induction of antioxidant enzymes was also investigated. The amounts of THU1 and its conjugates (as sulfates and glucuronides) in the liver and serum were larger in the THU1 group than in the U1 group. The amounts of U1 and its conjugates were small even in the U1 group. These results suggest that THU1 is more easily absorbed from the gastrointestinal tract than U1. Furthermore, THU1 induced antioxidant enzymes, such as glutathione peroxidase, glutathione S-transferase and NADPH: quinone reductase, as well as or better than U1 and scavenged Fe-NTA-induced free radicals in vitro better than U1. These results suggest that U1 is converted to THU1 in vivo and that THU1 is a more promising chemopreventive agent.
Discussion : Tetrahydrocurcumin, one of the major colorless metabolites of curcumin (U1), in the form of glucuronide conjugate, had stronger antioxidant activity than curcumin in several in vitro systems. In conclusion, the present study provided clear evidence for the suppression of oxidative stress-induced renal damage by dietary U1 and THU1. U1 and THU1 are probably working in two different ways: direct chelating or scavenging effects and induction of the antioxidant enzymes (monofunctional inducers). The in vivo antioxidant effects of THU1 were greater than were those of U1. THU1 may be more easily absorbed than U1 from the gastrointestinal tract. THU1 also has some advantages as a food additive because it is colorless and yet is easily prepared by the standard hydrogenation of U1. Additional studies of the effects of curcuminoids on oxidative stress, especially on their molecular mechanisms, are necessary. We believe that THU1 has the potential to be used as a chemopreventive agent in humans.
KEY WORDS: curcumin tetrahydrocurcumin lipid peroxidation oxidative stress rats
Curcumin and Especially Tetrahydrocurcumin Ameliorate Oxidative Stress- Induced Renal Injury in Mice, Kunihiko Okada, Biochemical and Molecular Action of Nutrients, J. Nutr. 131: 2090–2095, 2001.

Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on tetrahydrocurcuminoids from turmeric (Curcuma longa L.) as a novel food (NF) pursuant to Regulation (EU) 2015/2283. Tetrahydrocurcuminoids are derivatives of curcuminoids, produced chemically by hydrogenation of curcuminoids extracted from the rhizomes of C. longa L. The NF consists of more than 95% of tetrahydrocurcuminoids. The applicant proposed to use the NF in food supplements at a maximum dose of 300 mg/day for adults excluding pregnant and lactating women. Taking into account the composition of the NF and the proposed conditions of use, consumption of the NF is not nutritionally disadvantageous. There are no concerns regarding genotoxicity of the NF. Based on a 90-day oral toxicity study and a reproduction/developmental toxicity screening test performed with the NF, the Panel derives a safe level of 2 mg/kg body weight per day. For the target population this level corresponds to 140 mg/day, which is lower than the use level as proposed by the applicant. The Panel concludes that the NF, tetrahydrocurcuminoids from turmeric (C. longa L.), is safe for the target population at 140 mg/day
Note : an other onternal study on the safety/toxicological profile of THC
● Acute oral toxicity LD50: >500 mg/kg body weight
● Acute dermal toxicity LD50: >2000 mg/kg body weight
● Primary skin irritation test: Did not cause any irritation
● Mucous membrane irritation test: Did not cause any irritation
● AMES test: Non-mutagenic
20 healthy human volunteers and orally administered 300 mg of THC once daily for 28 days. Laboratory parameters analyzed at the baseline and at end of the study showed no significant difference in hematological parameters such as leukocyte count, erythrocyte count, hemoglobin, hematocrit, platelets etc. There was no significant change in body mass index (BMI) and adverse effects observed during the study.
Keywords: novel foods, tetrahydrocurcuminoids, Curcuma longa L., turmeric, food supplement, safety
Safety of tetrahydrocurcuminoids from turmeric (Curcuma longa L.) as a novel food pursuant to Regulation (EU) 2015/2283 - EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA)

Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.
Curcumin / Piperine : Besides these natural compounds have been also used to increase the bioavailability of curcumin. One of them is piperine, a major component of black pepper, known as inhibitor of hepatic and intestinal glucuronidation and is also shown to increase the bioavailability of curcumin. This effect of piperine on the pharmacokinetics of curcumin has been shown to be much greater in humans than in rats. In humans, curcumin bioavailability was increased by 2,000% at 45 minutes after co-administering curcumin orally with piperine, whereas in rats, it has been found that concomitant administration of piperine 20 mg/kg with curcumin 2 g/kg increased the serum concentration of curcumin by 154% for a short period of 1-2 hours post drug. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects
Key words : Curcumin, Nano-formulation, Biological availability, Metabolism, Anticancer
Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice, Cancer Res Treat. 2014;46(1): 2-18

Background : Dietary bioactive compounds capable of improving metabolic profiles would be of great value, especially for overweight individuals undergoing a caloric restriction (CR) regimen. Curcumin (Cur), a possible anti-obesity compound, and piperine (Pip), a plausible enhancer of Cur’s bioavailability and efficacy, may be candidate agents for controlling body fat, metabolism and low grade inflammation.
Methods : 47 eight-week-old male C57BL/6 mice were fed a high fat diet (HFD) for 23 weeks to induce obesity. Then, mice were divided into 5 groups. Group 1 continued on HFD ad libitum. The other 4 groups underwent CR (reduced 10% HFD intake for 10 weeks, 20% for 20 weeks) with Cur, Pip, Cur + Pip or none of these. Percent body fat, plasma inflammatory markers associated with obesity (interferon (IFN)-γ, interleukin (IL)-10, IL-12 p70, IL-1β, IL-6 and KC/GRO), plasma Cur metabolites and liver telomere length were measured.
Results : Compared to the other groups, obese mice who underwent CR and received Cur + Pip in their diet lost more fat and had significantly lower IL-1β and KC/GRO. Tandem mass spectrometry analysis of plasma from obese mice under CR showed no difference in Cur metabolite levels between groups supplemented with Cur alone or combined with Pip. However, plasma IL-1β levels were inversely correlated with curcumin glucuronide. Minor modulation of telomere length were observed.
Conclusions : It is plausible that supplementing the high fat diet of CR mice with Cur + Pip may increase loss of body fat and suppresses HFD induced inflammation. Combination of Cur and Pip has potential to enhance CR effects for the prevention of metabolic syndrome.
Curcumin and piperine supplementation of obese mice under caloric restriction modulates body fat and interleukin - Nutrition Metabolism - Taiki Miyazawa, Kiyotaka Nakagawa, Sharon H. Kim, Michael J. Thomas, Ligi Paul, Jean-Marc Zingg, Gregory G. Dolnikowski, Susan B. Roberts, Fumiko Kimura, Teruo Miyazawa, Angelo Azzi and Mohsen Meydani - Miyazawa et al. Nutrition & Metabolism (2018) 15:12

