There is little evidence of benefit from resveratrol in those who already have heart disease. A 2014 meta-analysis found that resveratrol supplementation at usual doses has no effect on blood pressure but may help if high doses are used.
As of 2014[update], evidence of an effect of resveratrol on cancer in humans is inconsistent.
There is very little human evidence of an effect of resveratrol on metabolism. Tentative data supports a potential benefit in controlling some biomarkers in diabetes but further evidence is needed before it can be recommended.
The effect of resveratrol on lifespan in humans is unclear as of 2011.
Long-term effects of using resveratrol are currently unknown but clinical trials have shown that it is well tolerated during the trials.
Discovery and name
The first mention of resveratrol was in a Japanese article in 1939 by Michio Takaoka, who isolated it from the poisonous, but medicinal, Veratrum album, variety grandiflorum. The name presumably comes from the fact that it is a resorcinol derivative coming from a Veratrum species. In 2003, D. Sinclair from Harvard Medical School reported in Nature that resveratrol activated sirtuins in yeast cells. This was immediately followed by the launch of Sirtris Pharmaceuticals. While pharmacological effects of resveratrol did not turn out to be commercially viable, their discovery lead to efforts to develop other types of SIRT genes' activators.
One way of administering resveratrol in humans may be buccal delivery, that is without swallowing, by direct absorption through tissues on the inside of the mouth. When one milligram of resveratrol in 50 ml 50% alcohol/ water solution was retained in the mouth for one minute 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. However, the viability of a buccal delivery method is called into question due to the low aqueous solubility of the molecule. For a drug to be absorbed transmucosally it must be in free-form or dissolved. Resveratrol fits the criteria for oral transmucosal dosing, except for this caveat. The low aqueous solubility greatly limits the amount that can be absorbed through the buccal mucosa. Resveratrol that is attempted to be taken buccally was expected to pass through the mucous membrane of the mouth and be absorbed as an oral dose, however, the need to explore buccal delivery in future pharmaceutical formulations was expressed.
While 70% of orally administered resveratrol is absorbed its oral bioavailability is approximately 0.5% due to extensive hepatic gluconuridation and sulfation. 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 (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level claimed to be necessary for the systemic cancer prevention. A formulation of resveratrol in a chewing gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached five to eight times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments. On May 5, 2010, however, GlaxoSmithKline (GSK) said it had suspended a small clinical trial of SRT501, a proprietary form of resveratrol, due to safety concerns, and terminated the study on December 2, 2010.
In humans and rats less than 5% of the oral dose was 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 refuted 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 mcg(?)/ml resveratrol; total dose about 0.5 mg) was taken with a 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 30 minutes, and it completely disappeared from blood after four hours. The authors of both studies concluded the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. The beneficial effects of wine apparently 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.
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. Some studies indicates resveratrol activates Sirtuin 1 and PGC-1α and improves the functioning of the mitochondria. Resveratrol's ability to directly activate sirtuin 1 has been called into question, however newer research has reconfirmed this link.
In cells treated with resveratrol, a fourteen-fold increase in the action of MnSOD (SOD2) is observed. 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 complexes 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. It has been reported too that the disproportional up-regulation of superoxide dismutase (SOD), catalse (CAT) and glutathion peroxidase (GPX) expression (high expression of MnSOD, but mild change in CAT or GPX) and their enzymatic activity in cancer cells results in the mitochondrial accumulation of H2O2, which in turn induces cancer cell apoptosis.
Resveratrol was reported to be effective against neuronal cell dysfunction and cell death, and, in theory, could be effective against diseases such as Huntington's disease and Alzheimer's disease. Again, this has not yet been tested in humans for any disease.
Resveratrol has direct inhibitory action on cardiac fibroblasts, and may inhibit the progression of cardiacfibrosis.
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.
Another potentially important mechanism common to both resveratrol supplementation and caloric restriction is the modulation of autophagy. SIRT1 is a hypothesized target of both resveratrol and caloric restriction, and has been shown to facilitate autophagy through the inhibition of mTOR, which itself negatively regulates autophagy.
In 2012, it was shown that resveratrol is capable of competitively inhibiting various phosphodiesterases, which results in an increase in cytosolic concentration of cAMP, which acts as a second messenger for the activation of the pathway Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α. This rise of cAMP concentration allows an increase in oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis.
Chemical and physical properties
Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivate of stilbene.
It exists as two geometric isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. The trans- and cis-resveratrol can be either free or bound to glucose.
Recently, it is noted that ultraviolet irradiation to cis-resveratrol induces further photochemical reaction, produces a fluorescent molecule named "Resveratrone".
Trans-resveratrol in the powder form was found to be stable under "accelerated stability" conditions of 75% humidity and 40 °C in the presence of air. The trans isomer is also stabilized by the presence of transport proteins. Resveratrol content also was stable in the skins of grapes and pomace taken after fermentation and stored for a long period.lH- and 13C-NMR data for the four most common forms of resveratrols are reported in literature.
Resveratrol gets extensively metabolized in the body. Liver and gut are the major site of its metabolism. Lungs are also involved in its metabolism, with inter-species difference in its pulmonary metabolism.
Resveratrol was originally isolated by Takaoka from the roots of hellebore in 1940, and later, in 1963, from the roots of Japanese knotweed. It attracted wider attention only in 1992, however, when its presence in wine was suggested as the explanation for cardioprotective effects of wine.
In grapes, trans-resveratrol is a phytoalexin produced against the growth of fungal pathogens such as Botrytis cinerea. Its presence in Vitis vinifera grapes can also be constitutive, with accumulation in ripe berries of different levels of bound and free resveratrols, according to the genotype. In grapes, resveratrol is found primarily in the skin, and, in muscadine grapes, also in the seeds. The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.
