Evidence-Based Complementary and Alternative Medicine

Review Article

Role of Resveratrol in Regulating Cutaneous Functions

Table 1

Benefits of resveratrol for cutaneous functions.


Models	Treatments	Benefits	Mechanisms	Ref.

Keratinocyte proliferation/differentiation
Keratinocytes	Cells cultured with 0.25–100 μM resveratrol for 24–72 hr	↓Proliferation	ND	[77]
	Cells cultured with 20 or 40 μM resveratrol for 24 hr	↓Proliferation	↑SIRT1	[78]
	Cells cultured with 50 μM resveratrol for 12 hr	↓Proliferation	ND	[79]
	Cells cultured with 25–100 μM resveratrol for 24 hr	↓Proliferation	ND	[80, 81]
	Cells treated with 0.197 μM resveratrol for 2 weeks	↓Proliferation	ND	[82]
	Cells cultured with 3 μM resveratrol until 3 days postconfluence	↓Differentiation	↑SIRT1	[83]
	Cells cultured with 100 μM resveratrol for 24 hr	↓Proliferation ↓Differentiation	↓Protein kinase D	[84]

Anti-UV irradiation
Keratinocytes	Immediately after irradiation with UVA (5 J/cm²), cells were treated with 0.01–0.1 mM resveratrol for 24 hr	↑Cell viability ↓MDA content	↑SOD and GSH-Px expression	[85]
	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 ↑SOD and GST	↑NRF2 in nuclear translocation ↓Keap1	[86]
	Cells first treated with 10 μM resveratrol for 1 hr, followed by UVB irradiation (30 mJ/cm²)	↑Cell viability ↓Apoptosis	↑Activation of SIRT1	[87]
	Cells first treated with 2% of resveratrol for 2 hr, followed by UVB irradiation (5–100 mJ/cm²)	↑Cell viability	ND	[88]
	Cells treated with 5–25 μM resveratrol for 24 hr, followed by irradiation with UVB (40 mJ/cm²)	↓NF-κB content and activity	↑IκBα ↓IKKα	[89]
	Cells treated with 5–10 μM pterostilbene, analog of resveratrol, for 24 hr, followed by irradiation with UVB (30 mJ/cm²).	↑Cell viability ↓ROS ↓DNA damage	↑Nrf2	[90]
	Cells treated with 50 μM resveratrol 30 min prior to irradiation with 1 J/cm² UVA +0.1 J/cm² UVB	↓IL-6, MCP-1, and TNF-α mRNA	↑ARH	[91]
	Cells treated with 25 or 100 μM resveratrol for 2 or 24 hr, followed by irradiation with UVB (10, 20, 40, or 100 mJ/cm²)	↑ROS ↓Autophagy	↑ERK activation ↑Bax/Bcl2 ratio	[92]
	Cells first irradiated with 1 J/cm² UVA +0.1 J/cm² UVB, followed by treatment with 10 μM resveratrol.	↓CYP1A1, CYP1B1, IL-1β, IL-6, and COX2 mRNA levels	↓Peroxide content	[93]
Dermal fibroblasts	Immediately after UVB irradiation (144 mJ/cm²), fibroblasts were treated with 10 or 100 μg/L of resveratrol-enriched rice extract at various concentrations for 24–72 hr	↑Cell viability ↓ROS ↓MMP1, p53, Bax, TNF-α, IL-6, iNOS, and COX2 ↑PIP1 and TGF-β protein	ND	[94]
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 ↑PIP1, type I procollagen, and collagen fibers	ND	[94]
Mice	Mice were treated topically with 25 μM resveratrol in 200 μl acetone 30 min prior to irradiation with 180 mJ/cm² UVB	↓Ear weight and edema ↓Inflammatory infiltrate ↓ODC activity and COX2 activity ↓Lipid peroxidation	ND	[95]
	Mice were treated topically with 10 μM resveratrol in 200 μl acetone 30 min prior to irradiation with 180 mJ/cm² UVB	↑Cell proliferation ↓COX2 and ODC expression	↓Survivin	[96]
	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 ↓Epidermal thickness in mice treated with resveratrol before UVB irradiation	↑NRF2	[97]
	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 ↑Activity and expression of antioxidant enzymes		[97]