Abstract : Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant of the ginger family, has been used for the treatment of diabetes in Ayurvedic and traditional Chinese medicine. The active component of turmeric, curcumin, has caught attention as a potential treatment for diabetes and its complications primarily because it is a relatively safe and inexpensive drug that reduces glycemia and hyperlipidemia in rodent models of diabetes. Here, we review the recent literature on the applications of curcumin for glycemia and diabetes-related liver disorders, adipocyte dysfunction, neuropathy, nephropathy, vascular diseases, pancreatic disorders, and other complications, and we also discuss its antioxidant and anti-inflammatory properties. The applications of additional curcuminoid compounds for diabetes prevention and treatment are also included in this paper. Finally, we mention the approaches that are currently being sought to generate a “super curcumin” through improvement of the bioavailability to bring this promising natural product to the forefront of diabetes therapeutics.
Conclusion : Recent research has provided the scientific basis for “traditional” curcumin and confirmed the important role of curcumin in the prevention and treatment of diabetes and its associated disorders. Curcumin could favorably affect most of the leading aspects of diabetes, including insulin resistance, hyperglycemia, hyperlipidemia, and islet apoptosis and necrosis (Figure 2). In addition, curcumin could prevent the deleterious complications of diabetes. Despite the potential tremendous benefits of this multifaceted nature product, results from clinical trials of curcumin are only available in using curcumin to treat diabetic nephropathy, microangiopathy and retinopathy so far. Studies are badly needed to be done in humans to confirm the potential of curcumin in limitation of diabetes and other associated disorders. Further, multiple approaches are also needed to overcome limited solubility and poor bioavailability of curcumin. These include synthesis of curcuminoids and development of novel formulations of curcumin, such as nanoparticles, liposomal encapsulation, emulsions, and sustained released tablets. Enhanced bioavailability and convinced clinical trial results of curcumin are likely to bring this promising natural product to the forefront of therapeutic agents for diabetes by generating a “super curcumin” in the near future.
Curcumin and Diabetes: A Systematic Review, Dong-wei Zhang, Min Fu, Si-Hua Gao, and Jun-Li Liu, Evidence-Based Complementary and Alternative Medicine Volume 2013, Article ID 636053, 16 pages

Dietary deficiency of docosahexaenoic acid (C22: 6n-3; DHA) is linked to the neuropathology of several cognitive disorders, including anxiety. DHA, which is essential for brain development and protection, is primarily obtained through the diet or synthesized from dietary precursors, however the conversion efficiency is low. Curcumin (diferuloylmethane), which is a principal component of the spice turmeric, complements the action of DHA in the brain, and this study was performed to determine molecular mechanisms involved. We report that curcumin enhances the synthesis of DHA from its precursor, α-linolenic acid (C18: 3n-3; ALA) and elevates levels of enzymes involved in the synthesis of DHA such as FADS2 and elongase 2 in both liver and brain tissue. Furthermore, in vivo treatment with curcumin and ALA reduced anxiety-like behavior in rodents. Taken together, these data suggest that curcumin enhances DHA synthesis, resulting in elevated brain DHA content. These findings have important implications for human health and the prevention of cognitive disease, particularly for populations eating a plant-based diet or who do not consume fish, a primary source of DHA, since DHA is essential for brain function and its deficiency is implicated in many types of neurological disorders.
Conclusion : The n-3 fatty acids DHA and EPA are essential for human health that are obtained through dietary animal sources or synthesized from precursors. We provide evidence that curcumin enhances the biosynthesis of hepatic DHA from n-3 precursors and enhances DHA accretion in the brain. These data provide a novel insight into a potential mechanism by which curcumin ameliorates neurocognitive disease.
Keywords : DHA synthesis; Curcumin; ALA; DPA; omega 3 fatty acids; docosahexaenoic acid
Curcumin boosts DHA in the brain: implications for the prevention of anxiety disorders, Biochim Biophys Acta. 2015 May ; 1852(5): 951–961. doi:10.1016/ j.bbadis. 2014.12.005, Aiguo Wu, Emily E. Noble, Ethika Tyagi, Zhe Ying, Yumei Zhuang

Several compounds extracted from spices and herbs exhibit antiviral effects in vitro, suggesting potential pharmacological uses. Curcumin, a component of turmeric, has been used as a food additive and herbal supplement due to its potential medicinal properties. Previously, curcumin exhibited antiviral properties against several viruses, including dengue virus and hepatitis C virus, among others. Here, we describe the antiviral effect of curcumin on Zika and chikungunya viruses, two mosquito-borne outbreak viruses. Both viruses responded to treatment of cells with up to 5 mM curumin without impacting cellular viability.We observed that direct treatment of virus with curcumin reduced infectivity of virus in a dose- and timedependent manner for these enveloped viruses, as well as vesicular stomatitis virus. In contrast, we found no change in infectivity for Coxsackievirus B3, a non-enveloped virus. Derivatives of curcumin also exhibited antiviral activity against enveloped viruses. Further examination revealed that curcumin interfered with the binding of the enveloped viruses to cells in a dose-dependent manner, though the integrity of the viral RNA was maintained. Together, these results expand the family of viruses sensitive to curcumin and provide a mechanism of action for curcumin's effect on these enveloped viruses.
The ability of curcumin to prevent viral replication strongly suggests that this molecule and its derivatives may hold promise for the development of broad-range antivirals. Curcumin in the human diet, further, could provide a simple means to prevent infection by enveloped viruses.
Keywords: Curcumin Enveloped virus Viral binding
Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding - Bryan C. Mounce, Teresa Cesaro, Lucia Carrau, Thomas Vallet, Marco Vignuzzi - Antiviral Research 142 (2017)