The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/l, depending on the grape variety, while white wine has much less, because red wine is fermented with the skins, allowing the wine to extract the resveratrol, whereas white wine is fermented after the skin has been removed. The composition of wine is different from that of grapes since the extraction of resveratrols from grapes depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolised, yielding both trans- and cis-resveratrol. A number of reports have indicated muscadine grapes may contain high concentrations of resveratrol, and that wines produced from these grapes, both red and white, may contain more than 40 mg/l, however, subsequent studies have found little or no resveratrol in different varieties of muscadine grapes.
One of the most promising sources is peanuts, especially sprouted peanuts where the content rivals that in grapes. Before sprouting, it was in the range of 2.3 to 4.5 μg/g, and after sprouting, in the range of 11.7 to 25.7 μg/g depending upon peanut cultivar.
The fruit of the mulberry (esp. the skin) is a source, and is sold as a nutritional supplement.
The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/l in the 32 red wines tested and had a maximum of 0.1 mg/l in the 8 white wines in the test. Both the cis- and trans-isomers of resveratrol were detected in all tested samples. cis-resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/l to 1.9 mg/l in red wines and had a maximum of 0.2 mg/l in white wines.
In a review of published resveratrol concentrations, the average in red wines is 1.9 ± 1.7 mg trans-resveratrol/L (8.2 ± 7.5 μM), ranging from nondetectable levels to 14.3 mg/l (62.7 μM) trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.
Reports suggest some aspect of the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.
In general, wines made from grapes of the Pinot Noir and St. Laurent varieties showed the highest level of trans-resveratrol, though no wine or region can yet be said to produce wines with significantly higher concentrations than any other wine or region.
Ounce for ounce, peanuts have about half as much resveratrol as red wine. The average amount in peanuts in the marketplace is 79.4 µg/ounce.
In comparison, some red wines contain approximately 160 µg/fluid ounce. Resveratrol was detected in grape, cranberry, and wine samples. Concentrations ranged from 1.56 to 1042 nmol/g in Concord grape products, and from 8.63 to 24.84 µmol/L in Italian red wine. The concentrations of resveratrol were similar in cranberry and grape juice at 1.07 and 1.56 nmol/g, respectively.
Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than 10% of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half.
As a result of extensive news coverage, sales of supplements greatly increased in 2006. This was despite the existence of studies cautioning that benefits to humans are unproven.
Supplements vary in purity and can contain anywhere from 50 percent to 99 percent resveratrol. Many brands consist of an unpurified extract of Japanese knotweed (Polygonum cuspidatum), an introduced species in many countries. These contain about 50 percent resveratrol by weight, as well as emodin, which, while considered safe in moderate quantities, can have a laxative effect in high amounts. Resveratrol can be produced from its glucoside piceid from Japanese knotweed fermented by Aspergillus oryzae.
Harvard University scientist and professor David Sinclair is often quoted in online ads for resveratrol supplements, many of which imply endorsement of the advertized product; however, Sinclair, who has studied resveratrol extensively, has gone on record in Bloomberg Businessweek to say he never uttered many of the statements attributed to him on these sites.
There are a number of promising animal studies and some data from human clinical trials is emerging. Nevertheless, there is not enough evidence to recommend consumption of resveratrol beyond the amount that can be obtained through dietary sources, and more human clinical trials are needed.
As of 2014, the results of limited human clinical trials with small samples sizes of the effects of resveratrol on cancer are inconsistent. Testing of resveratrol in animal models of cancer have also shown mixed results. The strongest evidence of anticancer action of resveratrol exists for tumors it can contact directly, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used. 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 prepubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.
Moderate drinking of red wine has long been known to reduce the risk of heart disease. This is best known as "the French paradox".
The cardioprotective effects of resveratrol also are theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy. Study into the cardioprotective effects of resveratrol is based on the research of Dipak K. Das. However, he has been found guilty of scientific fraud, and many of his publications related to resveratrol have been retracted.
Other diabetic animal model studies by different researchers have also demonstrated the antidiabetic effects of resveratrol. This compound was shown to act as agonist of PPARgamma, nuclear receptor that is current pharmacological target for the treatment of diabetes type 2.
The oxidative stress induced by ultraviolet radiation is one of the main causes for premature skin ageing. The photoprotective effects of several polyphenols known for their antioxidant properties, including resveratrol, have been investigated in silico and in topical application conditions.
The neuroprotective effects have been confirmed in several animal model studies.
Some of the benefits demonstrated in previous studies were overstated, however, this study was challenged immediately, and a few experiments were suggested to be of inferior quality.
In a number of animal models resveratrol has had an antidepressant-like effect. Whether or not there is any effect in humans is unclear.
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^Hudson TS, Hartle DK, Hursting SD, Nunez NP, Wang TT, Young HA, Arany P, Green JE; Hartle; Hursting; Nunez; Wang; Young; Arany; Green (September 2007). "Inhibition of prostate cancer growth by muscadine grape skin extract and resveratrol through distinct mechanisms". Cancer Res.67 (17): 8396–405. doi:10.1158/0008-5472.CAN-06-4069. PMID17804756. MSKE [muscadine grape skin extract] does not contain significant quantities of resveratrol and differs from MSEE. To determine whether MSKE contains significant levels of resveratrol and to compare the chemical content of MSKE (skin) with MSEE (seed), HPLC analyses were done. As depicted in Supplementary Fig. S1A and B, MSKE does not contain significant amounts of resveratrol (<1 ?g/g by limit of detection).
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