Antioxidant defense
Keratinocytes	Cells cultured with 20 and 60 μM resveratrol for 24 hr	↑GST activity	↑NRF2 expression and activation	[98]
	Cells pretreated with 10 or 20 μM resveratrol for 16 hr	↑NQO1 and GSH-Px mRNA ↑GSH protein synthesis	↑NRF2 activation	[99]
	Cells treated with both 0.3–3 mM sodium nitroprusside and 1–30 μM resveratrol for 24 hr	↑Cell viability ↓Caspase 3 and 9 activity	↓IL-8, NOS3, and NADPH dehydrogenase mRNA ↑GSH-Px mRNA	[100]
	Cells pretreated with 25 or 100 μM resveratrol 24 hr prior to addition of 200, 400, or 800 μM H₂O₂ and cells were harvested 48 hr postaddition of H₂O₂	↓ROS	ND	[92]
	Cells pretreated with 140 μM resveratrol for 1 h, then 500 μM H₂O₂ was added, and incubated for additional 2–16 h	↓DNA damage and HSP70 expression	ND	[101]
	Cells treated with 10 μM resveratrol for 24 hr, and then 100 μM H₂O₂ was added and incubated for additional 30 min	↓ROS ↓MDA	ND	[102]
	Cells pretreated with 0.5–10 μM resveratrol for 24 hr, followed by removal of media, and then exposed to cigarette smoking for 50 min	↑Scavenger receptor class B type I protein and mRNA ↓4-Hydroxynonenal adducts	ND	[103]
	Cells pretreated with 10 μM resveratrol for 24 hr, followed by removal of media, and then exposed to cigarette smoking for 50 min	↓ROS and carbonyl groups	↑Methionine sulfoxide reductase A mRNA ↓Transient receptor potential cation channel subfamily A member 1 mRNA and protein	[104]
	Cells pretreated with 0.5 μM resveratrol for 3 hr, followed by addition of 0.1–20 μM arsenic and incubation for additional 20 hr	↓Arsenic-induced increase in metabolic activity and expression of DNA polymerase beta ↑Arsenic-induced reduction in Y419 phosphorylation and Src protein	ND	[105]
Reconstructed human skin	Keratinocytes were pretreated with 20 or 100 μM resveratrol for 16 hr, followed by removal of media, and then exposed to 800 μM cumen hydroperoxide for 8 hr	↑GSH expression ↓Apoptosis	↑NRF2 activation	[99]
Mice	Mice were treated topically with 16 μM resveratrol, and four hours later, skin samples were collected	↑GST activity and content	↑NRF2 activation	[98]
Mice	Mice were treated topically with 8 or 16 μM resveratrol, and twenty-four hours later, skin samples were collected	↑Glucuronosyltransferase and NADPH:quinone oxidoreductase activity	ND	[106]
Humans	Stratum corneum was collected with tape strip 24 hr after single application of resveratrol at a dose of 537 μg/cm² on the ventral forearm	↓Production of free radical	ND	[107]

Anticancer
Melanoma cell line	Cells were treated with 20–40 μg/ml resveratrol for up to 5 days	↓Proliferation ↓Apoptosis and necrosis	↑Cells in S phase arrest ↓Cells in G1 and G₂/M phase	[108]
A431 human skin carcinoma cells	A431 cells were treated with 20–100 mg/L resveratrol for 24 hr	↑Apoptosis ↓Proliferation	↑Activation of MAPK pathway	[81]
A431 human skin carcinoma cells	A431 cells were treated with 20, 50, and 100 μM resveratrol for up to 72 hr	↓DNA synthesis and proliferation ↓Cells in G₂/M phase ↓Cell cycle regulatory proteins	↓DNA-binding activity of AP-1 ↓ERK1/2 signaling pathway	[109]
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	[110]
Head and neck squamous cell carcinoma cells	Head and neck squamous cell carcinoma cells were treated with 15 and 50 μM resveratrol for up to 72 hr	↓Proliferation ↑Apoptosis	↑H2AX ser-139 phosphorylation	[111]
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

