11. Pharm Res. 2009 Jan;26(1):211-7. Epub 2008 Sep 13.  Chemopreventive potential of resveratrol in mouse skin tumors through regulation  of mitochondrial and PI3K/AKT signaling pathways.  Roy P, Kalra N, Prasad S, George J, Shukla Y.  Proteomics Laboratory, Indian Institute of Toxicology Research, (Council of Scientific & Industrial Research, India), P.O. Box 80, M.G. Marg, Lucknow, 226001, India. 

 PURPOSE: To investigate the chemopreventive potential of resveratrol, a phytoalexin found in seeds and skin of grapes, berries and peanuts in 7,12 dimethyl benz(a)anthracene (DMBA) induced mouse skin tumorigenesis. METHODS: Topical treatment of resveratrol was given to the animals 1 h prior to DMBA for 28 weeks. At the end of the study period, the skin tumors were dissected out and western blotting was carried out to examine the regulation of proteins involved in anti-tumorigenesis in response to resveratrol. RESULTS: Chemopreventive properties of resveratrol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Results of the western blotting showed that resveratrol treatment increased the DMBA suppressed p53 and Bax while decreased the expression of Bcl-2 and Survivin. Further, resveratrol supplementation resulted in release of cytochrome C, caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction. Resveratrol was also found to inhibit skin tumorigenesis through regulation of Phosphatidylinositol-3-kinase (PI3K)/ and AKT proteins which are implicated in cancer progression because it stimulates proliferation and suppresses apoptosis. CONCLUSIONS: Based on the results we can conclude that resveratrol regulates apoptosis and cell survival in mouse skin tumors as mechanism of chemoprevention  hence deserve to be a chemopreventive agent.  PMID: 18791811  [PubMed - indexed for MEDLINE] 

10. Biol Pharm Bull. 2008 May;31(5):955-62.  Delivery of resveratrol, a red wine polyphenol, from solutions and hydrogels via  the skin.  Hung CF, Lin YK, Huang ZR, Fang JY.  School of Medicine, Fu Jen Catholic University, Taipei County 242, Taiwan. 

 Resveratrol, the main active polyphenol in red wine, has been demonstrated to show benefits against skin disorders. The bioavailability of orally administered  resveratrol is insufficient to permit high enough drug concentrations for systemic therapy. In this study, we examined the feasibility of the topical/transdermal delivery of resveratrol. The effects of vehicles on the in vitro permeation and skin deposition from saturated solutions such as aqueous buffers and soybean oil were investigated. The general trend for the delivery from solutions was: pH 6 buffer=pH 8 buffer>10% glycerol formal in pH 6 buffer>pH 9.9 buffer>pH 10.8 buffer>soybean oil. A linear relationship was established between the permeability coefficient (K(p)) and drug accumulation in the skin reservoir. Viable epidermis/dermis served as the predominant barrier for non-ionic resveratrol permeation. On the other hand, both the stratum corneum (SC) and viable skin acted as barriers to anionic resveratrol. Several prototype  hydrogel systems were also studied as resveratrol vehicles. The viscosity but not the polarity of the hydrogels controlled resveratrol permeation/deposition. Piceatannol, a derivative of resveratrol with high pharmacological activity, showed 11.6-fold lower skin permeation compared to resveratrol. The safety profiles of resveratrol suggested that the hydrogel caused no SC disruption or skin erythema. It was concluded that delivery via a skin route may be a potent way to achieve the therapeutic effects of resveratrol. This is the first report to establish the permeation profiles for topically applied resveratrol.  PMID: 18451526  [PubMed - indexed for MEDLINE] 

9. J Inflamm (Lond). 2008 Feb 8;5:1.  Topical anti-inflammatory activity of Polygonum cuspidatum extract in the TPA model of mouse ear inflammation.  Bralley EE, Greenspan P, Hargrove JL, Wicker L, Hartle DK.  Department of Food and Nutrition, Nutraceutical Research Laboratories, University of Georgia, Athens, GA, USA. jhargrov@fcs.uga.edu. 

