Resveratrol:Trans-3,5,4'-trihydroxystilbene.:Introduction and Its Benefit Applications.

Common Benefits of Resveratrol.

Resveratrol:Trans-3,5,4'-trihydroxystilbene CAS:501-36-0 trans.61434-67-1.cis transresveratrol flavonoids,Phytoestrogen,Antioxidant,Anticancer,Antitoxic photo picture image Properties:

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
Resveratrol:Trans-3,5,4'-trihydroxystilbene CAS:501-36-0 trans.61434-67-1.cis transresveratrol flavonoids,Phytoestrogen,Antioxidant,Anticancer,Antitoxic photo picture image

While present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as mulberries and peanuts, resveratrol's most abundant natural sources are Vitis vinifera, labrusca, and muscadine grapes, which are used to make wines. It occurs in the vines, roots, seeds, and stalks, but its highest concentration is in the skin, which contains 50-100 micrograms (ug) per gram. Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease. For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA. Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration.

The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process. Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted. Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A fluid ounce of red wine averages 160 ug of resveratrol, compared to peanuts, which average 73 ug per ounce. Since wine is the most notable dietary source, it is the object of much speculation and research.

Resveratrol is a compound produced by many plant species and is thought to be helpful in reducing serum lipids and may have favorable cardiovascular implications. It is produced by Vitis vinifera and labrusca grapes and is found in grape products including red and white wines. There is a lack of information about resveratrol in muscadine (V. rotundifolia), so two studies were made to check bronze- and dark-skinned muscadines (and products made from them) for resveratrol. The first study established that resveratrol is a natural constituent of muscadine berries, berries without seed and seeds alone. The second study measured resveratrol in such muscadine products as wine, unfiltered juice, pomace and in purees made from pomace. Significant amounts of resveratrol were found in pomace. Muscadines wines compared favorably in resveratrol concentration with wines reported in the literature. The consumption of muscadines and muscadine products, especially those made from pomace purees, could help incorporate a sign ificant quantity of resveratrol into the average diet.
Resveratrol:Trans-3,5,4'-trihydroxystilbene CAS:501-36-0 trans.61434-67-1.cis transresveratrol flavonoids,Phytoestrogen,Antioxidant,Anticancer,Antitoxic photo picture image

Phytoestrogen:

The similarity in structure between resveratrol and diethylstilbestrol (a synthetic estrogen) has prompted investigations into resveratrol's potential as a phytoestrogen (a plant compound that produces estrogen-like effects). However, these properties also stimulate the growth of human breast cancer cells. This finding seems contrary to its other anticancer activities, and is a cause for concern.

Antioxidant:

In vitro studies have shown that resveratrol inhibits the oxidative damage caused by the heavy metal cadmium. The antioxidant activity of resveratrol reduces damage to endothelial cells exposed to nitrite radicals and protects skin cells against damage caused by UV radiation.

Anticancer:

The antioxidant action of resveratrol helps to prevent damage to DNA but it also influences the transcriptions of genes responsible for redox metabolism and inhibits proliferartion of cancer cells. Resveratrol appears to decrease tumor promotion activity by inhibiting the enzyme cyclooxygenase-1, which converts arachidonic acid to substances that promote tumor growth.

Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation, and as an anti-mutagen in rat models. Resveratrol appears to decrease tumor promotion activity by inhibiting cyclooxygenase-1 (COX-1), an enzyme that converts arachidonic acid to pro-inflammatory substances that stimulate tumor-cell growth. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation and inhibited ribonucleotide reductase, an enzyme needed for DNA synthesis in proliferating cells. One appealing characteristic of resveratrol's anti-cancer potential is its minimal toxicity to blood-forming cells. More studies using both cellular and animal models are needed before any such data would be applicable to human use.