Anti-inflammation
Keratinocytes	Cells treated with 20 ng/ml TNF-α for 6 hr 10 μM, followed by incubation with resveratrol for additional 16 hr	↓IL-6 and MCP-1	↓Phosphorylation of IκBα	[102]
	Cells treated with 7.5 μg/mL lipopolysaccharide for 12 hr, followed by incubation with 10–50 μM resveratrol for additional 12 hr	↑Proliferation ↑Apoptosis ↓IL-6, IL-8, and TNF-α mRNA and protein	↑miR-17 expression	[112]
	Cells treated with 50 μM resveratrol 1 hr prior to addition of 2.5 μg/mL lipopolysaccharide	↓IL-6, IL-8, MCP-1, and COX2 mRNA	↓EGFR-ERK signaling pathway	[91]
	Cells pretreated with 25 and 50 μM resveratrol for 30 min, followed by incubation with 25 μg/ml cetuximab or 2 μM gefitinib for additional 3 hr	↓CCL2 and CXCL10 mRNA and protein	↓Interferon regulatory factor 1 and phosphorylated STAT1	[113]
	Cells pretreated with 50 μM resveratrol for 1 hr, followed by incubation with for 10 ng/ml IFN-γ and TNF-α 24 hr	↓IL-6	ND	[114]
	Cells pretreated with 44 μM resveratrol for 24 hr, followed by exposure to heat stress for 40 min	↓IL-6, IL-8, and TNF-α	ND	[115]
Mast cells	RBL-2H3 mast cells were pretreated with 1–25 μM resveratrol for 2 hr, followed by exposure to 200 ng/ml dinitrophenyl-human serum albumin	↓IL-3, IL-4, IL-13, and TNF-α ↓Fc epsilon receptor I expression	↓P38-MAPK, ERK1/2, JNK	[116]
Reconstructed human skin	3D skin was treated 10 ng/ml IFN-γ and TNF-α twice a week, followed by treatment with 1% resveratrol thrice weekly for 2 weeks	↓IL-6	ND	[114]
Mice	BALB/c mouse ears were treated topically with 10 mM resveratrol 2 hr prior to DNFB challenge	↓Ear thickness ↓CD3-positive cells ↓ICAM-1, CCL2, and CXCL10 expression	↓Interferon regulatory factor 1 and phosphorylated STAT1	[113]
	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 ↓Dermatitis score ↓Serum IgE ↓TEWL ↑Skin hydration	ND	[114]
	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 μg dinitrophenyl-human serum albumin	↓IL-4 and TNF-α ↓CD11b-positive cells	↓Tyk2-STAT1 activation	[116]
	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 ↓Epidermal thickness ↓Cytokine mRNA	ND	[117]
	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 ↓Cytokine mRNA and protein	↓High mobility group box 1 expression	[118]
	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 ↓Skin thickness ↓Cytokine mRNA	ND	[119]

Accelerating wound healing
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 ↑Neovascularization ↑Fibroblast maturation	ND	[120]
Rats	Following induction of full-thickness skin wound, wound was treated topically with 225 μL of 50 μM once daily for 17 days	↑Epithelialization ↓Wound size ↑Collagen deposition ↑Vascularization	↑AMPK pathway and SIRT1	[121]
Mice	Immediately after wound, a wound dressing containing 0.04% resveratrol was applied to full-thickness skin wound for 10 days	↓Wound size ↑Collagen fibers ↓Inflammation	ND	[122]
Mice	Placing scaffolds containing 5% resveratrol on the wound for 7 days	↓Wound size	↑Expression of thioredoxin-1, heme oxygenase-1, and VEGF	[123]
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	[124]
	10 μM resveratrol was applied to the cutaneous wound area in diabetic mice, and wound healing was assessed 7 days later	↓Wound size ↑Endothelial cell proliferation	Sirt1 activation	[125]
	Fourteen days after topical application of resveratrol (0.1 mg/ml) to wound area in diabetic rats once, wound healing was assessed	No benefit		[126]

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; IKKα, ΙκB kinase α; CYP1B1, cytochrome P540 family 1 subfamily B member 1; COX, cyclooxygenase; ODC, ornithine decarboxylase; NRF2, nuclear factor erythroid 2-related factor 2; ERK: extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; TPA, 12-O-tetradecanoyl13-phorbol acetate; DNFB, 2,4-dinitro-1-fluorobenzene; NOS, nitric oxide synthase; VEGF, vascular endothelial growth factor; AMPK, adenosine monophosphate‐activated protein kinase.