 BACKGROUND: This study tested the ability of a characterized extract of Polygonum cuspidatum (PCE) to inhibit mouse ear inflammation in response to topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA). METHODS: A 50% (wt:vol) ethanolic solution of commercial 200:1 PCE was applied to both ears of female Swiss mice (n = 8) at 0.075, 0.15, 0.3, 1.25 and 2.5 mg/ear 30 min after TPA administration (2 mug/ear). For comparison, 3 other groups were  treated with TPA and either 1) the vehicle (50% ethanol) alone, 2) indomethacin (0.5 mg/ear), or 3) trans-resveratrol (0.62 mg/ear). Ear thickness was measured before TPA and at 4 and 24 h post-TPA administration to assess ear edema. Ear punch biopsies were collected at 24 h and weighed as a second index of edema. Myeloperoxidase activity was measured in each ear punch biopsy to assess neutrophil infiltration. RESULTS: PCE treatment at all doses significantly reduced ear edema compared to the TPA control. The PCE response was dose-dependent and 2.5 mg PCE significantly inhibited all markers of inflammation to a greater extent than indomethacin (0.5  mg). MPO activity was inhibited at PCE doses >/= 1.25 mg/ear. Trans-resveratrol inhibited inflammation at comparable doses. CONCLUSION: PCE inhibits development of edema and neutrophil infiltration in the  TPA-treated mouse ear model of topical inflammation.  PMCID: PMC2267461 PMID: 18261214  [PubMed] 

8. Biochem Pharmacol. 2006 Nov 30;72(11):1506-15. Epub 2006 Sep 26.  Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction  pathways in mouse skin in vivo: NF-kappaB and AP-1 as prime targets.  Kundu JK, Shin YK, Surh YJ.  National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-9-dong, Kwanak-gu, Seoul  151-742, South Korea. 

 Functional abnormalities of intracellular signaling network cause the disruption  in homeostasis maintained by critical cellular components, thereby accelerating premalignant and malignant transformation. Multiple lines of evidence suggest that an elevated expression of cyclooxygenase-2 (COX-2) is causally linked to tumorigenesis. The exposure to oxidative/pro-inflammatory stimuli turns on signaling arrays mediated by diverse classes of kinases and transcription factors, which may lead to aberrant expression of COX-2. We have attempted to unravel the signal transduction pathways involved in elevated COX-2 expression in mouse skin stimulated with a prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and its modulation by resveratrol, a phytoalexin known to exert potential chemopreventive effects. Our study revealed  that topical application of TPA induced COX-2 expression in mouse skin via activation of nuclear factor-kappaB (NF-kappaB), which is regulated by upstream IkappaB kinase (IKK) or differentially by mitogen-activated protein (MAP) kinases. Besides NF-kappaB, the p38 MAP kinase-mediated activation of activator protein-1 (AP-1) has also been attributed to TPA-induced COX-2 expression in mouse skin. Among the MAP kinases, extracellular signal-regulated protein kinase  (ERK) and p38 MAP kinase have been shown to regulate TPA-induced NF-kappaB activation, while p38 MAP kinase and c-Jun-N-terminal kinase are preferentially involved in TPA-induced activation of AP-1 in mouse skin in vivo. This commentary focuses on resveratrol modulation of intracellular signaling pathways involved in aberrant COX-2 expression in TPA-stimulated mouse skin to delineate molecular mechanisms underlying antitumor promoting effects of resveratrol.  PMID: 16999939  [PubMed - indexed for MEDLINE] 

7. Med Chem. 2005 Nov;1(6):629-33.  Resveratrol enhances UVA-induced DNA damage in HaCaT human keratinocytes.  Seve M, Chimienti F, Devergnas S, Aouffen M, Douki T, Chantegrel J, Cadet J, Favier A.  Laboratoire des Lésions des Acides Nucléiques, DRFMC/SCIB, CEA/Grenoble, Grenoble, France. seve@drfmc.ceng.cea.fr 

