Protective role of the skin is against external insults and maintenance of electrolyte homeostasis of the body. Cutaneous dysfunction can account for the development of both cutaneous and systemic disorders. Thus, improvements in cutaneous functions can benefit a number of extracutaneous and cutaneous functions. Resveratrol, a natural ingredient, displays multiple benefits for various systems/organs, including the skin. The benefits of resveratrol for cutaneous functions include stimulation of keratinocyte differentiation and antimicrobial peptide expression, inhibition of keratinocyte proliferation and cutaneous inflammation, UV protection, anticancer, antiaging, and inhibition of melanogenesis. The mechanisms of action of resveratrol include activation of sirtuin 1 and nuclear factor erythroid 2-related factor 2, and inhibition of mitogen-activated protein kinase signaling. Evidence suggests that topical resveratrol could be a valuable alternative not only for daily skin care, but also for the prevention and treatment of various cutaneous disorders. This review summarizes the benefits of resveratrol for cutaneous functions.
In the traditional view, the skin serves as a protective barrier between the body and the external environment. Yet, more and more evidence suggests that cutaneous function extends far beyond mere protection. In fact, cutaneous function regulates a wide spectrum of cutaneous and systemic functions. Compromised epidermal function has been linked to the development of a variety of cutaneous and extracutaneous disorders. For example, disruption of epidermal permeability barrier not only provokes the release and production of proinflammatory cytokines [
Importantly, recent studies showed that the epidermal dysfunction-induced elevations in cutaneous cytokines lead to increased levels of proinflammatory cytokines not only in the skin, but also in circulation, supporting not only a pathogenic role for epidermal function in cutaneous and extracutaneous inflammation, but also suggesting a link between cutaneous function and inflammation-associated systemic disorders [
Because of the importance of cutaneous function, much recent attention has focused on the identification of active ingredients that could lead to the development of products that improve cutaneous function. In comparison with synthetic chemicals, natural ingredients are generally considered to be cheaper and more widely available, but still exhibit comparable benefits [
Resveratrol (3,5,4′-trihydroxy-
Structure of resveratrol.
Synthesis of resveratrol [
Biosynthesis of natural resveratrol.
Stilbene synthase is a key enzyme in the synthesis of resveratrol in the plants. Studies demonstrated that both expression levels of stilbene synthase and resveratrol content are regulated by a transcription factor, Myb14, which binds to Box L5 motif, leading to elevated stilbene synthase gene expression [
Infections of grapes can also change the expression of stilbene synthase mRNA. Dai et al. reported that incubation of cabernet sauvignon leaves with powdery mildew fungal spores for 24 hours significantly increased expression levels of stilbene synthase mRNA [
Among plants, resveratrol is most abundant in the skin of red grapes [
Other factors, such as cultivation sites and nitrogen availability, can also influence the resveratrol content in plants [
Variation of resveratrol content in plants is likely due to different environment/weather conditions [
The benefits of resveratrol for health have been demonstrated in multiple systems and/or organs, including cardiovascular system, diabetes, and immune as well as the neural system [
Benefits of resveratrol for cutaneous functions.
