Resveratrol

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Resveratrol

Resveratrol

Resveratrol (3,5,4’-trihydroxystilbene) is a natural plant-derived polyphenol found naturally in red grape skins, grape juice, mulberries, blueberries, blackberries, huckleberries, pomegranates, almonds, pistachios, peanuts, dark chocolate, tea and Japanese knotweed (Polygonum cuspidatum) 1, 2, 3, 4, 5, 6, 7. It seems the roots of Japanese knotweed (Polygonum cuspidatum), a plant which is widely used in Chinese medicine, has abundant resveratrol 8, 9. The root extracts of field-grown Japanese knotweed (Polygonum cuspidatum) are currently used to manufacture most of the resveratrol sold on the global market 10. In plants, resveratrol is produced as a defense mechanism, where it has a role in defense against ultraviolet (UV) related injuries, diseases, physical damage and pathogenic attacks 11, 12. Resveratrol was first isolated from the root of white hellebore lily (Veratrum grandiflorum O. Loes) in 1940 13, and detected in Vitis vinifera grapevines in 1976 14. The discovery of resveratrol in red wine in 1992 was used to explain “French Paradox”, assumed to be responsible for low rates of coronary heart disease death in some areas of France, despite the elevated intake of fat and cholesterol through the daily diet 15, 4, 16. However, a definitive correlation between resveratrol in red wine and low rates of coronary heart disease death may not be there as several other factors could have influenced the “French paradox” such as dietary habits and genetics as well 17.

Resveratrol is a member of the stilbene family with two phenol rings that are joined by an ethylene bridge 18, 19. Due to the presence of the central ethylene moiety in its structure, resveratrol has two possible stereoisomers: cis-resveratrol and trans-resveratrol 20. The naturally occurring resveratrol is usually its trans-isomer (E-configuration) and the majority of reported health benefits are attributed to the trans-resveratrol form 21. When exposed to UV and visible light, trans-resveratrol converts to cis-resveratrol (Z) by photo-isomerization 22. Cis-resveratrol is not well studied despite the findings from in vivo intestinal epithelial model studies that trans-resveratrol converts to cis-resveratrol in vivo 23 and that cis-resveratrol is also a biologically active form 24. The glucose-bound form of resveratrol, piceid also called Polydatin, is the major resveratrol derivative in food sources and it is converted to trans-resveratrol by hydrolysis 21. As a result of its hydroxyl groups and double C-C bond, resveratrol is sensitive to light, oxygen, alkaline pH and increased temperature 25.

Resveratrol has been shown to possess a variety of health-promoting effects, including anti-inflammatory, immunomodulating activity, liver-protective, neuroprotective, and antioxidant activities 26, 27, 28, 29, 30, 31. In addition, resveratrol is known to protect liver cells from oxidative stress by increasing the activity of an antioxidant enzyme and altering the gene expressions 3. Resveratrol is also reported to affect various antioxidant enzymes, affecting their expression and activity 32, 33, 34 and improve urinary protein excretion, kidney oxidative stress, and kidney dysfunction 35. In the recent years, resveratrol received renewed interest as several findings implicated resveratrol could increase cell survival and slow aging in yeast and later in mice by activating a “longevity” gene known as SIRT1 capable of mimicking the effects of calorie restriction, and regulating longevity in lower organisms 36, 37, 38. But the dose of resveratrol administered in experiments is always much higher than you’d normally consume in a daily diet. You would need to drink a hundred to a thousand glasses of red wine to equal the doses that improve health in mice 39. Resveratrol has been revealed to sensitize numerous resistant cancer cells to anticancer drugs through overcoming chemoresistance mechanisms 40 and promoting the efficacy of anticancer drugs at a low dosage 41. It has been reported that resveratrol has cytotoxic effects against numerous tumor cells, such as lymphoid, myeloid, breast, cervix, skin, ovary, prostate, stomach, colon, liver, and thyroid carcinoma cells 42, 43, 44.

Given the worldwide increase in age-related metabolic diseases and obesity, resveratrol supplement has been promoted as a treatment for many conditions — including aging. The first real interest in this compound came when in 1992 resveratrol was postulated to explain some of the cardio-protective effects of red wine 45. Five years later, in 1997, Jang and colleagues reported resveratrol to work as a chemo-preventive agent, by the ability to inhibit carcinogenesis at multiple stages in lab mice 46. Meanwhile, anti-inflammatory and anti-oxidant properties were identified for resveratrol 47, 48.

Resveratrol supplements have not been well studied in people. Scientists don’t really know what benefits and risks resveratrol might have as clinical studies on resveratrol toxicity and adverse effects are relatively scarce 49, 50. Also, when taking resveratrol with anticoagulant and antiplatelet drugs, it could enhance both bruising and bleeding risk due to resveratrol ability to hinder human platelet aggregation in vitro 49. On the other hand, it is speculated that higher resveratrol doses could compete with other polyphenols for transporters, reducing both their uptake and potential synergistic effects 51.

Nonetheless, resveratrol has become a popular supplement. People use it for many different conditions. Some take resveratrol supplements to try to prevent or treat serious diseases, like cancer or heart disease. Others hope that they will slow the aging process. For now, these uses are unsupported by evidence.

Figure 1. Resveratrol chemical structure

Resveratrol chemical structure
[Source 27 ]

Figure 2. Resveratrol chemical structure

Resveratrol chemical structure

Footnote: The chemical structure of two geometric isomers of resveratrol: cis-resveratrol (Z) and trans-resveratrol (E). Trans-resveratrol can undergo to cis-resveratrol when exposed to UV irradiation. Trans-resveratrol is dominant in terms of its prevalence and different biological activities are attributed, namely in inducing cellular responses such as cell cycle arrest, differentiation, apoptosis, and to enhance cancer cells anti-proliferation 52.

[Source 17 ]

Figure 3. Factors influencing the synthesis of resveratrol

Factors influencing the synthesis of resveratrol

Footnote: Plants produce resveratrol as a stress response with the aid of enzymes.