 Resveratrol, a polyphenolic phytoalexin, is a very effective antioxidant that also exhibits strong antiproliferative and anti-inflammatory properties. Recent studies have provided support for the use of resveratrol in human cancer chemoprevention, in combination with either chemotherapeutic drugs or cytotoxic factors for a most efficient treatment of drug refractory tumor cells. Resveratrol is also widely used in topical preparations, as a chemoprotective compound against development of several cutaneous disorders, including skin cancer. Nevertheless, the combined effect of resveratrol and UVA irradiation on cellular toxicity and DNA damage has never been assessed. The aim of this work was to investigate the effect of resveratrol on cell fate in immortalized human keratinocytes HaCaT cells. The results indicated that resveratrol potentiates the production of significant amounts of 8-oxo-7,8-dihydro-2'-deoxyguanosine in UVA-irradiated genomic DNA. Moreover, the combination of resveratrol with UVA significantly enhances the induction of DNA strand breaks and cell death in HaCaT keratinocytes. The conclusion is a potential hazardous effect of topical application of resveratrol, particularly on regions exposed to sunlight.  PMID: 16787346  [PubMed - indexed for MEDLINE]  

6. Oncogene. 2004 Jul 1;23(30):5151-60.  Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B-mediated responses by resveratrol in SKH-1 hairless mouse skin.  Reagan-Shaw S, Afaq F, Aziz MH, Ahmad N.  Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. 

 Multiple exposures to solar ultraviolet (UV) radiation cause critical damages that may lead to the development of several cutaneous disorders including skin cancer, the most frequently diagnosed malignancy in the USA. Therefore, efforts are needed to: (i) study the mechanism(s) of UV-mediated cutaneous damages, and (ii) design novel approaches for the management of skin cancer. 'Chemoprevention' via plant-based agents may be a useful approach for the management of neoplasia.  Here, we evaluated the involvement of cell cycle regulatory molecules during resveratrol-mediated protection from multiple exposures of UVB (180 mJ/cm(2); on  alternate days x 7 exposures) radiations in the SKH-1 hairless mouse skin. Resveratrol was topically applied on the skin of SKH-1 hairless mice at a dose of 10 micromol/mouse (in 0.2 ml acetone; 30 min prior to each UVB exposure). Studies were performed at 24 h following the last UVB exposure. Topical application of resveratrol resulted in significant decrease in UVB-induced bi-fold skin thickness, hyperplasia, and infiltration of leukocytes. The data from immunoblot  and/or immunohistochemical analyses revealed that multiple exposure to UVB radiations causes significant upregulation in: (i) proliferating cell nuclear antigen (PCNA), a marker of cellular proliferation, and (ii) cyclin-dependent kinase (cdk)-2, -4 and -6, cyclin-D1, and cyclin-D2. Resveratrol treatment resulted in significant downregulation in UV-mediated increases in these critical cell cycle regulatory proteins. An interesting observation of this study was that resveratrol treatment resulted in a further stimulation of UVB-mediated increases in cyclin kinase inhibitor WAF1/p21 and tumor suppressor p53. Further, resveratrol was also found to cause significant decreases in UVB-mediated upregulation of: (i) the mitogen-activated protein kinase kinase, and (ii) the 42 kDa isotype of mitogen-activated protein kinase (MAPK). Thus, our data suggested  that the antiproliferative effects of resveratrol might be mediated via modulation in the expression and function of cell cycle regulatory proteins cyclin-D1 and -D2, cdk-2, -4 and -6, and WAF1/p21. Our data further suggest that  the modulation of cki-cyclin-cdk network by resveratrol may be associated with inhibition of the MAPK pathway. We suggest that resveratrol may be useful for the prevention of UVB-mediated cutaneous damages including skin cancer.  PMID: 15122319  [PubMed - indexed for MEDLINE]  

5. Antiviral Res. 2004 Jan;61(1):19-26.  Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice.  Docherty JJ, Smith JS, Fu MM, Stoner T, Booth T.  Department of Microbiology/Immunology, Northeastern Ohio Universities, College of Medicine, PO Box 95, State Route 44, Rootstown, OH 44272, USA. jjd@neoucom.edu 

