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Research Articles: Therapeutics, Targets, and Development

Dietary grape seed proanthocyanidins inhibit UVB-induced oxidative stress and activation of mitogen-activated protein kinases and nuclear factor-B signaling in in vivo SKH-1 hairless mice

¹ Department of Dermatology, University of Alabama at Birmingham and ² Birmingham VA Medical Center, Birmingham, Alabama

Requests for reprints: Santosh K. Katiyar, Department of Dermatology, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall 557, P.O. Box 202, Birmingham, AL 35294. Phone: 205-975-2608; Fax: 205-934-5745. E-mail: skatiyar{at}uab.edu

Abstract

We have shown previously that dietary grape seed proanthocyanidins (GSP) inhibit UVB-induced photocarcinogenesis in mice. As UVB-induced oxidative stress and oxidative stress–mediated signaling has been implicated in photocarcinogenesis, this study was designed to investigate the effect of dietary GSPs on UVB-induced oxidative stress in in vivo SKH-1 hairless mice. Here, we report that provision of dietary GSPs (0.2 and 0.5%, w/w) to mice exposed to either acute UVB irradiation (120 mJ/cm²) or chronic irradiation of UVB inhibited depletion of glutathione peroxidase, catalase, and glutathione, and inhibited UVB-induced H₂O₂, lipid peroxidation, protein oxidation, and nitric oxide in mouse skin. As UV-induced oxidative stress mediates activation of mitogen-activated protein kinase (MAPK) and nuclear factor-B (NF-B) signaling pathways, we determined the effect of dietary GSPs on these pathways. We observed that dietary GSPs inhibited UVB-induced phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun-NH₂-kinase, and p38 proteins of MAPK family, which seems to be mediated through reactivation of MAPK phosphatases. GSPs inhibited UVB-induced activation of NF-B/p65 through inhibition of degradation of IB and activation of IB kinase (IKK). As NF-B–targeted genes play critical roles in inflammation and cellular proliferation, we assessed the effect of GSPs on proteins encoded by these genes. Dietary GSPs resulted in inhibition of the expression of proliferating cell nuclear antigen, cyclin D1, inducible nitric oxide synthase, and cyclooxygenase-2 in the skin. Collectively, our data show that GSPs have the ability to protect the skin from the adverse effects of UVB radiation via modulation of the MAPK and NF-B signaling pathways and provide a molecular basis for the photoprotective effects of GSPs in an in vivo animal model. [Mol Cancer Ther 2007;6(3):995–1005]

Grant support: National Cancer Institute/NIH grant CA104428-01 and the Veterans Administration Merit Review Award (S.K. Katiyar).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/26/06; revised 12/26/06; accepted 2/ 1/07.