Abstract Background: The dietary spice Curcuma longa, also known as turmeric, has various biological effects. Both a water extract and a supercritical carbon dioxide extract of C. longa showed anti-inflammatory activities in animal studies. However, the anti-inflammatory effect in humans of a mixture of these two C. longa extracts (CLE) is poorly understood. Therefore, we investigated the effect of CLE containing anti-inflammatory turmeronols on chronic inflammation and general health.
Methods: We performed a randomized, double-blind, placebo-controlled study in healthy subjects aged 50 to 69 years with overweight. Participants took two capsules containing CLE (CLE group, n = 45) or two placebo capsules (placebo group, n = 45) daily for 12 weeks, and serum inflammatory markers were measured. Participants also completed two questionnaires: the Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF-36) and the Profile of Mood States (POMS) scale. Treatment effects were analyzed by two way analysis of variance followed by a t test (significance level, p max 0.05).
Results: After the intervention, the CLE group had a significantly lower body weight (p max 0.05) and body mass index (p max 0.05) than the placebo group and significantly lower serum levels of C-reactive protein (p max 0.05) and complement component 3 (p max 0.05). In addition, the CLE group showed significant improvement of the MOS SF-36 mental health score (p max 0.05) and POMS anger-hostility score (p max 0.05).
Conclusion: CLE may ameliorate chronic low-grade inflammation and thus help to improve mental health and mood disturbance.
Discussion : Compared with the placebo group, body weight, BMI, and serum levels of CRP and C3 were significantly lower in the CLE group. In addition, the CLE group showed a significant improvement in the SF-36 subscale score for mental health and the POMS score for anger and hostility. These results suggest that intake of a mixture of a hot water extract and supercritical carbon dioxide extract of C. longa may have the potential to improve mental health and negative mood state by reducing chronic low-grade inflammation.
Curcuma longa extract improves serum inflammatory markers and mental health in healthy participants who are overweight: a randomized, double-blind, placebo-controlled trial Ryusei Uchio , Kengo Kawasaki, Chinatsu Okuda‑Hanafusa, Ryosuke Saji, Koutarou Muroyama, Shinji Murosaki, Yoshihiro Yamamoto and Yoshitaka Hirose

