title: 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 >5μg/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.
authors.affiliation: Lab of Translational Medicine, Gachon University of Medicine and Science, Lee Gil Ya Cancer and Diabetes Institute, Songdo-dong 7-45, Yeonsu-gu, Incheon, Republic of Korea.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Ock
authors.forename: Kyung Sook
authors.initials: KS
authors.lastname: Hong
authors.forename: Ki-Seok
authors.initials: KS
authors.lastname: Choi
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Chung
authors.forename: Yun soo
authors.initials: Ys
authors.lastname: Kim
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Ki-Baik
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005756:Gastritis / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013047:Specific Pathogen-Free Organisms; D013312:Stress, Physiological / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine