guanosine-triphosphate and Hyperplasia

Studies from our laboratory have shown that epigallocatechin-3-gallate, the major polyphenol present in green tea, inhibits ultraviolet (UV)B-exposure-mediated phosphorylation of mitogen-activated protein kinases (MAPKs) (Toxicol. Appl. Pharmacol. 176: 110-117, 2001) and activation of nuclear factor kappa B (NF-kappaB) (Oncogene 22: 1035-1044, 2003) pathways in normal human epidermal keratinocytes. This study was designed to investigate the relevance of these findings to the in vivo situations in SKH-1 hairless mouse model, which is regarded to have relevance to human situations. SKH-1 hairless mice were topically treated with GTP (5 mg/0.2 ml acetone/mouse) and were exposed to UVB 30 min later (180 mJ/cm2). These treatments were repeated every alternate day for 2 weeks, for a total of seven treatments. The animals were killed 24 h after the last UVB exposure. Topical application of GTP resulted in significant decrease in UVB-induced bifold-skin thickness, skin edema and infiltration of leukocytes. Employing Western blot analysis and immunohistochemical studies, we found that GTP resulted in inhibition of UVB-induced: (i) phosphorylation of extracellular-signal-regulated kinases (ERK1/2), (ii) c-Jun N-terminal kinases, and (iii) p38 protein expression. Since NF-kappaB plays a major role in inflammation and cell proliferation, we assessed the effect of GTP on UVB-mediated modulations in the NF-kappaB pathway. Our data demonstrated that GTP inhibited UVB-induced: (i) activation of NF-kappaB, (ii) activation of IKKalpha, and (iii) phosphorylation and degradation of IkappaBalpha. Our data suggest that GTP protects against the adverse effects of UV radiation via modulations in MAPK and NF-kappaB signaling pathways, and provides molecular basis for the photochemopreventive effect of GTP in an in vivo animal model system.

Topics: Animals; Blotting, Western; Cell Division; Cell Nucleus; Edema; Female; Flavonoids; Guanosine Triphosphate; Hyperplasia; I-kappa B Kinase; I-kappa B Proteins; Immunohistochemistry; Leukocytes; MAP Kinase Signaling System; Mice; Mice, Hairless; Mice, Mutant Strains; Mitogen-Activated Protein Kinases; NF-kappa B; NF-KappaB Inhibitor alpha; Phenols; Phosphorylation; Polyphenols; Protein Serine-Threonine Kinases; Signal Transduction; Skin; Tea; Time Factors; Ultraviolet Rays

In the present study we found that exocrine pancreatic hyperplasia observed after proximal small bowel resection is accompanied by an increase in pancreatic somatostatin (SS) content at 1 mo and an increase in the number of SS receptors at 2 wk and 1 mo after intestinal surgery. At 6 mo after small bowel resection SS content and SS receptors had returned to control values. However, the original increase in SS receptor number was accompanied by a decrease in the ability of SS to inhibit forskolin-stimulated adenylyl cyclase (AC) activity. In addition, the ability of 5'-guanylylimidodiphosphate (a nonhydrolyzable GTP analogue) to inhibit SS receptor binding was decreased in pancreatic acinar membranes from enterectomized rats at 2 wk and 1 mo after jejunoileal resection. These data suggest that there is an abnormality in the integrity of SS receptor binding site-G protein interactions and would explain the decreased inactivation of AC by SS at 2 wk and 1 mo after proximal small bowel resection.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Colforsin; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Hyperplasia; Intestine, Small; Male; Pancreas; Postoperative Period; Rats; Receptors, Somatostatin; Somatostatin; Time Factors