Models | Treatments | Benefits | Mechanisms | Ref. |
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Keratinocytes | Cells cultured with 0.25–100 |
↓Proliferation | ND | [ |
Cells cultured with 20 or 40 |
↓Proliferation | ↑SIRT1 | [ | |
Cells cultured with 50 |
↓Proliferation | ND | [ | |
Cells cultured with 25–100 |
↓Proliferation | ND | [ | |
Cells treated with 0.197 |
↓Proliferation | ND | [ | |
Cells cultured with 3 |
↓Differentiation | ↑SIRT1 | [ | |
Cells cultured with 100 |
↓Proliferation |
↓Protein kinase D | [ | |
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Keratinocytes | Immediately after irradiation with UVA (5 J/cm2), cells were treated with 0.01–0.1 mM resveratrol for 24 hr | ↑Cell viability |
↑SOD and GSH-Px expression | [ |
Either before or after irradiation with UVA (2.796 J/cm2), cells were treated with 2.5 and 5.0 mg/l resveratrol, respectively | ↑Cell viability |
↑NRF2 in nuclear translocation |
[ | |
Cells first treated with 10 |
↑Cell viability |
↑Activation of SIRT1 | [ | |
Cells first treated with 2% of resveratrol for 2 hr, followed by UVB irradiation (5–100 mJ/cm2) | ↑Cell viability | ND | [ | |
Cells treated with 5–25 |
↓NF- |
↑I |
[ | |
Cells treated with 5–10 |
↑Cell viability |
↑Nrf2 | [ | |
Cells treated with 50 |
↓IL-6, MCP-1, and TNF- |
↑ARH | [ | |
Cells treated with 25 or 100 |
↑ROS |
↑ERK activation |
[ | |
Cells first irradiated with 1 J/cm2 UVA +0.1 J/cm2 UVB, followed by treatment with 10 |
↓CYP1A1, CYP1B1, IL-1 |
↓Peroxide content | [ | |
Dermal fibroblasts | Immediately after UVB irradiation (144 mJ/cm2), fibroblasts were treated with 10 or 100 |
↑Cell viability |
ND | [ |
Reconstructed human skin | Reconstructed human skin was treated with 1% of resveratrol-enriched rice extract for 24 hr, followed by irradiation with UVB (100 mJ/cm2) | ↓MMP1 |
ND | [ |
Mice | Mice were treated topically with 25 |
↓Ear weight and edema |
ND | [ |
Mice were treated topically with 10 |
↑Cell proliferation |
↓Survivin | [ | |
Mice were treated topically with 0.48% resveratrol 20 min prior to irradiation with 360 mJ/cm2 UVB | ↓Skin edema in mice treated with resveratrol either before or after UVB irradiation |
↑NRF2 | [ | |
Mice were treated topically with 0.48% resveratrol 20 min prior to irradiation with 180 mJ/cm2 UVB, 3 irradiation/week for a total of 30 weeks | ↓Lipid, DNA, and protein peroxidation |
[ | ||
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Keratinocytes | Cells cultured with 20 and 60 |
↑GST activity | ↑NRF2 expression and activation | [ |
Cells pretreated with 10 or 20 |
↑NQO1 and GSH-Px mRNA |
↑NRF2 activation | [ | |
Cells treated with both 0.3–3 mM sodium nitroprusside and 1–30 |
↑Cell viability |
↓IL-8, NOS3, and NADPH dehydrogenase mRNA |
[ | |
Cells pretreated with 25 or 100 |
↓ROS | ND | [ | |
Cells pretreated with 140 |
↓DNA damage and HSP70 expression | ND | [ | |
Cells treated with 10 |
↓ROS |
ND | [ | |
Cells pretreated with 0.5–10 |
↑Scavenger receptor class B type I protein and mRNA |
ND | [ | |
Cells pretreated with 10 |
↓ROS and carbonyl groups | ↑Methionine sulfoxide reductase A mRNA |
[ | |
Cells pretreated with 0.5 |
↓Arsenic-induced increase in metabolic activity and expression of DNA polymerase beta |
ND | [ | |
Reconstructed human skin | Keratinocytes were pretreated with 20 or 100 |
↑GSH expression |
↑NRF2 activation | [ |
Mice | Mice were treated topically with 16 |
↑GST activity and content | ↑NRF2 activation | [ |
Mice were treated topically with 8 or 16 |
↑Glucuronosyltransferase and NADPH:quinone oxidoreductase activity | ND | [ | |
Humans | Stratum corneum was collected with tape strip 24 hr after single application of resveratrol at a dose of 537 |
↓Production of free radical | ND | [ |
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Melanoma cell line | Cells were treated with 20–40 |
↓Proliferation |
↑Cells in S phase arrest |
[ |
A431 human skin carcinoma cells | A431 cells were treated with 20–100 mg/L resveratrol for 24 hr | ↑Apoptosis |
↑Activation of MAPK pathway | [ |
A431 cells were treated with 20, 50, and 100 |
↓DNA synthesis and proliferation |
↓DNA-binding activity of AP-1 |
[ | |
