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 resveratrolcontaining 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, 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, u planting gutter 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 sulfatedamaged 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.Keratinocyte proliferation and differentiation, which are inversely regulated, are both required to form the stratum corneum, the outmost 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 downregulation 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. Treatment of adipocytes with resveratrol significantly increased expression levels of SIRT1 mRNA. 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 downregulation 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. Interestingly, Nrf2 and SIRT1 can positively coregulate each other. For example, treatments of either renal tubular cells or glomerular mesangial cells with resveratrol parallelly increased Nrf2 and SIRT1 expression.

Knockdown of Nrf2 with siRNA decreases the expression levels of SIRT1, and vice versa. +erefore, resveratrol can sequentially or separately upregulate SIRT1 and Nrf2, while downregulation of Keap1 expression, resulting in increased expression of phase 2 antioxidant enzymes, which in turn protect the skin from UV irradiation- and oxidative stress-induced damage. Finally, one study showed that inhibition of phosphatidylinositol-3-kinase prevented the activation of Nrf2 induced by pterostilbene, a resveratrol analog, suggesting that resveratrol can also activate Nrf2 via activation of phosphatidylinositol- 3-kinase. Still other mechanisms could also account for the actions of anti-UV irradiation and antioxidative stress. For example, pretreatment of keratinocytes with resveratrol almost completely prevents the activation of NFκB induced by UVB irradiation, suggesting that resveratrol-induced inhibition of NFκB activation could contribute to its anti-UV irradiation properties. Resveratrol-induced upregulation of heat-shock protein 27 and downregulation of caspase 3 could also contribute to its anti-UV irradiation property. +us, resveratrol protects skin against UV irradiation and oxidative stress via multiple mechanisms.Both in vitro and in vivo studies have shown that resveratrol also inhibits proliferation, while stimulating apoptosis of cancer cells via several mechanisms. First, resveratrol induces apoptosis and phosphorylation of MAPK/ERK and MAPK/p38 in addition to increasing expression levels of caspase 3 and p53, while conversely, inhibition of p38 abolished its apoptotic effects. It appears that resveratrol-induced phosphorylation of p53 and apoptosis is mediated by c-Jun NH2-terminal kinases because knockdown of c-Jun NH2-terminal kinase genes prevented both phosphorylation of p53 and apoptosis induced by resveratrol. +erefore, resveratrol-induced activation of the MAPK/p38 signaling pathway likely accounts, at least in part, for its anticancer effects. Regarding antiproliferation of cancer cells, resveratrol inhibits expression of MEK1-P and ERK1/2-P, leading to reductions in cyclin D1 and cyclin-dependent kinase 6 expression, planting gutter resulting in cell cycle at rest. Moreover, resveratrol also decreased c-Jun levels and reduced DNA-binding and transcriptional activity of activator protein-1, which is required for initiation of DNA synthesis. Other studies showed that inhibition of NF-κB, cyclooxygenase 2, phosphatidylinositol-3-kinase, and P450 isoenzyme CYP1A1 and induction of caspases 3 and 9 also could contribute to anticancer effects of resveratrol. +us, resveratrol induced reductions in expression levels of MEK1-P and ERK1/2-P and decreased activator protein-1 activity could contribute to its inhibition of cancer cell proliferation.