Likewise, production of free radicals was reduced in human stratum corneum following topical treatment with resveratrol for 24 hr. Collectively, resveratrol exhibits antioxidant properties both in vitro and in vivo.Oxidative stress has been considered as a major contributor to the development of skin cancers, such as melanoma. Accordingly, antioxidants, including resveratrol, have been used to prevent and treat skin cancer, although exacerbation and increased risk of cancers have been reported. Melanoma is the most serious type of skin cancer, with mortality rates of 3.1/100,000 in the US and 1.4–1.9/100,000 in Germany. Antimelanoma benefits of resveratrol have been demonstrated both in vivo and in vitro. Studies in melanoma cell cultures showed that resveratrol inhibited proliferation of melanoma cells, with a concentration of 7 μg/ml inducing a 50% inhibition of cell growth. It seems that melanoma cells are more sensitive to resveratrol than keratinocytes, which instead required a concentration of 20 μg/ml to cause 50% inhibition of cell growth. Moreover, resveratrol dose-dependently increased both apoptotic and necrotic cells after 24 hr treatment of two melanoma cell lines. In addition,grow bucket resveratrol also inhibited the growth of squamous cell carcinoma cells. Resveratrol induced apoptosis and inhibition of cell proliferation were also observed in human head and neck squamous cell carcinoma cell lines, e.g., FaDu, Cal27, and Det562 cell lines. Moreover, rates of DNA synthesis were reduced by 78% following the treatment of carcinoma cells with 25 μM resveratrol for 72 hr.

In vivo studies showed that oral administration of resveratrol resulted in a dose- and timedependent inhibition of carcinoma cell growth, with over 50% reductions in both tumor volume and weight per mouse following 30-day treatment with resveratrol at a dose of 50 mg/kg body weight. Taken together, resveratrol demonstrates potential anticancer activity both in vivo and in vitro.Inflammatory dermatoses prove the most common clinical problems in dermatology. Because of the severe side effects of immune modulators, such as glucocorticoids and tacrolimus, safe and effective alternatives are highly demanded. Studies have shown that resveratrol is safe in both animals and humans, but it can effectively inhibit inflammation both in vitro and in vivo. For example, incubation of keratinocytes with 50 μM resveratrol for 3 hr lowered the expression levels of mRNA for IL-6, IL-8, TNF-α, and macrophage inflammatory protein 1 by over 50%. While production of proinflammatory cytokines markedly increased in keratinocytes exposed to TNF-α, lipopolysaccharide, interferon c , and UV irradiation, addition of 50 μM resveratrol 1 hr prior to lipopolysaccharide treatment dramatically decreased mRNA levels for MIF-1, IL-6, and cyclooxygenase 2 in comparison with keratinocytes treated with lipopolysaccharide alone. Yet, resveratrol also dose-dependently stimulated IL-8 production in keratinocyte cultures, suggesting that resveratrol differentially regulates cytokine production. Although there is still little or no evidence that resveratrol can inhibit cutaneous inflammation in humans, anti-in- flammatory benefits of resveratrol have been well demonstrated in murine models of inflammatory dermatoses.

For example, in acute allergic contact dermatitis model, pretreatment of mouse ears with resveratrol reduced the densityof CD3+ cells by≈90% in parallel with significant reduction of ear thickness and expression levels of intercellular adhesion molecule 1 , C-X-C motif chemokine ligand 10 , C-C motif chemokine ligand 2 , and IFN-κ in the epidermis, suggesting preventive benefits of topical resveratrol in acute allergic contact dermatitis. Moreover, the therapeutic effects of topical resveratrol have also been demonstrated in an atopic dermatitis-like disease model. Kang et al. showed that topical applications of either 2.5% resveratrol or resveratrol-enriched rice extract for five weeks markedly reduced dermatitis score and serum IgE levels in a dermatitis model induced by topical dinitrochlorobenzene. Likewise, both intravenously and orally given resveratrol significantly alleviated dermatitis score and decreased cytokine expression. Psoriasis is another common, inflammatory skin disorder. Kjaer et al. showed that oral administrations of transresveratrol at a daily dose of 400 mg/kg body weight induced over 50% reductions in both erythema and scale scores, along with 15% decrease in skin fold thickness of the back skin, in an imiquimod-induced psoriasis-like mouse model. In addition, topical resveratrol also decreased the expression levels of IL-17a and IL-19 mRNA by ≈60% in comparison with mice treated with imiquimod alone. Together, these results show that both topical and systemic administration of resveratrol can mitigate cutaneous inflammation.Cutaneous wound healing involves the proliferation of both fibroblast and keratinocytes, as well as collagen deposition.

A number of observations suggested that, in murine models of full-thickness wound, resveratrol stimulates cell proliferation and collagen, leading to acceleration in cutaneous wound healing. Application of wound dressings containing resveratrol to full-thickness skin wounds induced marked reductions in wound areas in comparison with the controls. Similar acceleration in wound closure occurs following the placement of scaffolds containing resveratrol over the wound. +is evidence indicates that topical resveratrol accelerates wound healing in normal mice. Management of slow wound healing in diabetics has been a substantial challenge. Yes, studies have shown that either topical or systemic administrations of resveratrol can improve cutaneous wound healing in animal model of diabetes. Moreover, the efficacy of topical resveratrol ointment for wound healing was superior to that of topical β-sitosterol, conventional wound healing product. Huang et al. also reported that a single application of resveratrol accelerated cutaneous wound healing in diabetic mice. However, other studies have shown little or no benefit of resveratrol in wound healing following a single application in diabetic rats. +us, the potential benefits of resveratrol for wound healing in diabetic models still need to be validated.Studies in both humans and murine models reveal that resveratrol also regulates other cutaneous functions, including skin aging, melanogenesis, and antimicrobial defense. In human keratinocyte cultures, resveratrol reduced 90% reduction in expression levels of beta-galactosidase, a biomarker of senescence, in an aging model induced by oxidative stress. Clinical trials have also demonstrated the antiaging properties of resveratrol. A study in 50 humans with clinical signs of aging showed that oral fruit extracts that contain resveratrol markedly improved multiple aging-associated parameters, including increased stratum corneum hydration and skin elasticity, decreased skin roughness and wrinkle depth, as well as reductions in the intensity of pigmented solar lentigines. In parallel, levels of plasma derivatives of ROS dramatically declined, while skin ferric-reducing ability increased. In addition, topical applications of resveratrol containing products also improved aging-associated signs, such as skin wrinkles, stratum corneum hydration, and pigmentation, in aged humans. But in one clinical trial in 30 subjects, oral supplement of product containing transresveratrol did not appreciably improve skin aging, despite reductions in cutaneous MDA content and elevations in SOD content. +ese discrepant results suggest that additional trials are still needed to determine whether resveratrol benefits skin aging. Other studies suggest that resveratrol exhibits antimicrobial properties. Cathelicidin antimicrobial peptides are a family of polypeptides,dutch bucket for tomatoes produced by keratinocytes, macrophages, and polymorphonuclear leukocytes, that display antibacterial, antifungal, and antiviral activities. Park et al. reported that incubation of keratinocytes with resveratrol for 24 hours increased the expression level of CAMP mRNA by over 4-fold. But resveratrol may also directly inhibit microbial growth because incubation with resveratrol induced time- and dose-dependent reductions in Propionibacterium acnes colony-forming units, possibly due to disruption of the bacterial membrane.

Studies have shown that resveratrol exhibits several bactericidal and bacteriostatic activity against several pathogens, including S. pyogenes, S. aureus, C. glabrata, and C. albicans, with minimum inhibitory concentrations as low as 1.25 mg/ml. Moreover, topical applications of 25% resveratrol cream markedly decreased lesion scores for herpes simplex infection, with an efficacy comparable to 5% acyclovir ointment, in a mouse model of herpes simplex infections. Similar results were also obtained with topical applications of oxyresveratrol in mice infected by herpes simplex virus. Furthermore, studies also suggest benefits of resveratrol for keloids. For example, resveratrol induced apoptosis of fibroblasts from keloids, in parallel with reductions in the expression levels of mRNA for collagen 1 and procollagen 3, while increasing expression of SIRT1, suggesting a potential application of resveratrol for the treatment of keloids and hypertrophic scars. Other studies have demonstrated that topical resveratrol improves epidermal permeability barrier function and stratum corneum hydration in sodium dodecyl sulfate damaged human skin. Additionally, both in vitro and in vivo studies have shown that resveratrol reduces skin pigmentation via inhibition of tyrosinase activity, cytokine production, and melanocytic microphthalmia-associated transcription factor expression. Yet, all of theseputative benefits of resveratrol for cutaneous function still lack sufficient clinical validation. +erefore, well-designed clinical trials are still required before resveratrol can be widely utilized in clinical settings.Evidence of resveratrol for multiple cutaneous functions has been well demonstrated, but the underlying mechanisms whereby resveratrol acts remain unclear. A line of evidence suggests that the actions of resveratrol could be via multiple mechanisms such as upregulation of nuclear factor erythroid 2-related factor 2 , activation of sirtuin 1 , and mitogen-activated protein kinase signaling pathway, depending on which function is regulated. +e major putative mechanisms by which resveratrol regulates cutaneous function are illustrated in Figure 4.Keratinocyte proliferation and differentiation, which are inversely regulated, are both required to form the stratum corneum, the out most layers of the skin, providing multiple cutaneous protective functions because resveratrol can stimulate keratinocyte differentiation while inhibiting proliferation, resulting in acceleration of epidermal maturation. +e inhibitory effects of resveratrol on keratinocyte proliferation occur via two mechanisms: activation/upregulation of SIRT1 and inhibition of protein kinase D. In keratinocyte cultures, resveratrol upregulated expression of SIRT1, leading to elevation in aryl hydrocarbon receptor nuclear translocator , resulting in down regulation of aquaporin 3, and consequently inhibiting cell proliferation. Lee et al. showed that resveratrol increased the expression level and deacetylase activity of SIRT1, resulting in apoptosis. Other studies suggest that resveratrol inhibits DNA synthesis, while increasing transglutaminase activity via inhibition of protein kinase D activity. Moreover, activation of SIRT1 by resveratrol could also increase keratinocyte differentiation. Activation of SIRT1 by resveratrol is likely via enhancement of the binding of specific substrates to SIRT1. +us, resveratrol could inhibit keratinocyte proliferation and stimulate differentiation via both activation of SIRT1 and/or inhibition of protein kinase D.Although the precise mechanisms by which resveratrol protects the skin against UV irradiation and oxidative stress are unclear, a handful of evidence points to a central role of Nrf2. +is transcription factor regulates phase 2 antioxidant enzymes, which protect against UV irradiation- and other oxidative stress-induced damage to the skin. Nrf2 deficiency accelerated UV irradiation-induced photoaging and in- flammation, while conversely activation of Nrf2 protects against UV irradiation-induced apoptosis and in- flammation. Normally, Nrf2 together with Kelch ECH associating protein 1 forms a complex, which is degraded by the ubiquitin-proteasome system. Upon oxidative stress , Nrf2 is released from Nrf2/Keap1 complex and translocates into the nucleus, where Nrf2 binds to antioxidant response element in a heterodimeric complex, consequently leading to increased production of phase 2 antioxidant enzymes. While UV irradiation can increase the production of reactive oxygen species and oxidative products, resveratrol can attenuate UV-induced oxidative stress via upregulation and/or activation of Nrf2. For example, treatment of keratinocytes with resveratrol either before or after UVA irradiation induced >50% increase in Nrf2 content, while increasing content of Nrf2 in the nuclear fraction. Similarly, treatment of either normal mice or oxidative-stressed keratinocytes with resveratrol increases Nrf2 expression and activation, leading to increased expression of phase 2 antioxidant enzymes and reductions in reactive oxygen species, ultimately protecting/ alleviating cell damage induced by UV irradiation or other oxidative stressors. With regard to how resveratrol upregulates Nrf2 expression and activity, at least three mechanisms probably are operative. One mechanism involves upregulation of SIRT1 expression. Resveratrol is a SIRT1 activator. Upregulation of SIRT1 expressions, in turn, increases expression levels of Nrf2 and phase 2 antioxidant enzymes, while silencing SIRT1 with siRNA decreases Nrf2 protein as well as activity of ARE promotor. Moreover, upregulation and activation of Nrf2 expression by SIRT1 were also observed. +e second mechanism comprises direct upregulation of Nrf2 expression because studies have shown that resveratrol increases Nrf2 expression in kidney, heart, and lung tissues. +e third mechanism is direct down regulation of Keap1 expression. Treatment of keratinocytes with resveratrol either before or post-UVA irradiation lowers expression levels of Keap1 protein. Resveratrol-induced reduction of Keap1 expression was also observed in the kidney and lung tissues of obese and asthmatic rats. Reductions in Keap1 expression can slow Nrf2 degradation, resulting in an increase in Nrf2 expression. Other studies also showed that resveratrol stimulated Nrf2 expression and nuclear translocation without changing the expression levels of Keap1.