In 1997, Jang reported that topical resveratrol applications prevented the skin cancer development in mice treated with a carcinogen.There have since been dozens of studies of the anti-cancer activity of resveratrol in animal models.No results of human clinical trials for cancer have been reported.However, clinical trials to investigate the effects on colon cancer and melanoma (skin cancer) are currently recruiting patients.

In vitro resveratrol interacts with multiple molecular targets (see the mechanisms of action), and has positive effects on the cells of breast, skin, gastric, colon, esophageal, prostate, and pancreatic cancer, and leukemia.However, the study of pharmacokinetics of resveratrol in humans concluded that even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer.This is consistent with the results from the animal cancer models, which indicate that the in vivo effectiveness of resveratrol is limited by its poor systemic bioavailability.The strongest evidence of anti-cancer action of resveratrol exists for tumors it can come into direct contact with, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is equivocal, even if massive doses of resveratrol are used.

Thus, topical application of resveratrol in mice, both before and after the UVB exposure, inhibited the skin damage and decreased skin cancer incidence. However, oral resveratrol was ineffective in treating mice inoculated with melanoma cells. Resveratrol given orally also had no effect on leukemia and lung cancer; however, injected intraperitoneally, 2.5 or 10 mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice. Resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen. In several studies, small doses (0.02~8 mg/kg) of resveratrol, given prophylactically, reduced or prevented the development of intestinal and colon tumors in rats given different carcinogens.

Resveratrol treatment appeared to prevent the development of mammary tumors in animal models; however, it had no effect on the growth of existing tumors. Paradoxically, treatment of pre-pubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.
Resveratrol:Trans-3,5,4'-trihydroxystilbene CAS:501-36-0 trans.61434-67-1.cis transresveratrol flavonoids,Phytoestrogen,Antioxidant,Anticancer,Antitoxic photo picture image

Diabetes:

Resveratrol may be benificial for diabetes. Administration of resveratrol may protect against oxidative damage caused by high glucose levels. It also reduces diabetic neuropathic pain.

Palsamy and Subramanian have recently published articles on the antihyperglycemic potential of resveratrol in experimental diabetic rats. In their study, the oral administration of resveratrol (5mg/kg b.w) to streptozotocin-nicotinamide-induced experimental diabetic rats for 30 days significantly normalizes the levels of blood glucose, plasma insulin, glycosylated hemoglobin, AST, ALP, ALT,[20] and modulates the altered activities of carbohydrate metabolizing enzymes in the liver and kidney tissus of diabetic rats. The results thus obtained showed the antidiabetic property of resveratrol in experimental diabetes.

Heart health:

Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Several studies have demonstrated that resveratrol is an effective antioxidant. It inhibits lipid peroxidation of low-density lipoprotein (LDL), prevents the cytotoxicity of oxidized LDL, and protects cells against lipid peroxidation. It is thought that because it contains highly hydrophilic and lipophilic properties, it can provide more effective protection than other well-known antioxidants, such as vitamins C and E. On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine. Reduced platelet aggregation has also been demonstrated in studies on resveratrol, further contributing to its prevention of atherosclerosis. To date, most of the research on resveratrol's antioxidant and anti-platelet properties has been done in vitro (in an artificial environment using test-tube or tissue-culture preparations). Further studies in animals and humans are necessary to determine whether resveratrol supplementation makes sense.

Resveratrol protects our heart and blood vessels by directly scavenging oxidants, which could cause oxidation of lipids, and by preventing apoptosis of endothelial cells. It may also help to prevent heart damage after a cardiac arrest. Reduced platelet aggregation has been attributes to resveratrol, thereby reducing the risk of atherosclerosis.

Increase of lifespan:

Tests with animals have shown that that high food intake reduces lifespan. One study showed that resveratrol was able to able to increase the life span of mice on a high calorie diet.

Resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In 2007, a different group of researchers was able to reproduce Sinclair's results with C. elegans,but a third group could not achieve consistent increases in lifespan of D. melanogaster or C. elegans.