ABSTRACT : Endurance running training can lead to gradual accumulation of inflammation and soreness ultimately resulting in overuse injuries. Management of soreness and inflammation with pharmaceuticals (i.e. non-prescription pain relievers) during long-term training is not a suitable solution due to known side effects (e.g. gastrointestinal complications, etc.). Dietary polyphenols (i.e. curcumin, pomegranate, etc.) have been purported to reduce inflammation and muscle sore-ness, without these negative side effects making them ideal for use in an exercise model. The purpose of the present feasibility study was to explore the combined effect of optimized curcumin and pomegranate extract supplementation prior to (PRE) and after (4H and 24H) an organized half-marathon race on blood inflammatory proteins and inflammation-associated RNA. Daily supplementation (1000 mg/d) started 26 days before a half-marathon which doubled on days 27-31. Data were analyzed with R software and Welch t-test, significance set at p max 0.05. At both 4H and 24H, supplementation was associated with alterations in protein (IL-10, IL-13, IL-4, ITAC, MIP-1alpha, MIP-3alpha, BDNF, sIL-2Ralpha, and TNF-alpha; p max 0.05) and RNA (CCL22, GUSB, IL-6, LINC00305, NKILA, PTGES, THRIL, TRAF6, ARG2, CD1A, CD55, CFI, CSF2, CXC3CL1, CX3CR1, EDNRB, GATA3, LILRB5, THY1, CD3D, MRC1, GPR183, HAMP, MBL2, CASP3, B2M, KLRF2, PDCD1LG2, IL-10, PTGS2, TLR2, IL-6R, IL-8, IL-7R, MASP1, MYD88, TNFRSF1B, TNFRSF1A, and TIRAP; p max 0.05) biomarkers com-pared to control. Pathway classification of these biomarkers indicated supplementation may be associated with a more favorable muscle recovery profile. Our findings support the notion that combined cur-cumin and pomegranate supplementation may represent a useful addition to a comprehensive exercise training plan.
Study for Curcumin + Pomegranate
Conclusion : Our findings support the notion that combined curcumin and pomegranate supplementation may represent a useful addition to a comprehensive exercise training plan. In conclusion, it is well documented that reduced post-exercise inflammation is associated with a faster return to normal function in activities of daily living or training The key findings of the present study when subjects were supplemented is consistent with previously reported reductions in post-exercise inflammation with curcumin alone Additionally, previous research with resistance training has shown an improvement in muscle damage with the consumption of pomegranate juice that is in line with the results of the current study it is reasonable to speculate that combined supplementation with optimized curcumin and pomegranate extract may be useful as part of a comprehensive plan designed to mitigate post-exercise inflammation/injury and improve subsequent recovery between sessions.
Additional research in this area of study is warranted to further characterize additional supplementation strategies (i.e. flexible dosing, short-term dosing, etc.) and methods for incorporating combined curcumin and pomegranate supplementation into individualized training plans.
Alterations in Systemic Inflammatory Response Following a Half-Marathon Race with a Combined Curcumin and Pomegranate Supplement: A Feasibility Study - Elizabeth A. Tanner , Melody A. Gary , Asheal A. Davis , Stephan Michalik & Brian K. McFarlin

Abstract : Diabetes mellitus (DM) is an ensemble of metabolic conditions that have reached pandemic proportions worldwide. Pathology’s multifactorial nature makes patient management, including lifelong drug therapy and lifestyle modification, extremely challenging. Currently, there is growing evidence about the effectiveness of using herbal supplements in preventing and controlling DM. 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. Nanocurcumin is also associated with a significant reduction in triglycerides, VLDL-c, total cholesterol, LDL-c, HDL-c, serum C reactive protein, and plasma malonaldehyde. Therefore, it can be considered in the therapeutic approach of patients with DM.
Conclusion : T2DM has a multifactorial pathology and affects thousands of people worldwide. Its treatment consists of lifestyle changes, diet, physical activity, and therapies with medications for the rest of life. Curcumin is a natural anti-inflammatory and anti-diabetic agent representing a safe and low-cost alternative for this condition’s therapeutic approach, although it is still necessary to know its effective dose. We suggest that more robust and rigorous randomized controlled clinical trials are carried out to establish the role of curcumin in the therapeutics of T2DM.
Keywords: Curcuma longa, curcumin, curcuminoids, diabetes, type 2 diabetes mellitus
The Effects of Curcumin on Diabetes Mellitus: A Systematic Review, Ledyane Taynara Marton, Laís Maria Pescinini-E-Salzedas, Maria Eduarda Côrtes Camargo, Sandra M Barbalho, Jesselina F Dos Santos Haber, Renata Vargas Sinatora, Claudia Rucco Penteado Detregiachi, Raul J S Girio, Daniela Vieira Buchaim, Patricia Cincotto Dos Santos Bueno, Front Endocrinol (Lausanne), 2021 May 3