 Resveratrol (3,5,4'-trihydroxystilbene) is a natural component of certain foods,  such as grapes, that has been shown to have anti-herpes simplex virus (HSV) activity in vitro. To determine if it is active in vivo, the abraded epidermis of SKH1 mice were infected with HSV-1 and topically treated with 12.5 or 25% resveratrol cream or cream only. Initial studies demonstrated that: (1). 25% resveratrol cream topically applied two, three, or five times a day effectively suppressed lesion development whereas 12.5% resveratrol cream effectively suppressed lesion formation when applied five times a day starting 1h after infection; (2). when treatment was begun 1, 6, or 12h after infection, both 12.5  and 25% resveratrol were effective at 1 and 6h after infection, but not if applied 12h after infection. Comparative studies between resveratrol cream, 10% docosanol cream (Abreva) and 5% acyclovir ointment (Zovirax) were also carried out. When treatment was begun 1h after infection and repeated every 3h five times a day for 5 days, 12.5 and 25% resveratrol significantly (P=0.0001) inhibited the development of HSV-1 induced skin lesions. Acyclovir was as effective (P=0.0001)  as resveratrol. Animals that were topically treated with docosanol were not protected and developed lesions in a manner indistinguishable from cream only controls. These studies were repeated with an HSV-1 acyclovir-resistant virus. As before, 12.5 and 25% resveratrol cream effectively suppressed lesion formation. The skin of resveratrol-treated animals showed no apparent dermal toxicity such as erythema, scaling, crusting, lichenification, or excoriation. These studies demonstrate that topically applied resveratrol inhibits HSV lesion formation in the skin of mice.  PMID: 14670590  [PubMed - indexed for MEDLINE]  

4. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):28-37.  Prevention of short-term ultraviolet B radiation-mediated damages by resveratrol  in SKH-1 hairless mice.  Afaq F, Adhami VM, Ahmad N.  Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.  

Nonmelanoma skin cancer is the most common cancer among humans and solar UV radiation, particularly its UVB component (290-320 nm), is its major cause. One way to reduce the occurrence of the cancer is via the use of substances (often antioxidants) termed "photochemopreventive agents". Resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin found in grapes, nuts, fruits, and red wine, is a potent antioxidant with strong anti-inflammatory and antiproliferative properties. This study was designed to examine whether resveratrol possesses the potential to ameliorate the damages caused by short-term UVB exposure to mouse skin. Single topical application of resveratrol  (25 micromol/0.2 ml acetone per mouse) to SKH-1 hairless mice was found to result in significant inhibition of UVB (180 mJ/cm(2))-mediated increase in bifold skin  thickness and skin edema. The resveratrol treatment to mouse skin was also found  to result in significant inhibition of UVB-mediated induction of cyclooxygenase and ornithine decarboxylase (ODC) enzyme activities and protein expression of ODC, which are well-established markers for tumor promotion. We also observed that resveratrol inhibits UVB-mediated increased level of lipid peroxidation, a marker of oxidative stress. Taken together, our results suggest that resveratrol  may afford substantial protection against the damages caused by UVB exposure, and these protective effects may be mediated via its antioxidant properties.  Copyright 2003 Elsevier Science (USA)  PMID: 12583990  [PubMed - indexed for MEDLINE] 

3. Ann N Y Acad Sci. 2002 May;957:239-49.  Oxygen, oxidants, and antioxidants in wound healing: an emerging paradigm.  Sen CK, Khanna S, Gordillo G, Bagchi D, Bagchi M, Roy S.  Laboratory of Molecular Medicine, Dorothy M. Davis Heart and Lung Research Institute, Department of Surgery (CMIS), The Ohio State University Medical Center, Columbus, Ohio 43210, USA. sen-1@medctr.osu.edu 

 Disrupted vasculature and high energy-demand by regenerating tissue results in wound hypoxia. Wound repair may be facilitated by oxygen therapy. Evidence supporting the mode of action of hyperbaric oxygen in promoting wound healing is  sketchy, however. Topical oxygen therapy involves local administration of pure oxygen. The advantages of topical oxygen therapy include low cost, the lack of systemic oxygen toxicity, and possibility of home treatment. While this modality  of wound care is of outstanding interest, it clearly lacks the support of mechanism-oriented studies. The search for mechanisms by which oxygen supports wound healing has now taken another step. Respiratory burst-derived oxidants support healing. Oxidants serve as cellular messengers to promote healing. Although this information is of outstanding significance to the practice of oxygen therapy, it remains largely unexplored. The search for "natural remedies"  has drawn attention to herbals. Proanthocyanidins or condensed tannins are a group of biologically active polyphenolic bioflavonoids that are synthesized by many plants. Proanthocyanidins and other tannins facilitate wound healing. A combination of grape seed proanthocyanidin extract and resveratrol facilitates inducible VEGF expression, a key element supporting wound angiogenesis. Strategies to manipulate the redox environment in the wound are likely to be of outstanding significance in wound healing.  PMID: 12074976  [PubMed - indexed for MEDLINE] 