[Source 53 ]

Resveratrol food sources

Resveratrol is found in a wide variety of plants, such as peanuts, blueberries, cranberries, legumes, rhubarb, grapes, eucalyptus, and various grasses. Although resveratrol is naturally occurring, it can only be isolated in a few milligram quantities per kilogram of the plant material, for example, grape skin. Therefore, resveratrol has been chemically synthesized in its purest form for biological use. Food processing byproducts are considered readily available economical sources of resveratrol, such as grape pomace, cane and leaves, peanut roots, soybean seed coat and hop pellets 54, 55, 56, 57. For example, grape cane contains about 5 mg/g dry weight 58. Non-dietary alternative resveratrol sources are black spruce bark, Japanese knotweed roots and tree peony seed coats 59, 8, 60.

Table 1. Food sources of Resveratrol

Food sourceResveratrol amount
Red grape wine0.27 mg/100 mL
Rose grape wine0.12 mg/100 mL
White grape wine0.04 mg/100 mL
Muscadine grape red wine1.41–4.41 mg/100 mL
Lingonberry3 mg/100 g FW
Cranberry1.92 mg/100 g FW
Redcurrant1.57 mg/100 g FW
Bilberry0.67 mg/100 g FW
Strawberry0.35 mg/100 g FW
Black grapes0.15 mg/100 g FW
Green grapes0.02 mg/100 g FW
Dark chocolate0.04 g/100 g
Pistachio0.11 mg/100 g
Peanut0.04 mg/100 g
[Source 21 ]

Resveratrol supplement

Resveratrol supplementation may be an effective method to make this bioactive compound accessible to consumers. One resveratrol supplement capsule could provide more than 500 mg of pure trans-resveratrol. The yield of resveratrol extracted from plants or chemical synthesis is relatively low; therefore, tissue culture 61, genetic engineering 62, microbial 63, 64 and biocatalytic 65 approaches are alternatively implemented for higher production yield of resveratrol and its derivatives. The aromatic amino acids L-phenylalanine (L-Phe) and L-tyrosine (L-Tyr), both of which are produced from the shikimate pathway, are commonly used in the biosynthesis of resveratrol 66.

While chemical synthesis enables the production of significant quantities of resveratrol, this method is fraught with the generation of numerous undesirable byproducts, complicating the Resveratrol’s purification process and posing challenges to its consumption safety.

Resveratrol on Healthy Subjects

Clinical trials of resveratrol treatment, when performed in the patients having insulin resistance due to obesity, diabetes, cancer or cardiovascular disease, confirmed positive results, but a negative effect was observed in people in good health 67, 68. In these clinical trials, the majority of the people were obese, however they were otherwise healthy and not getting any medications for cardiovascular, metabolic or inflammatory disease. In healthy subjects, positive responses with resveratrol treatment, increases in triglyceride level of plasma 69, 70, response suppression of postprandial glucagon 71, improved metabolic mobility with lesser HOMA-IR index 67 and decreased level of cytokines 67, 72, 73. Resveratrol not only reduces resting metabolic rate, but also reduces the respiratory system in the overweight healthy people 69. As compared to treatment with resveratrol only 68, a significantly higher decline in the resting metabolic rate was noted when healthy participants were supplemented with resveratrol diet and another polyphenol, epigallocatechin gallate 74. It is evident from these findings that the effects of resveratrol are more prominent in diseased subjects than in healthy ones 75.

Athletes receiving exercise training along with 150 mg of resveratrol per day did not experience any increase in the normal training response triggered by high intensity training and low dose of resveratrol 76. In addition, athletes conducted exercise training with concomitant use of resveratrol and quercetin experienced substantial decline in exercise-triggered lipid peroxidation with no alteration in inflammation 77. In elderly men, resveratrol impeded the positive outcomes of a 48 days exercise training on cardiovascular status 78. With exercise training either using resveratrol supplementation or not, no change was observed in SIRT1 protein expression. Neither the activity of oxidative proteins and muscle endurance was significantly improved by the use of resveratrol, not it showed any effect on decrease in protein carbonylation level and skeletal muscle TNF mRNA content which are enhanced by doing exercise 78.

How much resveratrol should you take?

Resveratrol levels in the diet are too low to obtain beneficial health effects 79, 80. In addition, resveratrol bioavailability is affected by race, sex, age, gut microbiota 81, diet, physical exercise, genetic polymorphism 82 and differences in gene expression between individuals. Moreover, resveratrol is quickly metabolized in the digestive tract, thus new drug delivery tools are required to deliver it directly to the blood or the target site for improved therapeutics 83. In most current studies, resveratrol has been administered as a conventional powder or encapsulated grains or as a solution, solid lipid nanoparticles 84, 85 and topical dendrimers 86.

Resveratrol is an unproven treatment and there is no standard dose.

Given the lack of evidence about their safety, resveratrol supplements are not recommended for children or for women who are pregnant or breastfeeding.

Taking resveratrol supplements comes with some risks 39, because no one knows

  • the safe, effective dose for humans
  • how long-term use will affect us for better or for worse.

That makes taking a resveratrol supplement a bit of an experiment—sort of like the tests on lab mice. A big difference is that mice have researchers assessing their response to resveratrol, but we don’t. If you take a resveratrol supplement, or plan to, let your doctor know so you both can be alert for any possible harms.

If you believe that resveratrol will help you live longer and healthier, get it from food or wine, not by choking down resveratrol pills. Why ? Eating red grapes, blueberries, and pistachios, or having a glass of your favorite red wine, are pleasurable ways to take in resveratrol. Plus you get all the other healthful plant products that come with the resveratrol.

Resveratrol Health Benefits

The bioactivities and therapeutic potential of resveratrol as a pharmaceutical and nutraceutical compound have been widely investigated ever since it was reported to exhibit strong anticancer properties in 1997 87. Resveratrol has been found to have antioxidant, anti-inflammatory, and immunomodulatory properties in several test tube and animal studies 88, 89, 90, 91, 92, 93, 94, 95. Promising results from many experimental studies indicate the positive effect of resveratrol supplementation in regulating gut health 96, cardiovascular diseases 97, inflammatory bowel disorders 98, cancer 99, liver diseases 100, diabetes 101, obesity 102, respiratory disorders 103, hypersensitivity 88, Alzheimer’s disease 88 and Parkinson’s disease 88.