Human squamous cell carcinoma cell lines | HSC2 cells were treated with both resveratrol and benzoxazinotropone at various concentrations for 48 hr | Resveratrol and benzoxazinotropone synergistically inhibited proliferation | ND | [ |
Head and neck squamous cell carcinoma cells | Head and neck squamous cell carcinoma cells were treated with 15 and 50 |
↓Proliferation |
↑H2AX ser-139 phosphorylation | [ |
Mice | Mice with squamous cell tumor graft were gavaged orally with 10 and 50 mg/kg body weight of resveratrol for 30 days | ↓Tumor weight and volume per mouse | ||
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Keratinocytes | Cells treated with 20 ng/ml TNF- |
↓IL-6 and MCP-1 | ↓Phosphorylation of I |
[ |
Cells treated with 7.5 |
↑Proliferation |
↑miR-17 expression | [ | |
Cells treated with 50 |
↓IL-6, IL-8, MCP-1, and COX2 mRNA | ↓EGFR-ERK signaling pathway | [ | |
Cells pretreated with 25 and 50 |
↓CCL2 and CXCL10 mRNA and protein | ↓Interferon regulatory factor 1 and phosphorylated STAT1 | [ | |
Cells pretreated with 50 |
↓IL-6 | ND | [ | |
Cells pretreated with 44 |
↓IL-6, IL-8, and TNF- |
ND | [ | |
Mast cells | RBL-2H3 mast cells were pretreated with 1–25 |
↓IL-3, IL-4, IL-13, and TNF- |
↓P38-MAPK, ERK1/2, JNK | [ |
Reconstructed human skin | 3D skin was treated 10 ng/ml IFN- |
↓IL-6 | ND | [ |
Mice | BALB/c mouse ears were treated topically with 10 mM resveratrol 2 hr prior to DNFB challenge | ↓Ear thickness |
↓Interferon regulatory factor 1 and phosphorylated STAT1 | [ |
Following induction of allergic contact dermatitis, NC/Nga mice were treated topically with 2.5% resveratrol or resveratrol-enriched rice extract twice weekly for 5 weeks | ↓Epidermal thickness |
ND | [ | |
BALB/c mice were orally treated with resveratrol at a dose of 10 mg/kg body weight 1 hr prior to intravenous challenge with 200 |
↓IL-4 and TNF- |
↓Tyk2-STAT1 activation | [ | |
Atopic dermatitis-like lesions were induced by topical applications of DNFB to the back of BALB/c mice for 5 weeks, followed by orally given resveratrol at a daily dose of 30 mg/kg body weight for 1 week | ↓Dermatitis scores |
ND | [ | |
Atopic dermatitis-like lesions were induced by topical applications of dermatophagoides farinae to the back of NC/Nga mice for 2 weeks, followed by orally given resveratrol at a daily dose of 20 mg/kg body weight for 2 weeks | ↓Dermatitis scores |
↓High mobility group box 1 expression | [ | |
Psoriasis-like skin lesions were induced by topical applications of imiquimod to the back of BALB/c mice, which were orally given resveratrol at a daily dose of 400 mg/kg body weight, for 7 days. | ↓Erythema and scale scores |
ND | [ | |
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Rats | Rats were fed with resveratrol at a daily dose of 0.5 mg/kg body weight 7 days prior to operation and continued throughout the whole experiment period | ↑Collagen deposition |
ND | [ |
Following induction of full-thickness skin wound, wound was treated topically with 225 |
↑Epithelialization |
↑AMPK pathway and SIRT1 | [ | |
Mice | Immediately after wound, a wound dressing containing 0.04% resveratrol was applied to full-thickness skin wound for 10 days | ↓Wound size |
ND | [ |
Placing scaffolds containing 5% resveratrol on the wound for 7 days | ↓Wound size | ↑Expression of thioredoxin-1, heme oxygenase-1, and VEGF | [ | |
Diabetic models | 0.5% resveratrol ointment was applied to wound area in diabetic rats once daily for 21 days | ↓Wound size | ↑Activity of antioxidant enzymes | [ |
10 |
↓Wound size |
Sirt1 activation | [ | |
Fourteen days after topical application of resveratrol (0.1 mg/ml) to wound area in diabetic rats once, wound healing was assessed | No benefit | [ |
Abbreviations: ND, not determined; AQP3, aquaporin 3; SOD, superoxide dismutase; MDA, malondialdehyde; GSH-Px, glutathione peroxidase; GST, glutathione S-transferase; GSH, reduced glutathione; NQO, NAD(P)H:quinone oxidoreductase; ROS: reactive oxygen species; CYP1A1, cytochrome P540 family 1 subfamily A member 1; IKK
Both keratinocyte proliferation and differentiation are required for the epidermis to reach its ultimate goal of the formation of the stratum corneum, an essential structure for epidermal permeability barrier. Several studies have demonstrated that resveratrol inhibits keratinocyte proliferation while stimulating differentiation. Resveratrol at a concentration as low as 2
The activities of keratinocyte proliferation and differentiation are coordinated in an inverse manner, while terminal differentiation is crucial for the formation of permeability barrier. In contrast to proliferation, resveratrol stimulates keratinocyte differentiation. For example, treatment of keratinocytes with 3
While suberythemogenic doses of UVB irradiation instead enhance epidermal function, including improvements in epidermal permeability barrier function, stimulation of epidermal lipid synthesis and keratinocyte differentiation, and antimicrobial defense [
The protective effects of resveratrol against UV irradiation have also been demonstrated
A number of factors, including psychological stress, cigarette smoke, air pollution, and UV irradiation, can cause oxidative stress, contributing to the development of aging and a line of disorders such as dermatoses, inflammation, cardiovascular diseases, cancer, and neurodegenerative diseases [
The skin, an interface between the body and external environment, is vulnerable to environmental insults, including oxidative stress, leading to acceleration of skin aging and the development of a variety of skin disorders [
Oxidative stress has been considered as a major contributor to the development of skin cancers, such as melanoma [
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 [
Although there is still little or no evidence that resveratrol can inhibit cutaneous inflammation in humans, anti-inflammatory 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 density of CD3+ cells by≈90% in parallel with significant reduction of ear thickness and expression levels of intercellular adhesion molecule 1 (ICAM-1), C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 2 (CCL2), and IFN-
Psoriasis is another common, inflammatory skin disorder. Kjaer et al. showed that oral administrations of
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 [
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
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 [
Other studies suggest that resveratrol exhibits antimicrobial properties. Cathelicidin antimicrobial peptides (CAMP) 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 [
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 (Nrf2), activation of sirtuin 1 (SIRT1), and mitogen-activated protein kinase (MAPK) signaling pathway, depending on which function is regulated. The major putative mechanisms by which resveratrol regulates cutaneous function are illustrated in Figure
Schematic diagram of the mechanisms by which resveratrol regulates cutaneous functions.
Keratinocyte proliferation and differentiation, which are inversely regulated, are both required to form the
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. This 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 inflammation [
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 [
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 NF
Both
The anti-inflammatory effects of resveratrol have been demonstrated in various
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 (AMPK) pathway [
The 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 [
Resveratrol inhibits melanogenesis by at least four different mechanisms: (1) 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 (MIFT) or tyrosinase [
Both
All authors declare no conflicts of interest.
MQM originated the concept and drafted the manuscript; SW and JZ performed literature search, drafted the manuscript, and contributed equally to this work; BY and PME critically reviewed the manuscript. All authors approved the final version.
This work was supported, in part, by the NIH grant AR061106, administered by the Northern California Institute for Research and Education, with resources from the Research Service, Department of Veterans Affairs.
Supplemental Table 1: content of resveratrol in some plants and foods/beverages.