2. J Nutr. 2001 Jun;131(6):1844-9.  Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice.  Kimura Y, Okuda H.  Second Department of Medical Biochemistry, School of Medicine, Ehime University,  Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. yokim@m.ehime-u.ac.jp 

 Resveratrol is a naturally occurring phytoalexine found in medicinal plants. We found that resveratrol, at doses of 2.5 and 10 mg/kg, significantly reduced the tumor volume (42%), tumor weight (44%) and metastasis to the lung (56%) in mice bearing highly metastatic Lewis lung carcinoma (LLC) tumors, but not at a dose of 0.6 mg/kg. Resveratrol did not affect the number of CD4(+), CD8(+) and natural killer (NK)1.1.(+) T cells in the spleen. Therefore, the inhibitory effects of resveratrol on tumor growth and lung metastasis could not be explained by natural killer or cytotoxic T-lymphocyte activation. In addition, resveratrol inhibited DNA synthesis most strongly in LLC cells; its 50% inhibitory concentration (IC(50)) was 6.8 micromol/L. Resveratrol at 100 micromol/L increased apoptosis to 20.6 +/- 1.35% from 12.1 +/- 0.36% (P < 0.05) in LLC cells, and decreased the S phase population to 22.1 +/- 1.03% and 29.2 +/- 0.27% from 35.2 +/- 1.72% (P < 0.05) at concentrations of 50 and 100 micromol/L, respectively. Resveratrol inhibited tumor-induced neovascularization at doses of 2.5 and 10 mg/kg in an in  vivo model. Moreover, resveratrol significantly inhibited the formation of capillary-like tube formation from human umbilical vein endothelial cells (HUVEC) at concentrations of 10-100 micromol/L; the degree of the inhibition of capillary-like tube formation by resveratrol was 45.5% at 10 micromol/L, 50.2% at 50 micromol/L and 52.6% at 100 micromol/L. Resveratrol inhibited the binding of vascular endothelial growth factor (VEGF) to HUVEC at concentrations of 10-100 micromol/L, but not at concentrations of 1 and 5 micromol/L. The degree of inhibition of VEGF binding to HUVEC by resveratrol was 16.9% at 10 micromol/L, 53.2% at 50 micromol/L and 47.8% at 100 micromol/L. We suggest that the antitumor and antimetastatic activities of resveratrol might be due to the inhibition of DNA synthesis in LLC cells and the inhibition of LLC-induced neovascularization and tube formation (angiogensis) of HUVEC by resveratrol  PMID: 11385077  [PubMed - indexed for MEDLINE] 

1. Int J Cosmet Sci. 2000 Jun;22(3):219-26.  Resveratrol: an original mechanism on tyrosinase inhibition.  Bernard P, Berthon JY.  Greentech S. A., Biopôle Clermont Limagne, 63360 Saint Beauzire Cedex, France. 

 This paper forms part of studies searching for new bioactive ingredients for cosmetics, for example, in the whitening agent field. The aim of our work was to  present resveratrol as an original substrate for tyrosinase with very promising cosmetic perspectives. This study was based on several spectrophotometric analyses with minor adaptations. These analyses suggested that resveratrol is biotransformed by tyrosinase into an oxydated form, becoming a powerful inhibitor of tyrosinase. Furthermore, we show that resveratrol can be used as an additive compound in whitening cosmetics, particularly with a Morus alba extract. These results may help in understanding tyrosinase active site structure and mechanism.  PMID: 18503477  [PubMed - in process] 

Resveratrol research has shown resveratrol to be an effective antioxidant, and an anti-inflammatory. It also has qualities that make it useful in sun damage repair, and for color correction in the skin.

Resveratrol research