Insufficient evidence to rate effectiveness of resveratrol for:

  • Acne. Early evidence shows that applying a gel containing resveratrol to the face might reduce the severity of acne.
  • Lung disease (chronic obstructive pulmonary disease, COPD). Early research suggests that taking a combination product containing resveratrol, vitamin C, zinc, and flavonoids slightly reduces coughing and mucus production in people with COPD.
  • Diabetes. Some research suggests that taking 5 mg of resveratrol twice daily for 4 weeks does not affect insulin levels in people with diabetes. However, other evidence shows that taking a specific product that contains resveratrol (Biofort) daily for 3 months reduces blood sugar, blood pressure and fat levels in the blood.
  • “Hardening of the arteries” (atherosclerosis).
  • High cholesterol.
  • Preventing cancer.
  • Other conditions.

More evidence is needed to rate resveratrol for these uses.

Resveratrol antioxidant effects

Resveratrol is well known as a potent antioxidant such as radical scavenging and metal ion chelation abilities 104. Previous studies showed that hydroxyl group in 4′ position is not the sole determinant for antioxidant activity, but also the 3- and 5-OH groups 105, 106. The study of antioxidant effect against hydroxyl (•OH) and hydroperoxyl (•OOH) radicals in aqueous simulated media using density functional quantum chemistry and computational kinetics methods revealed that trans-resveratrol may act as an efficient hydroperoxyl (•OOH), and also presumably hydroxyl (•OH) radical scavenger 107. Resveratrol can also be used in minimizing or preventing lipid oxidation in pharmaceutical products, delaying toxic oxidation products formation, and maintaining both nutritional quality and prolonging pharmaceuticals shelf-life 108, 109, 110. In addition, resveratrol’s antioxidant properties have been successfully employed to protect cells against hydrogen peroxide-induced oxidative stress, where the pre-treatment with resveratrol promoted cell survival and protection against UV-irradiation-induced cell death. Resveratrol cellular defense could be achieved by its ability to act as a direct antioxidant and an indirect cellular antioxidant system inducer through modulation of several cellular antioxidant pathways, thereby balancing cellular redox status 111, 112, 113.

Resveratrol in cancer prevention

Numerous studies have demonstrated that resveratrol possesses antitumor action and is a likely candidate for treatment and prevention several types of cancer 114, 115. Jang et al. 116 found that resveratrol inhibited carcinogenesis in a mouse-skin cancer model in 1997. Resveratrol is considered as a potent anticancer agent because it has both chemopreventive and chemotherapeutic effects by targeting multiple molecular pathways 117, 118, 119, 120, 79. It has been shown in test tube studies that resveratrol has cytotoxic effects against a large range of human tumor cells, including myeloid and lymphoid cancer cells, and breast, skin, cervix, ovary, stomach, prostate, colon, liver, pancreas, and thyroid carcinoma cells 43, 121, 122, 123, 124. Although resveratrol is currently marketed in various traditional dosage forms (tablets, capsules, and powders), there is a lack of sufficient data on resveratrol effectiveness against cancer prevention and treatment 125.

Resveratrol has also been shown to stop cellular processes associated with the development of tumors through mutation 126. It has been reported that resveratrol possesses several active antioxidant capacities 127, acts as an active scavenger of hydroxylenes/superoxides 128 and significantly blocks the formation of free radicals caused by 12-O-tetradecanoylphorbol-13-acetate (TPA) in cancer cells 129. Furthermore, resveratrol also contributes to protection against lipid peroxidation in cell membranes and DNA damage caused by the release of reactive oxygen species (ROS) 130, 131. In addition, resveratrol has been found to have mutation-inhibiting and anti-carcinogenic effects, such as preventing the mutagenicity of N-methyl-N’-nitro-N-nitrosoguanidine in Salmonella typhimurium 132.

However, despite the anticancer activity of resveratrol being reported to be enhanced when used as combination therapy with other chemotherapeutic drugs in preclinical test tube and animal studies 133, 134, 135. Although it is clear that resveratrol has shown excellent anti-cancer properties, most of the studies were performed in test tube cell cultures and pre-clinical animal studies. The literature is lacking in correlating these results to enable human application because it cannot be assumed that the results of tests in animal models will hold true for humans due to differences in genetics and metabolism profile 136, 53, 137.

The pharmacokinetics, metabolism, and toxicity of resveratrol have been assessed in healthy volunteers and cancer patients 138, 139, 140. Resveratrol is metabolized swiftly, mainly into glucuronide and sulfate conjugates that are excreted via the urine. Because of the poor bioavailability of resveratrol due to its extensive metabolism, large doses (up to a maximum of 5 g/day) have been utilized by researchers. These studies have shown that resveratrol seems to be well tolerated and safe. However, side effects including diarrhea, nausea, and abdominal pain were observed in subjects taking more than 1 g of resveratrol daily 138. Subsequent clinical trials are currently investigating this dose limit 141. Resveratrol’s low aqueous solubility, chemical instability, poor absorption and poor bioavailability is a significant issue with regard to extrapolating its effects to humans, and limiting resveratrol’s usage as a chemopreventive or therapeutic agent 142, 143, 144, 145, 146, 147, 136, 53, 137.

There is only limited clinical evidence of resveratrol as an effective supplement for cancer treatment and prevention 148. The first clinical trial dealing with resveratrol and cancer was performed by Nguyen et al. 149. Nguyen et al. 149 examined the effects of freeze-dried grape powder containing resveratrol and resveratrol derived from plants in colorectal cancer patients (n = 8) on the Wnt signaling pathway, which is known to be involved in colon carcinogenesis 150, in regular colon cancer and colonic mucosa. The freeze-dried grape powder containing resveratrol administration (80 g/day containing 0.07 mg of resveratrol) for two weeks resulted in decreased Wnt target gene expression within regular mucosa, but had no effect on cancerous mucosa 149. This indicates that the freeze-dried grape powder containing resveratrol or resveratrol may play a beneficial part in the prevention of colon cancer, rather than in the treatment of established colon cancer.

In the second clinical trial involving colorectal cancer patients with liver metastasis, SRT501 (a micronized resveratrol formulation manufactured by Sirtris Pharmaceuticals, a GSK Company, Cambridge, MA, USA) supplementation at 5 g/day for 10‐21 days (n = 6) increased the amount of cleaved caspase‐3 expression within liver tissue, which suggests that there was increased apoptosis of cancerous tissue compared with subjects treated with a placebo 151. This trial suggested the administration of higher doses to achieve significant apoptosis induction 152.

