A novel approach for stress-induced gastritis based on paradoxical anti-oxidative and anti-inflammatory action of exogenous 8-hydroxydeoxyguanosine

Abstract

Reactive oxygen species (ROS) attack guanine bases in DNA and form 8-hydroxydeoxyguanosine (8-OHdG), which has been regarded simply as an oxidative mutagenic by-product. On the other hand, our previous report showed paradoxically ROS attenuating action of generated 8-OHdG. In the current study, both in vitro and in vivo experiments were executed in order to document anti-oxidative and anti-inflammatory actions of 8-OHdG in cell model and to elucidate the therapeutic efficacy against water immersion restraint stress (WIRS)-induced gastritis animal model. Electron spin resonance measurements showed that 8-OHdG at >5 μg/ml completely scavenged OH − radicals, which was further confirmed by checking 2′-7′-dichlorodihydrofluorescein diacetate (DCFDA) spectroscopy. On molecular assay, 8-OHdG antagonized the action of GTP on Rac, a small GTP binding protein, without affecting Rac-guanosine exchange factor (GEF) or phosphoinositide 3-kinases (PI3K) activity. In Raw264.7 cells, 8-OHdG was found to be associated with marked attenuations of NOX1, NOXO1, and NOXA1 accompanied with the decreased expressions of LPS-induced inflammatory mediators including COX-2, iNOS, IL-1β, and IL-6. Similarly, 8-OHdG attenuated hypoxia-induced angiogenesis and platelet endothelial cell adhesion molecule-1 (PECAM-1), COX-2, iNOS, IL-8, and VEGF expressions in HUVEC cells. At transcriptional level, 8-OHdG inhibited the nuclear translocation of NF-κB, inhibitory κB kinase (IKK) β kinase activation, and decreased phospho-IκBα levels. 8-OHdG efficiently ameliorated WIRS-induced gastric mucosal injury as evidenced with improvement of gross lesion index and attenuation of engaging mediators. Taken together, exogenous 8-OHdG can be a functional molecule regulating oxidative stress-induced gastritis through either antagonizing Rac-GTP binding or blocking the signals responsible for gastric inflammatory cascade.