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

Mol Cancer Ther. 2007 Mar;6(3):995-1005. doi: 10.1158/1535-7163.MCT-06-0661.

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/cm(2)) or chronic irradiation of UVB inhibited depletion of glutathione peroxidase, catalase, and glutathione, and inhibited UVB-induced H(2)O(2), 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-kappaB (NF-kappaB) 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-NH(2)-kinase, and p38 proteins of MAPK family, which seems to be mediated through reactivation of MAPK phosphatases. GSPs inhibited UVB-induced activation of NF-kappaB/p65 through inhibition of degradation of IkappaBalpha and activation of IkappaB kinase alpha (IKKalpha). As NF-kappaB-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-kappaB signaling pathways and provide a molecular basis for the photoprotective effects of GSPs in an in vivo animal model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Blotting, Western
  • Catalase / metabolism
  • Cell Cycle Proteins / metabolism
  • DNA Damage / drug effects
  • Diet
  • Dual Specificity Phosphatase 1
  • Enzyme Activation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glutathione / metabolism
  • Glutathione Peroxidase / metabolism
  • Grape Seed Extract
  • Humans
  • Immediate-Early Proteins / metabolism
  • Lipid Peroxidation / drug effects
  • Mice
  • Mice, Hairless
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects*
  • Oxidative Stress / radiation effects
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Plant Extracts / pharmacology*
  • Proanthocyanidins / pharmacology*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / metabolism
  • Reactive Oxygen Species / metabolism
  • Seeds / chemistry
  • Signal Transduction / drug effects*
  • Signal Transduction / radiation effects
  • Skin / drug effects*
  • Skin / metabolism
  • Skin / radiation effects
  • Sunlight / adverse effects
  • Ultraviolet Rays / adverse effects*
  • Vitis / chemistry

Substances

  • Antioxidants
  • Cell Cycle Proteins
  • Grape Seed Extract
  • Grape Seed Proanthocyanidins
  • Immediate-Early Proteins
  • NF-kappa B
  • Plant Extracts
  • Proanthocyanidins
  • Proliferating Cell Nuclear Antigen
  • Reactive Oxygen Species
  • Nitric Oxide
  • Catalase
  • Glutathione Peroxidase
  • Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse
  • Protein Tyrosine Phosphatases
  • Glutathione