Other clinical studies focused on supplementation of resveratrol (2.5 g/day for 29 days) for reducing the levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) 153. Patel et al. 154 studied the effects of the administration of resveratrol at 0.5 or 1 g/day for eight days on proliferation marker Ki-67 expression in colorectal tissue, and reported a 5% decrease in the proliferation of tumor cells.

In a muscadine grape skin extract phase 1 study with biochemically recurrent prostate cancer patients who were assigned to a high dose (4000 mg/patient) of pulverized muscadine grape (Vitis rotundifolia) skin that contains ellagic acid, quercetin, and resveratrol was found to be safe and warrants further investigation in dose-evaluating phase 2 trial 155. In another randomized placebo controlled clinical study using two doses of resveratrol (150 mg or 1000 mg resveratrol daily) for 4 months was found to significantly lowered serum levels of androstenedione, dehydroepiandrosterone and dehydroepiandrosterone-sulphate, whereas prostate size was unaffected in benign prostate hyperplasia patients 156. It has also been reported that resveratrol supplementation at 5 mg/day for six days increased the degree of protein carbonyl concentrations and cytoprotective enzyme NQO1 in colorectal mucosa tissues from patients with colorectal cancer, compared with their control subjects 157.

However, contrary to these positive findings, some evidence that resveratrol supplementation may have negative effects in certain cancer patients also exist. In a phase 2 clinical trial involving multiple myeloma patients, SRT501 (a micronized resveratrol formulation manufactured by Sirtris Pharmaceuticals, a GSK Company, Cambridge, MA, USA) supplementation at 5 g/day caused several unexpected adverse effects, including kidney toxicity, which may have led to the death of one patient 146. This high dose of SRT501 (a micronized resveratrol formulation manufactured by Sirtris Pharmaceuticals, a GSK Company, Cambridge, MA, USA) was determined to be safe in other clinical trials involving several healthy and diseased populations 151, 146. There are very low amounts of human data regarding the efficacy of resveratrol in cancer treatment. Since most of these clinical trials have had a small patient sample size and used different doses and different routes of resveratrol, the data from human clinical studies have shown inconsistent outcomes of resveratrol administration.

In addition to the effects in subjects with cancer, the effect of resveratrol in subjects with a higher cancer risk has also been demonstrated. For instance, resveratrol supplementation at 50 mg two times per day for 12 weeks reduced the DNA methylation of the tumor-suppressor gene Ras association domain-containing protein 1 (RASSF1A) in the breasts of women with higher risk of breast cancer 158. It has also been shown that resveratrol supplementation at 1 g/day for 12 weeks increases the concentrations of sex steroid hormone binding globulin (SHBG), which has been linked to a reduction in the risk of breast cancer 159, and has favorable effects on estrogen metabolism; therefore, it can lower risk factors for breast cancer in obese and overweight postmenopausal women 160. Another clinical study concentrated on resveratrol’s effects on potential biomarkers for cancer risk reduction. Circulating concentrations of insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) are linked to a higher risk of common cancers 161. Brown et al. 162 showed that resveratrol administration at 2.5 g/day for 29 days resulted in a reduction of the circulating levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) in healthy volunteers. Their research suggests that resveratrol’s ability to decrease circulating IGF-1 and IGFBP-3 in humans may constitute an anti-carcinogenic mechanism. In another study, Chow et al. 141 found that resveratrol administration at 1 g/day for four weeks modulated phase 1 isoenzymes (cytochrome P450) and phase 2 detoxification enzymes involved in carcinogen activation and detoxification. However, these beneficial effects are mostly minimal and sometimes controversial. Nevertheless, it seems that resveratrol has had some beneficial effects with regard to the prevention and treatment of cancer.

Overall, all these clinical trials had a very small patient sample size, highlighting the scarcity of human data for resveratrol focusing on the need for more research into the safety and efficacy of resveratrol to better understand and develop its therapeutic potential for cancer patients. In addition to the completed trials, some of the ongoing trials focused on determining the optimal dose of resveratrol formulation that will result in effective plasma levels in cancer patients. This is important because the optimal dose of resveratrol is yet to be established. All these trials provide us with key suggestions for future clinical studies to make the most effective treatment regimens. Based on the analysis of these clinical trials, it is essential to focus on (a) the exact mechanism of action of resveratrol, (b) establishing the optimal dose, and (c) developing novel formulations of resveratrol with other agents.

Resveratrol cardioprotective effects

Resveratrol protective effect was shown to improve cardiovascular function in diabetic rats by preserving the functional abilities of cardiac stem/progenitor cell compartments and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function 163, 164. Resveratrol showed beneficial effect in heart failure by improving left ventricle function, decreased cardiac hypertrophy, contractile dysfunction and remodeling, interstitial fibrosis, and the level of plasma B-type natriuretic peptide (BNP) 165. Some molecular mechanism of resveratrol action include inhibition of prohypertrophic signaling molecules, improvement of myocardial Ca2+ handling, phosphorylation of prosurvival (Akt-1, GSK-3β) and stress signaling (MKP-1) pathways and the reduction of oxidative stress and inflammation (iNOS, COX-2 activity, and ROS formation) 165. Yan et al. 163 suggest that resveratrol act by preventing the expressions of endothelial nitric oxide synthase, vascular endothelial growth factor, and suppressing phosphorylation of p38 in rats with diabetes-related heart attack (myocardial infarction). Resveratrol administration in heart attacked diabetic rats significantly reduced blood glucose, body weight, plasma triglyceride levels, heart rate and aspartate transaminase (AST)/alanine transaminase (ALT) ratio, at same time that markedly increased total plasma insulin levels 163, 166. In addition, resveratrol significantly reduced inflammation factors and malondialdehyde levels, which is a marker of oxidative stress 167. These results showed that resveratrol treatment can improve cardiovascular function by reducing heart muscle ischemia-reperfusion injury, vasodilation and atherosclerosis 168. At physiological concentrations, resveratrol induces widening of blood vessels (vasodilation) and consequently decreases hypertension and cardiovascular diseases risk 169. On the other hand, these results have also confirmed the uses of Japanese knotweed as a resveratrol source to treat and to prevent hyperlipidemia and arteriosclerosis in traditional chinese medicine 170, 171, 172. Overall, the cardiovascular protective effect of resveratrol have been linked to multiple molecular targets and might be useful to the development of novel therapy for atherosclerosis, metabolic syndrome, ischemia/reperfusion, and heart failure 173.