In 2006, Italian scientists obtained the first positive result of resveratrol supplementation in a vertebrate. Using a short-lived fish, Nothobranchius furzeri, with a median life span of nine weeks, they found that a maximal dose of resveratrol increased the median lifespan by 56%. Compared with the control fish at nine weeks, that is by the end of the latter's life, the fish supplemented with resveratrol showed significantly higher general swimming activity and better learning to avoid an unpleasant stimulus. The authors noted a slight increase of mortality in young fish caused by resveratrol and hypothesized that it is its weak toxic action that stimulated the defense mechanisms and resulted in the life span extension.

Later the same year, Sinclair reported that resveratrol counteracted the detrimental effects of a high-fat diet in mice. The high fat diet was compounded by adding hydrogenated coconut oil to the standard diet; it provided 60% of energy from fat, and the mice on it consumed about 30% more calories than the mice on standard diet. Both the mice fed the standard diet and the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet. Gene expression analysis indicated the addition of resveratrol opposed the alteration of 144 out of 155 gene pathways changed by the high-fat diet. Insulin and glucose levels in mice on the high-fat+resveratrol diet were closer to the mice on standard diet than to the mice on the high-fat diet. However, addition of resveratrol to the high-fat diet did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet.A further study by a group of scientists, which included Sinclair, indicated that resveratrol treatment had a range of beneficial effects in elderly mice but did not increase the longevity of ad libitum-fed mice when started midlife.

Antitoxic:

Many studies on animals have shown antitoxic effects of resveratrol. Resveratrol was able to reverse damages caused by the administration of the chemotherapeutic drug bleomycin. Resveratrol also helped to reduce brain damage and oxidative damage of the liver during ethanol intoxication. It also reduced kidney damage of rats treated with the antibiotic gentamicin.

Other applications:

Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal Cell in November, 2006. Mice fed resveratrol for fifteen weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of the Sirtuin 1 gene.

Nicholas Wade's interview-article with Dr. Auwerx states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in Auwerx's mouse study would come to 32,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data (see above). Long-term safety has not been evaluated in humans.

In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn energy more efficiently~indicating that the same pathway shown in the lab mice works in humans.

In November 2008, researchers at the Weill Medical College of Cornell University reported that dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a component of Alzheimer and other Neurodegenerative diseases. In mice, oral resveratrol produced large reductions in brain plaque in the hypothalamus (-90%), striatum (-89%), and medial cortex (-48%) sections of the brain. In humans it is theorized that oral doses of resveratrol may reduce beta amyloid plaque associated with aging changes in the brain. Researchers theorize that one mechanism for plaque eradication is the ability of resveratrol to chelate (remove) copper.

Pharmacokinetics:

The most efficient way of administering resveratrol in humans appears to be buccal delivery, that is without swallowing, by direct absorption through the inside of the mouth. When one mg of resveratrol in 50 mL solution was retained in the mouth for one min before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form.

About 70% of the resveratrol dose given orally as a pill is absorbed; nevertheless, oral bioavailability of resveratrol is low because it is rapidly metabolized in intestines and liver into conjugated forms: glucuronate and sulfonate. Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose. Even when a very large dose of resveratrol (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level necessary for the systemic cancer prevention.However, resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached 5~8 times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments.

In humans and rats, less than 5% of the oral dose is being observed as free resveratrol in blood plasma. The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Walle suggests sulfate conjugates are the primary source of activity, Wang et al. suggests the glucuronides, and Boocock et al. also emphasized the need for further study of the effects of the metabolites, including the possibility of deconjugation to free resveratrol inside cells. Goldberd, who studied the pharmacokinetics of resveratrol, catechin and quercetin in humans, concluded "it seems that the potential health benefits of these compounds based upon the in vitro activities of the unconjugated compounds are unrealistic and have been greatly exaggerated. Indeed, the profusion of papers describing such activities can legitimately be described as irrelevant and misleading. Henceforth, investigations of this nature should focus upon the potential health benefits of their glucuronide and sulfate conjugates."