Infection with the HCV is one of the major causes of chronic liver disease with an estimated 184 million persons worldwide positive for HCV antibodies and 4 million newly infected each year. The situation is worrying in emerging countries of Central and Southeast Asia, North Africa and Middle East with seroprevalence around 3%–5%. Central Africa and Egypt remain regions of very high endemicity with a 25% prevalence in the latter. Hepatitis C is therefore a global health problem with striking inequalities in the access to healthcare and implementation of treatments between world regions.
(...) Several aspects of this study deserve attention. Curcumin is inexpensive, efficiently blocks HCVentry into hepatocytes, exerts pan-genotypic antiviral activity and can be orally administered and preliminary data from Anggakusuma et al seem to indicate a high barrier to resistance. Recent clinical trials have pointed its high tolerance and favourable safety profile in healthy subjects.10 Curcumin is combinable with existing therapies,9 and may be judiciously combined to per os IFN-free therapies currently under trials, based upon novel pan-genotypic DAA. (...)
Comments for Curcumin
Curcumin against hepatitis C virus infection: spicing up antiviral therapies with ‘nutraceuticals’ - Eve-Isabelle Pécheur, Gut July 2014 Vol 63 No 7

The dengue virus is considered to be a globally important human pathogen prevalent in tropical and subtropical regions of the world. According to a recent estimate, the disease burden due to DENV infections is ∼390 million infections per year globally in ∼100 countries including the southern US, Puerto Rico and Hawaii, resulting in nearly ∼25,000 deaths mostly among children. Despite the significant morbidity and mortality that results from DENV infections, there is currently no effective chemotherapeutic treatment for DENV infections. We identified curcumin as an inhibitor of DENV2 NS2B/NS3protease in a previous high-throughput screening (HTS) campaign. We synthesized four analogues of curcumin (curcuminoids) and tested the in vitro protease inhibition activity and inhibition of replication by cell-based assays. The results revealed that curcumin is a weak inhibitor of the viral protease. However, the analogues exhibited more potent inhibition of DENV infectivity in plaque assays suggesting that the cellular pathway(s) required for viral replication and/or assembly are targeted by these compounds. Further analysis shows that inhibition of genes involved in lipid biosynthesis, and of actin polymerization by curcuminoids, are likely to be involved as their mode of action in DENV2-infected cells. Three of the curcumin derivatives possess good selectivity indices (SI) ( min 10) when compared to the parent curcumin.
Conclusion : We conclude that curcuminoids exhibit their anti-viral activities through a variety of ways on the host cells, but with modest effect in DENV protease. Modulation of host actin and lipids may be involved in regulating the viral binding and entry. Recent studies on DENV mouse models indicated that curcumin treatment reduced the DENV viremia effectively (Ichsyani et al., 2017) indicating that these analogues might be promising in antiviral therapy against DENV.
Inhibition of dengue virus by curcuminoids - Anuradha Balasubramanian, Rajendra Pilankatta, Tadahisa Teramoto, Ayyiliath M. Sajith, Evaristus Nwulia, Amol Kulkarni, Radhakrishnan Padmanabhan - Antiviral Research 162 (2019) 71–78

In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines.
Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models.
Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDHhigh/ CD133−). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily.
Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.
Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy Cancer Letters 364 (2015) 135–141