Resveratrol supplements appeared to aid those with the stiffest blood vessels in small study

The antioxidant resveratrol — found in red wine, peanuts and berries — might improve the health of blood vessels in people with type 2 diabetes, a small study suggests 174.

Some preliminary evidence also suggests that resveratrol in humans may have anti-inflammatory effects, prevent cancer, diminish arterial stiffness, and improve endothelial reactivity in older women 175, 176, 177.

The study 174, 178 found that resveratrol supplements lessened artery stiffness in some people with type 2 diabetes. Stiffening of the arteries, called arteriosclerosis, raises the risk of heart attack and stroke. As you age, your arteries stiffen, which can lead to an increased risk of heart disease. In people with type 2 diabetes and obesity, this process starts earlier and can have more severe consequences.

The body’s largest artery is the aorta, which carries blood from the heart toward the rest of the body. For the study, the researchers measured the aortic thickness of 57 patients with type 2 diabetes (age 56 and obese, on average). The investigators also conducted tests to measure blood-vessel health.

Some patients were given resveratrol supplements, while the others were given a placebo. Overall, the study found a trend toward less aortic stiffness in participants taking resveratrol supplements, but it wasn’t statistically significant.

However, in a subset of 23 patients who had an exceptionally stiff aorta at the start of the study, 100-milligram (mg) daily doses of resveratrol for two weeks reduced stiffness nearly 5 percent. That regimen was followed by 300-mg doses over two weeks, which decreased stiffness by 9 percent, the researchers said.

Aortic stiffness increased among those taking a placebo for four weeks, the researchers found.

In treatment with resveratrol among people with diabetes, there was a trend toward improvement in the stiffness. And in people with higher stiffness there was more of a benefit.

“While the research suggests there might be ways to improve blood vessel abnormalities in people with type 2 diabetes, it’s too soon to recommend resveratrol for that purpose”, said the lead researcher Dr. Naomi Hamburg. She is chief of the vascular biology section at Boston University School of Medicine. The author added that a longer study is needed to look at whether resveratrol is going to reduce heart attacks and stroke. However, Hamburg pointed out that the doses of resveratrol used in the study were much greater than exists in a glass of red wine, a major dietary source of the antioxidant.

For now, the overall recommendation is to have a diet that’s rich in fruits and vegetables.

In animal studies, resveratrol has been shown to activate a “longetivity” gene (SIRT1) that appears to delay aging and development of several diseases 179, 180.

To see if the same thing would happen in humans, the same researchers took samples from the blood-vessel linings of seven patients and looked at SIRT1 activity. They found that gene activity increased slightly after resveratrol supplementation. This doesn’t prove that reservatrol activates the longevity gene, only that there was an association.

This study shows that a natural antioxidant in these foods can reverse age-related changes in the arteries.

Impressively, the effect was seen after just a few weeks of treatment. Who knows what more prolonged antioxidant treatment could do to the arteries and other organs. Many people obtain resveratrol in their daily diet.

However, a recent phase 2 study of SRT501, a micronized oral formulation of resveratrol that activates SIRT1, in multiple myeloma patients was halted early owing to a high level of adverse effects and renal failure 181.

Another cloud: a company called Sirtris Pharmaceuticals, which was established to develop drugs from resveratrol, pulled the plug on the program in 2010 when a clinical trial showed that one of these drugs might be linked to kidney damage 182.

Resveratrol neuroprotective effects

Resveratrol has several neuroprotective roles in various neurodegenerative impairments, such as Alzheimer′s, Huntington′s and Parkinson′s diseases, amyotrophic lateral sclerosis and alcohol-induced neurodegenerative disorders 183, 184. It has been shown that resveratrol protective effects are not limited to the anti-inflammatory and antioxidant activity but also improved mitochondrial functions and biogenesis through SIRT1 (sirtuin 1)/AMPK/PGC1α pathway and vitagenes, which prevent the deleterious effects triggered by oxidative stress 184, 185, 186. Resveratrol decreases cholinergic neurotransmission, brain-derived neurotrophic factor (BDNF) expression, and oxidative stress, promotes beta-amyloid peptides clearance and anti-amyloidogenic cleavage of APP, and reduces neuronal apoptosis 187. A meta-analysis showed that resveratrol significantly decreased Profile of Mood States (POMS) including vigor and fatigue but had no significant effect on memory and cognitive performance 188. Among the isolated resveratrol oligomers, vitisin A and heyneanol A have been reported for better dose-dependent inhibitory potential compared with standard inhibitor (galantamine) on both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity 189, 190. Resveratrol is also able to improve rat motor abilities and to deactivate neuroinflammatory response following intracerebral bleed. Resveratrol may be used as a novel therapeutic agent to treat intracerebral hemorrhage 191, 192.

Resveratrol effect on type 2 diabetes

The American Diabetes Association anticipates that one third of American adults will suffer from type 2 diabetes by 2050 193, 194. Monkeys (Macaca mulatta) were kept on high sugar or fat-rich diet for two years with daily doses of 240 mg of resveratrol two times a day. It was reported that resveratrol caused significant decreases in glucose level, protection of pancreas cells and improvements in insulin actions 195, 196.

Resveratrol has a tissue-specific antihyperglycemic effect in insulin deficient states 197. In diabetic patients, resveratrol causes an improvement in insulin sensitivity and glucose-regulation, but causes no effect on control subjects, as proved by a meta-analysis of 11 randomly selected clinical trials, while another meta-analysis on type 2 diabetes patients showed unaltered outcomes 198, 199. Furthermore, 5 g daily of resveratrol given to type-2 diabetic patients for 28 days causes a significant reduction in insulin and glucose levels in empty stomach as well as fed state 200. Lower doses of resveratrol i.e., 5 mg twice a day, were given to male diabetic patients for one month and reduced level of oxidative stress markers as well as ameliorated insulin resistance were observed that could be due to activated AKT signaling 201. As compared to administering resveratrol alone, when resveratrol was given in a dose of 250 mg daily in combination with an antihyperglycemic agent for a trial period of three months, an additive effect on the glucose lowering activity of resveratrol was noted, besides glycated hemoglobin A1c (HbA1c), reduction of systolic blood pressure and total cholesterol. A similar study showed unaltered findings except HbA1c after 6 months 202, 203. Another study on concomitant administration of resveratrol and metformin showed that combined therapy may help the curative effect of diabetic disorders and the associated complications 204. Correspondingly, 1 g daily dosing of resveratrol for 45 days in diabetic patients receiving anti-diabetic treatment, not only provided typical anti-diabetic effects, but it also provided an excellent protection against type-2 diabetes 205. Despite these observations, when five type 2 diabetes patients were kept on a combination therapy of resveratrol (0.5–3 g/day) and hypoglycemic agents for 3 months no decrease in glucose metabolic markers and HbA1c level was observed 206.

Resveratrol anti-aging effects

Resveratrol is being examined in at least 110 clinical trials on: age-related macular degeneration (AMD), aging, Alzheimer’s disease and cancer including colon cancer, follicular lymphoma, liver cancer, multiple myeloma (MM) and neuroendocrine tumors; cardiovascular problems including diastolic heart failure, hypertensive heart disease, cerebral blood flow, heart failure, heart failure with preserved ejection fraction; chronic renal insufficiency, cellulite, cognitive disorders, dyslipidemia, diabetes, diabetic nephropathy, endometriosis, eye diseases, Friedreich Ataxia, Huntington disease, memory, metabolic disorders, mood disorders, polycystic ovary syndrome (PCOS), seasonal allergic rhinitis, nonalcoholic fatty liver disease, peripheral arterial disease, obesity, schizophrenia, sedentary lifestyle, sports concussion, and other disorders 207.

In summary 207, the anti-aging, anti-cancer, anti-neurological effects of resveratrol have been examined in many different diseases and environments. While there have been many beneficial effects postulated to be induced by consumption of resveratrol, the concentrations required to obtain those health benefits may be high. Although, there probably are many beneficial health effects of consumption of products rich in resveratrol. A good, well-balanced diet may prevent certain diseases from occurring 207.

In another study published online by JAMA Internal Medicine on May 12, 2014 208, researchers report that dietary resveratrol did not affect health, longevity in the population study. The study participants were men and women, 65 years or older, who participated in the Invecchiare in Chianti, “Aging in the Chianti Area” (InCHIANTI) Study, conducted in 2 small towns in Tuscany, Italy.  Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study.

Results are based on data collected from 1998 to 2009, as part of the Invecchiare in Chianti Study (“Aging in the Chianti Region”). The team of scientists from America and Italy, including NIA Scientific Director Dr. Luigi Ferrucci, found that resveratrol in the diet was not associated with a reduced incidence of cardiovascular disease, cancer, and inflammation, nor was it associated with longevity.

In the paper 208, researchers note the interest in resveratrol supplementation in the U.S. and elsewhere, and they caution against use of such supplements based on animal data thus far. The paper states there is “limited and conflicting human clinical data demonstrating any metabolic benefits of resveratrol, and there is no data concerning its safety in high doses or for long-term supplementation in older people, who often have multiple comorbidities for which they are taking multiple medications.”

The study authors suggest that more research with a larger group of participants is needed to determine whether resveratrol could have benefits in people, especially those who are overweight with health issues like diabetes.

Resveratrol anti-inflammatory activity

Stilbenoids including resveratrol are non-nitrogenous polyphenols with acidic and amphiphilic characters with anti-inflammatory activity. Many of their targets are occurring on cyclooxygenase (COX), 5-lipoxygenase (5-LOX) and protein kinase B 209, which is associated with its ability to inhibit COX-1 and COX-2 activity along with transcription factors activity inhibition, directly involved in COX activity regulation 210. Studies reported the ability of resveratrol to reduce the secretion and expression of inflammatory factors 211. The anti-inflammatory activity of resveratrol prevents acute pharyngitis-induced inflammation by inhibiting NF-κB, tumor necrosis factor-α and interleukin-6 serum levels, macrophage inflammatory protein-2 and cyclooxygenase-2 activity levels, reactive oxygen species production and caspase-3/9 in rabbit models 211. Resveratrol inhibit the ear edema of mice, white blood cell and pleurisy exudates, decrease the production of nitrogen monoxide (NO), and elevate the activity of superoxide dismutase (SOD) in serum in acetic acid-induced pleurisy test, reduce the content of malondialdehyde (MDA) and elevate the total superoxide dismutase (T-SOD) activity in serum. Resveratrol could inhibit the expressions of total protein, prostaglandin E2 (PEG2), nitrogen monoxide (NO), and malondialdehyde (MDA) in carrageenan-induced synovitis test supporting its analgesic and anti-inflammatory activities 212. Resveratrol inhibit the activation of microglia that lead to the release of various pro-inflammatory factors, the production of reactive oxygen species (ROS) and the activation of signal pathways leading to neuroinflammation 213. In test tube study resveratrol modulates the inflammatory response at moderate to high concentrations within intestinal cells by down-regulating NF-κB activation and preventing mitochondrial dysfunction. This result was confirmed in animal study where resveratrol inhibits TNF-α production and NF-κB activation, decreases neutrophil infiltration in the intestinal mucosa, and represses intestinal tumorigenesis by regulating anti-inflammatory miRNA 214, 154. Chen et al. 215 demonstrated that resveratrol significantly suppressed the TLR-4/MyD88/NF-κB signaling pathway in lysophosphatidylcholine-induced damage and inflammation that might be useful for treatment of arteriosclerosis. Taken together, these studies suggest that resveratrol can prevent inflammation and oxidative stress, reduce the risk of carcinogenesis and developed as anti-inflammatory agent to improve the quality of life of patients 52.

Resveratrol antimicrobial activities

Resveratrol has also been studied for its ability to inhibit the growth of some pathogenic microorganisms, such as Gram-positive and Gram-negative bacteria and fungi 216. Resveratrol has been shown to efficiently inhibit Candida albicans growth 217, 218. Dimethoxy resveratrol derivatives exhibited antifungal activity against Candida albicans with minimum inhibitory concentration (MIC) values of 29–37 μg/mL, including against 11 other Candida species 219. However, the putative candidacidal activity of resveratrol is a matter of controversy. A study indicates that resveratrol is not effective against both Candida albicans and non-Candida albicans species 217. In another study, resveratrol antifungal activity against Candida albicans could be reached at 400 μg/mL, thereby minimizing the antifungal role of resveratrol against Candida albicans-caused infections 218.

