|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Markedly reduces the number of microcomedones and other acne lesions by inhibiting inflammation and the growth of P. acnes.
30 days' application of a resveratrol cream improved the elasticity of the skin by nearly 50% in one study.
More effective than vitamins C and E at free radical scavenging and preventing lipid peroxidation.
Decreased oxidative damage to UVA-exposed human keratinocytes by reducing the levels of reactive oxygen species.
Skin hydration was improved by 20.5% in one study following the application of a resveratrol cream for 30 days.
A topical resveratrol cream lightened the skin by 6.2% over 30 days.
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Table of contents:
- 1. Sources
- 2. Bioavailability
- 3. Effects on the skin
- 4. Side Effects
Resveratrol occurs naturally in many plants and fruits, including the skin of red grapes, eucalyptus, spruce, blueberries, mulberries, peanuts and the root of Japanese knotweed.
In plants, trans-resveratrol is produced as a form of defense against harmful environmental stimuli, such as a fungus or an infection, and in response to stress conditions such as vicissitudes in climate, exposure to ozone, sunlight and heavy metals.
Fresh grape skin contains about 50-100µg of resveratrol per gram wet weight. Due to its presence in grape skins, resveratrol is also found in red and white wines. One study has shown that red wines contain on the order of 2.861 to less than 0.003µmol/L of resveratrol, while in white wines the concentration ranged from 0.438 to less than 0.001µmol/L.
2.1 Oral administration
The oral absorption of resveratrol is approximately 75%, and is thought to occur mainly by transepithelial diffusion. Yet, resveratrol's oral bioavailability is considerably less than 1%. This is because within 30-60 minutes after administration, resveratrol is very quickly metabolized by the intestine and the liver, mainly into glucuronides and sulfonates that are eliminated in urine. As a result, it is difficult to use resveratrol systematically as a drug treatment, since it disappears from the plasma in such a short period.
2.2 Topical administration
Applying resveratrol topically to the skin would allow resveratrol to come into direct contact with the area of interest, while avoiding the side effects associated with systemic metabolism. There appear to be specific polyphenol receptor sites in the skin that bind resveratrol. Through the study of localization signals in human skin tissue sections post-treatment with [3H]-resveratrol, significant binding was observed in the epidermis, and some binding in the dermis.
The non-ionic form of resveratrol is highly lipophilic and is a good candidate for skin absorption, since the stratum corneum is itself principally lipophilic in nature. A study on mice skin found non-ionic resveratrol delivered in aqueous solutions to have excellent permeability, even in the absence of enhancers such as α-terpineol and oleic acid. Another study using pig skin, which is similar in structure to human skin, found that lower oil content in the emulsion applied to the skin led to enhanced permeation. However, data on the permeation of topically applied resveratrol onto human skin is lacking.
In cosmetic formulations, in order to allow resveratrol to be incorporated into creams, it is often encapsulated in microparticles. Trans-resveratrol is unstable and is converted to its less active cis form when exposed to solar rays. The use of nanosuspensions and nanocarriers have been shown to increase stability, and promote permeation through the skin respectively. A trans-resveratrol/β-cyclodextrin binary system has also been shown to enhance solubility due to the formation of an inclusion complex.
3. Effects on the skin
3.1 Antioxidant effect
Resveratrol can scavenge free radicals and inhibit lipid peroxidation. In fact, it has been found to be both a better radical scavenger and more efficient at preventing lipid peroxidation than vitamin C and vitamin E. These antioxidant properties are beneficial, for they enable resveratrol to modulate the upregulation of reactive oxygen species in human skin fibroblasts caused by endogenous and UV-induced oxidation processes in human skin. Indeed, resveratrol at concentrations of just 0.01%, 0.001% and 0.0001% in human skin fibroblasts in vitro has been demonstrated to significantly and dose-dependently reduce intracellular production of reactive oxygen species by hydrogen peroxide.
In 2008, a skin care formulation containing 1% resveratrol and showing a 17-fold increase in antioxidant potency compared to a 1% idebenone product (Prevage MD) was reported to be undergoing clinical testing.
Resveratrol protected immortalized human keratinocytes that were exposed to UVA radiation against oxidative damage by lowering the levels of reactive oxygen species in one study, with electron microscopy confirming that ultrastructural changes could be prevented.
Resveratrate, a stable derivative of resveratrol, has been shown to reduce the damage caused to human skin by solar ultraviolet (UV) radiation. In a vehicle-controlled study, 15 women were exposed to combined UVA and UVB light at 5 sites on the upper back for 4 consecutive days. Immediately after each irradiation, test products were applied to the first 4 sites. The test products were a commercial moisturizer base containing 1% resveratrate, 1% resveratrate plus antioxidants, antioxidants alone, and vehicle. No product was applied to the fifth site, which served as a positive control. A sixth site acted as a negative control, without either exposure to UV radiation or topical application of the test products. The smallest change in skin lightness occurred at the UV exposed sites treated with the resveratrate cream alone or in combination with antioxidant. Further, cells sampled from sites treated with resveratrate, antioxidant or both all had significantly reduced sunburn cell formation compared to the control sites and the placebo site.
3.3 Age-related improvements
Resveratrol appears to alleviate age-related alterations to the skin. One double-blind, placebo-controlled study involving 50 subjects found that following 60 days of treatment with a commercial dietary supplement (Revidox) containing 8 mg of resveratrol, skin moisturization improved in the treated group but not in the placebo group. Skin elasticity likewise improved in the treated group, whereas it had deteriorated slightly in the placebo group. Furthermore, skin roughness and wrinkle depth diminished significantly in the treated group, but were significantly worse in the placebo group. The intensity of age spots also diminished to a significantly greater extent than in the placebo group. Yet, as Revidox also contains proanthocyanidins, it is not certain whether these anti-aging effects are attributable to resveratrol, another active, or a combination of both.
Another single-blind, split-face study on 8 women compared the effects on skin hydration, luminosity and elasticity of 2 creams containing trans-resveratrol alone or trans-resveratrol complexed with β-cyclodextrin. It was found that both creams led to visible improvements in skin hydration, luminosity and skin elasticity in particular, but that the effect was greater for the formulation containing the binary system. Specifically, the hemi-face treated with resveratrol alone saw improvements in skin hydration, elasticity and colorimetry of 20.5%, 49.7% and 6.2% respectively, whereas the hemi-face treated with the formulation containing the binary system had improvements of 28.6%, 57.4% and 8.7% for the same parameters.
3.4 Acne vulgaris treatment
In a single-blind, vehicle-controlled pilot study, a hydrogel containing resveratrol at a concentration of 1µg/g was administered to 20 patients affectd by acne vulgaris. The resveratrol-containing formulation was applied daily on the right side of the face for 60 days, while the hydrogel vehicel was applied to the left side of the face. Data collected from digital photographs showed an average 53.75% reduction in clinical lesions on the resveratrol-treated side, compared to 6.10% on the vehicle-treated side of the face. There was also a 66.7% mean decrease in the area and density of microcomedones on the resveratrol-treated side of the face, versus a 9.7% decrease on the vehicle-treated side, according to cyanoacrylate follicular biopsies. Resveratrol appears to inhibit the hyperproliferation of keratinocytes, the inflammatory process as well as the replication of P. acnes, and is thus considered an interesting molecule for acne treatment.
3.5 Cancer chemoprevention
Resveratrol possesses chemopreventive activity against all three major stages of carcinogenesis -- initiation, promotion and progression.
It has been demonstrated that resveratrol results in cell cycle arrest and apoptosis of human epithelial carcinoma cells. The cytotoxic effects of resveratrol on melanoma cell lines are uncertain however. One study found that resveratrol was a potent inducer of apoptosis in human melanoma cells. However, another study showed that resveratrol treatment inhibited the anchorage-dependent growth of melanoma cell lines, but without causing any cytotoxic effects.. Importantly, resveratrol appears to have low toxicity to normal cells and limited side effects. Resveratrol decreased the viability of melanoma cell lines but did not affect nonmalignant human fibroblast lines. Resveratrol may also have prospects to be used as an adjuvant therapy for melanoma, as it enhances the cytotoxicity of temozolomide and dacarbazine.
3.6 Antimicrobial activity
The antimicrobial effect of resveratrol against bacteria and dermatophytes that are major etiologic agents of human skin infections, has been evaluated. Resveratrol inhibits the growth of dermatophytes when applied at an concentration of 25-50µg/mL, indicating that resveratrol may be used to combat human fungal pathogens.
4. Side Effects
4.1 Altered drug efficacy
Resveratrol appears to modulate enzymes involved in carcinogen activation and detoxification, including CYP2D6 and CYP2C9. Studies have shown that individuals with decreased CYP2D6 metabolism due to genetic variations or enzyme inhibition have reduced plasma endoxifen concentration and increased risk of breast cancer relapse. It is therefore possible that resveratrol could decrease the formation of endoxifen, thus affecting the anticancer activity of tamoxifen. CYP2C9 is involved in the metabolic clearance of a wide variety of therapeutic drugs, including many NSAIDs, COX-2 inhibitors, oral anticoagulants and oral hypoglycemics. By decreasing the clearance of these drugs, resveratrol may increase their toxicity. 
4.2 Gastrointestinal problems
Gastrointestinal problems have been reported in some patients who have taken resveratrol as part of clinical trials. In one study, healthy volunteers receiving 2.5g and 5.0g of resveratrol daily for 29 days reported adverse events including nausea, flatulence, abdominal discomfort and diarrhoea. The side effects commenced after 2-4 days of the intervention, and occurred half to one hour after ingestion of resveratrol. Symptoms tended to improve throughout the day, and resolved within 2 days of completing the 29-day course. In another study, diarrhoea was frequently observed among 8 healthy volunteers taking 2g of trans-resveratrol twice daily.
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