+e anti-inflammatory effects of resveratrol have been demonstrated in various in vivo and in vitro models, but the mechanisms of the actions of resveratrol are often unclear, depending on the inflammatory models employed in the studies. One possible mechanism is inhibition of NF-κB signaling pathways. Hence, degradation of phosphorylated IκB would increase NF-κB activity. Resveratrol-containing mixture inhibited IκB phosphorylation and decreased NF- κB, resulting in reductions in cytokine production in keratinocytes stimulated by TNF-α . Another study suggests that inhibition of cytokine production by resveratrol seems linked to upregulation of miR-17 expression in keratinocytes stimulated with lipopolysaccharide because inhibition of miR-17 overcame the inhibitory effects of resveratrol on inflammation. But one study showed that resveratrol increases IL-8 production in keratinocytes stimulated with a combination of TNF-α and IFNc via upregulation of aryl hydrocarbon receptor expression. Inhibition of allergic contact dermatitis by resveratrol could be attributable to the downregulation of interferon regulatory factor 1/ STAT1 signaling pathway and inhibition of phosphorylation of MAPK/p38 and/or phospholipase Cc. Moreover, resveratrol inhibited proliferation and differentiation of CD+ T cells and proliferation of +17 T cells via upregulation of phosphorylated MAPK and downregulation of phosphorylated mammalian target of rapamycin in Jurkat cells Furthermore, resveratrol-induced inhibition of TNF- α-induced cytokine production in fibroblasts is via activation of SIRT1 because knockdown of SIRT1 abolishes the inhibitory effect resveratrol on inflammation.+us, resveratrol can inhibit cutaneous inflammation via a variety of mechanisms, including inhibition of NF-κB, MAPK/p38, phospholipase Cc, and p-mTOR, upregulation of miR-17, and activation of SIRT1.Cutaneous wound healing is a complex process that can be accelerated by resveratrol via stimulation of neovascularization, keratinocyte differentiation, permeability barrier maturation, and antimicrobial activity. One study showed that resveratrol accelerates cutaneous wound healing and vascularization in aged rats through upregulation of SIRT1 and adenosine monophosphate-activated protein kinase pathway. +e role of SIRT1 signaling in vascularization has also been demonstrated in cutaneous wounds of diabetic mice. Topical applications of resveratrol to the wounded area of diabetic mice stimulated proliferation and inhibited apoptosis of endothelial cells, leading to accelerated wound healing, while either SIRT1 inhibitor or knockout of SIRT1 abolished the benefits of resveratrol in wound healing. SIRT1-mediated benefits of resveratrol in diabetic wound healing can also be attributable to protection of endothelial cells from oxidative stress. In addition, studies in mice indicate that resveratrol accelerates cutaneous wound healing by upregulation of vascular endothelial growth factor mediated by activation of at least two antioxidant enzymes. Because wound infections are the major cause of delayed wound healing, the antimicrobial properties of resveratrol could be another mechanism whereby wound healing is accelerated. Lastly, the ultimate goal of cutaneous wound healing is the formation of intact permeability barrier, which requires both lipid production and keratinocyte differentiation. +us, resveratrol could also accelerate cutaneous wound healing through its well-known ability to stimulate keratinocyte differentiation and lipid production. Collectively, the resveratrol-induced acceleration of cutaneous wound healing can be attributable to activation of SIRT1 and AMPK signaling, antioxidative stress, and enhanced formation of epidermal permeability barrier.+e mechanisms whereby resveratrol induces apoptosis and inhibition of fibroblasts include inhibition of hypoxia-inducible factor 1, in which activation stimulates fibroblast proliferation while inhibiting apoptosis, downregulation of transforming growth factor β1, miR-17, as well as expression levels of mRNA for collagen 1 and procollagen 3, whereas resveratrol induced upregulation of antimicrobial peptides is via enhancing expression of sphingosine-1-phosphate, leading to activation of N-FκB-C/EBPα signaling pathway. Resveratrol inhibits melanogenesis by at least four different mechanisms: in human melanocyte cultures, resveratrol inhibited tyrosinase synthesis and activity along with accelerated transport of newly synthesized tyrosinase to proteasomal complex, without dramatic alterations in mRNA levels of either melanocytic microphthalmia-associated transcription factor or tyrosinase; in melan-A cells, inhibition of melanogenesis by resveratrol is via induction of autophagy, leading to reduction in α melanocyte-stimulating hormone levels. +e latter stimulates melanin production and release via activation of melanocortin-1 receptor.