Campylobacter jejuni and Campylobacter coli are the major causes of bacterial gastroenteritis, while Arcobacter species are also known to be human and animal pathogens. Resveratrol-hydroxypropyl-γ-cyclodextrin inclusion complexes improved resveratrol solubility and showed anti-Campylobacter and anti-Arcobacter effects 220. Furthermore, it inhibited biofilm formation and promoted biofilm dispersion even at sub-MIC concentrations and therefore could be developed as a new anti-biofilm agent to enhance foods shelf-life and safety 220.

Resveratrol showed antibacterial activity against Gram-positive bacteria and time-kill assays showed that its effects were due to its bacteriostatic action 221. However, the mechanism underlying its antibacterial activity is not clearly understood 222. Resveratrol was also able to affect cells with changes in cell morphology and DNA contents 221. Hwang and Lim 222 demonstrated that resveratrol led to DNA fragmentation in Escherichia coli, inducing an SOS response. The SOS response is DNA damage repair system that is also pivotal for bacterial adaptation, pathogenesis, and diversification allowing a cell to survive sudden increases in DNA damage by inducing the expression of multiple factors. Resveratrol also induced cell elongation without an SOS response and thereby inhibits bacterial cell growth by suppressing FtsZ (crucial for Z-ring formation) expression and Z-ring formation in E. coli 223.

From another point of view, reactive oxygen species (ROS), superoxide, peroxide, and hydroxyl radicals are thought to contribute to the rapid bactericidal activity of diverse antimicrobial agents. E. coli and Staphylococcus aureus culture supplemented with resveratrol and treated with antimicrobials reduced ROS concentrations to sublethal levels, that are mutagenic, while the absence of resveratrol allows reactive oxygen species (ROS) to high enough to kill mutagenized cells. Antimicrobial lethality suppression and mutant recovery promotion abilities evidenced by resveratrol suggests that this antioxidant may contribute to the emergence of several antimicrobials-resistant species, especially if new derivatives and/or resveratrol formulations markedly increase its bioavailability 224.

Pseudorabies virus is one of the devastating pathogen of swine for which there is no treatment and that often result in economic losses. Resveratrol showed antiviral activity by inhibiting the Pseudorabies virus replication and effectively increase the growth performance and reduce the mortality of Pseudorabies virus-infected piglets 225.

Pterostilbene is a methoxylated derivative of resveratrol that showed antibacterial activity against drug-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) superior of pterostilbene compared to resveratrol (8~16-fold) 226. Pterostilbene anti-MRSA potency was related to bacterial membrane leakage, chaperone protein downregulation, and ribosomal protein upregulation and can be topically applied for treatment of skin MRSA infection bearing it less toxicity to mammalian cells 226. Resveratrol is a potentially useful agent on Staphylococcus aureus pneumonia and S. aureus-induced infectious diseases treatment 227. Also, resveratrol could alleviate rotavirus infection-induced diarrhea 227.

Resveratrol other biological activities

Besides the cardioprotective, antioxidant, anticancer, neuroprotective, anti-inflammatory, anti-dyslipidemia, and antidiabetic effects of resveratrol, it also exhibits antiproliferative and androgen-lowering effects on theca-interstitial cells of ovary. Resveratrol exerts a cytostatic but not cytotoxic effect in granulosa cells, while inhibiting aromatization and vascular endothelial growth factor (VEGF) expression. These actions may be of clinical relevance in conditions associated with theca-interstitial cell hyperplasia, androgen excess, and abnormal angiogenesis, such as polycystic ovary syndrome. In addition, resveratrol may increase ovarian follicular reserve and prolong ovarian life span, serving as a potential anti-aging agent 228.

Resveratrol is also able to decrease histopathological and biochemical damages and to exert protective effects on ischemia-reperfusion injury induced ovarian damages. Research has demonstrated that resveratrol is helpful in relieving pulmonary function in general population and plays a protective role in respiratory system diseases. The main protective effects of resveratrol in respiratory system diseases, including its anti-inflammatory, antiapoptotic, antioxidant, antifibrotic, antihypertensive, and anticancer activities were also examined. In resveratrol-treated patients, serum levels of certain biochemical markers (i.e., C-reactive protein, erythrocyte sedimentation rate, undercarboxylated osteocalcin, matrix metalloproteinase-3, tumor necrosis factor alpha, and interleukin-6) were also significantly decreased 229. Therefore, the use of resveratrol as an add-on to conventional antirheumatic agents seems to be an optimum approach. Resveratrol can also be used as a protective and/or therapeutic agent, particularly in male infertility cases caused by testicular toxicity. On the other hand, resveratrol could be useful to protect health against several pathologies and ageing problems [84]. However, the comparative evaluation of animal and human studies shows that resveratrol cannot protect against metabolic diseases and their relevant complications. Nonetheless, it is important to point out that the clinical findings are influenced by many factors, such as sample size and study objectives. Till now, small sample size and high dosage levels were used to conduct most of clinical trials to assess resveratrol significance in chronic diseases 183. Further evaluations are needed before declaring resveratrol as a beneficial compound for human health.

Resveratrol for weight loss

Although many studies have investigated the beneficial effects of resveratrol on experimental animals with high fat diet-induced obesity 230, 231, 232, 233, human clinical trials undertaken to evaluate the effect of resveratrol on obesity are scarce and, at times, contradictory and inconclusive 234, 235, 236. This may also be due to the different dosages of resveratrol and the various lengths of treatment used in these clinical trials. Further studies will be needed to evaluate the long-term effects and on larger sample sizes to better understand the effects of resveratrol and its mechanisms of action. Table 2 below summarizes the results of the main clinical trials on the effects of resveratrol on obesity. A 2016 systematic review 237, including studies published between 1990 and November 2015, concluded that the evidence to support the beneficial role of resveratrol in obesity is insufficient in terms of body weight and body mass index (BMI) decrease 237. More recently, a systematic review with meta-analysis 238 investigated the effects of resveratrol on weight loss, concluding that its administration significantly reduces body weight, body mass index (BMI), waist circumference, and fat mass. In contrast, a 2021 systematic review with meta-analysis found no anti-obesity effects of resveratrol 239. Currently, we do not have enough high-quality evidence to advocate widespread and population-wide supplementation with dietary resveratrol 240.