Objective: To assess the efficacy and safety of Curcuma longa Extract and curcumin supplements on osteoarthritis (OA).
Methods: The databases such as Pubmed and Cochrane Library were searched to collect the article about Curcuma longa Extract and curcumin in the treatment of OA. Then, randomized controlled trials (RCTs) were selected and their data was extracted. Finally, the RevMan5.3 was utilized for risk of bias assessment and meta-analysis, the STATA15.0 were utilized for publication bias assessment, and GRADE tool were used for the evidence quality assessment of primary outcomes.
Results: A total of 15 RCTs involving 1621 participants were included. (1) Compared with placebo, Curcuma longa Extract and curcumin (C.) can decrease the VAS and WOMAC score-pain, the WOMAC score-function and the WOMAC score-stiffness. In terms of adverse events, Curcuma longa Extract and curcumin are comparable to those of placebo. (2) Compared with NSAIDs, Curcuma longa Extract and curcumin have similar effects on joint pain, function and stiffness. The incidence of adverse events in Curcuma longa Extract and curcumin was lower. (3) Compared with the NSAIDs group, C.+NSAIDs can also decrease the VAS and WOMAC score-pain, the WOMAC score-function and the WOMAC score-stiffness. In terms of adverse events, the addition of Curcuma longa Extract and curcumin to NSAIDs did not increase adverse events.
So, Results showed significant effects of supplementations on the VAS and WOMAC score-pain, the WOMAC score-function and the WOMAC score-stiffness.
Conclusion: Curcuma longa Extract and curcumin may be a safer and effective supplement for OA patients. It is recommended to use Curcuma longa Extract and curcumin supplement for OA patients for more than 12 weeks.
Keywords: Curcuma longa Extract; Curcumin; Meta-analysis; Osteoarthritis; Systematic review.
The efficacy and safety of Curcuma longa Extract and curcumin supplements on osteoarthritis: a systematic review and meta-analysis, Liuting Zeng, Kailin Yang, Wensa Hao, Ganpeng Yu, Hua Chen, Biosci Rep, 2021 May 21

Oxidative stress, Nrf2-HO-1 and TLR-MAPK/NF-κB signaling pathways have been proved to be involved in influenza A virus (IAV) replication and influenzal pneumonia. In the previous studies, we have performed several high-throughput drug screenings based on the TLR pathways. In the present study, through plaque inhibition test, luciferase reporter assay, TCID50, qRT-PCR, western blotting, ELISA and siRNA assays, we investigated the effect and mechanism of action of curcumin against IAV infection in vitro and in vivo. The results showed that curcumin could directly inactivate IAV, blocked IAV adsorption and inhibited IAV proliferation. As for the underlying mechanisms, we found that curcumin could significantly inhibit IAV-induced oxidative stress, increased Nrf2, HO-1, NQO1, GSTA3 and IFN-β production, and suppressed IAV-induced activation of TLR2/4/7, Akt, p38/JNK MAPK and NF-κB pathways. Suppression of Nrf2 via siRNA significantly abolished the stimulatory effect of curcumin on HO-1, NQO1, GSTA3 and IFN-β production and meanwhile blocked the inhibitory effect of curcumin on IAV M2 production. Oxidant H2O2 and TLR2/4, p38/JNK and NF-κB agonists could significantly antagonize the anti-IAV activity of curcumin in vitro. Additionally, curcumin significantly increased the survival rate of mice, reduced lung index, inflammatory cytokines and lung IAV titer, and finally improved pulmonary histopathological changes after IAV infection. In conclusion, curcumin can directly inactivate IAV, inhibits IAV adsorption and replication; and its inhibition on IAV replication may be via activating Nrf2 signal and inhibiting IAV-induced activation of TLR2/4, p38/JNK MAPK and NF-κB pathways.
In conclusion, besides directly inactivating IAV and inhibiting IAV adsorption, curcumin can activate Nrf2 signal, stimulates the production of many antioxidases, such as CAT, SOD, GSH-Px, HO-1, NQO1 and GSTA3, suppresses IAV-mediated oxidative stress and further indirectly inhibits IAV-induced activation of TLR2/4, p38/JNK MAPK and NF-κB pathways, which may inhibit both IAV-mediated inflammation and IAV replication. Meanwhile, activation of Nrf2-HO-1 pathway can increase the production of IFN-β which may also further suppress IAV replication. Finally curcumin improves IAV-induced ALI/ARDS (Fig. 8). Additionally, curcumin has been used as a coloring agent and spice in foods for thousands of years, it possesses very low cytotoxicity, this may make curcumin to be utilized to treat IAV infection in the clinic directly.
Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways - Jianping Dai, Liming Gu, Yun Su, Qianwen Wang, Ying Zhao, Xiaoxua Chen, Huixiong Deng, Weizhong Li, Gefei Wang, Kangsheng Li - International Immunopharmacology 54 (2018) 177–187