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill, has been disproved by experimental data. For example, after five men took 600 mL of red wine with the resveratrol content of 3.2 mg/L (total dose about 2 mg) before breakfast, unchanged resveratrol was detected in the blood of only two of them, and only in trace amounts (below 2.5 ng/mL). Resveratrol levels appeared to be slightly higher if red wine (600 mL of red wine containing 0.6 mg/mL resveratrol; total dose about 0.5 mg) was taken with meal: trace amounts (1~6 ng/mL) were found in four out of ten subjects. In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white wine or white grape juice. The highest level of unchanged resveratrol in the serum (7~9 ng/mL) was achieved after thirty minutes, and it completely disappeared from blood after four hours. The authors of both studies concluded that the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. It appears that the beneficial effects of wine could be explained by the effects of alcohol or the whole complex of substances wine contains; for example, the cardiovascular benefits of wine appear to correlate with the content of procyanidins.

Adverse effects and unknowns

While the health benefits of resveratrol seem promising, one study has theorized that it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen. However, other studies have found that resveratrol actually fights breast cancer.Some studies suggest that resveratrol slows the development of blood vessels, which suppresses tumors, but also slows healing.Citing the evidence that resveratrol is estrogenic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under eighteen, as no studies have shown how it affects their natural development. A small study found that a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.

Mechanisms of action

The mechanisms of resveratrol's apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. A new report indicates that resveratrol activates Sirtuin 1 (SIRT1) and PGC-1alpha and improve functioning of the mitochondria.Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction.

A paper by Robb et al. discusses resveratrol action in cells. It reports a fourteen-fold increase in the action of MnSOD (SOD2). MnSOD reduces superoxide to hydrogen peroxide (H2O2), but H2O2 is not increased due to other cellular activity. Superoxide O2- is a byproduct of respiration in complex 1 and 3 of the electron transport chain. It is "not highly toxic, [but] can extract an electron from biological membrane and other cell components, causing free radical chain reactions. Therefore it is essential for the cell to keep superoxide anions in check." MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases.It has been implicated in lifespan extension, inhibits cancer, (e.g. pancreatic cancer) and provides resistance to reperfusion injury and irradiation damage.These effects have also been observed with resveratrol. Robb et al. propose MnSOD is increased by the pathway RESV => SIRT1 / NAD+ => FOXO3a => MnSOD. Resveratrol has been shown to cause SIRT1 to cause migration of FOXO transcription factors to the nucleus which stimulates FOXO3a transcriptional activity and it has been shown to enhance the sirtuin-catalyzed deacetylation (activity) of FOXO3a. MnSOD is known to be a target of FOXO3a, and MnSOD expression is strongly induced in cells overexpressing FOXO3a.

Resveratrol interferes with all three stages of carcinogenesis,initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-kB, inhibition of the cytochrome P450 isoenzyme CYP1A1 (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene), alterations in androgenic actions and expression and activity of cyclooxygenase (COX) enzymes. In vitro, resveratrol "inhibited the proliferation of human pancreatic cancer cell lines." In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells.Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties.

Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could help against diseases such as Huntington's disease and Alzheimer's disease. Again, this has not yet been tested in humans for any disease.

Research at the Northeastern Ohio Universities College of Medicine and Ohio State University indicates that resveratrol has direct inhibitory action on cardiac fibroblasts, and may inhibit the progression of cardiac fibrosis.

According to Patrick Arnold, it also significantly increases natural testosterone production from being both a selective estrogen receptor modulator and an aromatase inhibitor.

In December 2007, work from Irfan Rahman's laboratory at the University of Rochester demonstrated that resveratrol increased intracellular glutathione levels via Nrf2-dependent upregulation of gamma-glutamylcysteine ligase in lung epithelial cells, which protected them against cigarette smoke extract induced oxidative stress.