Table 2. Clinical trials on the effects of resveratrol on human obesity

Type of StudyPatientsResveratrol DoseDuration of Resveratrol AdministrationConclusionsAuthors
Randomized, placebo-controlled, double-blind cross-over11 obese otherwise healthy men150 mg once daily30 daysReduction of glucose and insulin serum levels
Reduction of HOMA index and TGL
Improved sleeping and resting metabolic rate, blood pressure, and liver function
Improved mitochondrial function
Upregulation of gene pathway related to mitochondrial oxidative phosphorylation and downregulation of pathways related to inflammation
No effect on body weight
No adverse reactions		Timmers et al. 69
Randomized, open-label uncontrolled10 overweight/obese adults with moderate insulin-resistance1.0 g once daily
1.5 g once daily
2.0 g once daily		4 weeksSignificant reduction of post-meal peak of glucose
No change of fasting glucose, insulin secretion and HOMA index,
No effects on body weight, blood pressure, fasting lipid profile, reactive C-protein, and adiponectin		Crandall et al. 241
Randomized, placebo-controlled, double-blind, cross-over19 overweight/obese adults with hypertension30 mg once daily
90 mg once daily
270 mg once daily		4 weeksIncreased FMD after administration of resveratrol 270 mg
FMD increase in dose-related manner		Wong et al. 242
Randomized, placebo-controlled, double-blind, cross-over28 obese otherwise healthy adults75 mg once daily6 weeksIncreased FMD by 23%Wong et al. 243
Investigator-initiated, randomized, place-controlled24 male volunteers with obesity but otherwise healthy500 mg three times a day4 weeksNo effect on HbA1c and HOMA index
No effect on total cholesterol, HDL, LDL, and TGL
No change in resting energy expenditure, body weight, and total fat mass
No effects on blood pressure		Poulsen et al. 235
Randomized, placebo-controlled, cross-over45 overweight/obese patients with DM2150 mg once daily4 weeksNo effect on metabolic risk parameters
No changes of plasma markers of inflammation and endothelial function
No adverse reactions		Van der Made et al. 244
Randomized, placebo-controlled, double-blind, cross-over10 obese men150 mg once daily30 daysNo effect on fasting and post-prandial incretin hormone concentrations
Suppressed postprandial glucagon secretion		Knop et al. 245
Randomized, placebo-controlled, double-blind, cross-over8 overweight/obese subjects with mild hypertriglyceridemia1000 mg once daily for a week followed by 2000 mg once daily for another week2 weeksNo changes in insulin sensitivity and TGL concentration
Reduction of apoB-48 and apoB-100		Dash et al. 246
Randomized, placebo-controlled, double-blind32 overweight/obese adultsThree groups: placebo, moderate resveratrol dose 300 mg once daily, and high resveratrol dose 1000 mg once daily90 daysImproved glucose and bilirubin vs. placebo
Decreased hemoglobin and mean corpuscular volume in moderate dose group
Increased AST and alkaline phosphatase in high-dose group		Anton et al. 247
Randomized, placebo-controlled, double-blind, cross-over11 obese otherwise healthy men150 mg once daily30 daysReduction of adipocytes size, enhanced and improved adipogenesisKonings et al. 248
Randomized, placebo-controlled28 obese men with metabolic syndrome1000 mg twice a day30 daysNo substantial changes of glucose homeostasisWalker et al. 249
Randomized, placebo-controlled112 overweight/obese and insulin-resistant patients75 mg twice a day12 weeksNo effects on cardiometabolic risk markers and on liver fat contentKantartzis et al. 250
Randomized, placebo-controlled25 obese adults with metabolic syndrome250 mg once daily + physical activity program + diet3 monthsReduction of VLDL, HDL, total cholesterol, urea, creatinine, and albuminBatista-Jorge et al. 251
Randomized, placebo-controlled, double-blind41 overweight/obese adults150 mg once daily6 monthsNo effects on insulin sensitivity
Reduction of HbA1c		de Ligt et al. 252

Abbreviations: HOMA = homeostasis model assessment; TGL = triglycerides; FMD = flow mediated dilatation of the brachial artery; HbA1c = glycosylated hemoglobin; HDL = high density lipoprotein; LDL = low density lipoprotein; DM2 = diabetes mellitus type 2; AST = aspartate aminotrasferase; VLDL: very-low density lipoprotein.

[Source 236 ]

Is resveratrol supplement safe?

In monkeys, resveratrol causes dose-dependent harmful effects on pancreas development during pregnancy and leads to pancreatic islet hypervascularization, a possible cause of tumors in Macaca mulatta babies 253, 254. Contrasting results were found in another study, i.e., resveratrol administered to pregnant patients having type 2 diabetes averts embryonic malformation in diabetic-rat. This effect could be mediated through normalization of elevated blood sugar levels and enhanced oxidative stress 255. Given the lack of evidence about resveratrol safety, resveratrol supplements are not recommended for children or for women who are pregnant or breastfeeding. Further studies are required for the evaluation of resveratrol supplementation on human health and discover the methods for treatment and prevention of its side effects. Additionally, it is important to understand the interactions of resveratrol with drugs and other supplements to diminish undesirable happenings 256. Since cytochrome P450 enzymes are modulated by resveratrol, it can detoxify and metabolize drugs and pesticides in the liver 257.

Resveratrol supplement is generally safe in adults who are not pregnant or breastfeeding and reasonably tolerated at up to 5 g/day when taken for a month 138, 258, 259, 260. The ingestion of 500mg resveratrol in tablet form, resulting in plasma concentrations of about 70ng/ml, was reported to be well-tolerated and safe 261. The upper limit of resveratrol dose for clinical trials has been suggested as low as 1 g/day because of the observed minimal adverse reactions and metabolic interactions with cytochrome P-450 complex enzymes at this dose 262. Resveratrol supplement side effects include nausea, vomiting, diarrhea, flatulence, anemia, and liver dysfunction in patients with non-alcoholic fatty liver disease (NAFLD) were recorded at doses of more than 2.5 g/day 262. The specific resveratrol doses used in various clinical trials differ dramatically from 10 mg/day to 5 g/day 146, 263, with Brasnyo et al 201 showing resveratrol improves insulin sensitivity and Magyar et al 264 showing resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol (“bad” cholesterol) level in patients with coronary artery disease. Nihei and colleagues reported that oral resveratrol treatment improves clinical parameters of nephrotic syndrome, including proteinuria and hypoalbuminemia, and normalized dyslipidemia in rats 265.

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