A novel approach for stress-induced gastritis based on paradoxical anti-oxidative and anti-inflammatory action of exogenous 8-hydroxydeoxyguanosine.
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.
Ock
Chan Young
CY
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.
Hong
Kyung Sook
KS
Choi
Ki-Seok
KS
Chung
Myung-Hee
MH
Kim
Yun soo
Ys
Kim
Ju Hyun
JH
Hahm
Ki-Baik
KB
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
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine