hydroxyl radicals.(5,6) Rebamipide decreases LPO and nitrotyrosine levels, normalizes ERK1/2 phosphorylation, and improves the ulcer index; this suggests that defects in the mitogen-activated protein kinase (MAPK) pathway are involved in the increased susceptibility to gastric mucosal injury observed in portal hyper- tensive gastropathy, indicating a potential role of rebamipide for treatment. NSAIDs and aspirin. In addition to inhibiting cyclooxygenase and decreasing prostaglandin production, NSAIDs induce mucosal damage via ROS produced by recruited leukocytes. ROS-mediated mitochondrial damage as well as lipid, protein, and DNA oxida- tion lead to apoptosis and mucosal injury. Proton pump inhibitor (PPI) therapy is thought to primarily protect gastric mucosa by inhibiting gastric acid secretion. Nevertheless, Maity et al.(7) recently demonstrated that a PPI, lansoprazole, also inhibits NSAID-induced gastropathy by inhibiting mitochondrial and Fas-mediated apoptosis pathways. Lansoprazole’s anti-apoptotic activity appears to be mediated by preventing NSAID-induced reductions in anti-apoptotic genes (e.g., Bcl and Bcl-2) while inhibiting increases in Fas and Fas ligand as well as pro-apoptotic genes (e.g., Bax and Bak). On the other hand, aspirin increases the permeability of cultured gastric epithelial cell monolayers. The disruption in barrier integrity is mediated by p38 MAPK and involves the downregula- tion of claudin-7, a protein component of tight junctions.(8) This differs from the effects of other NSAIDs (i.e., non-aspirin NSAIDs), which increase epithelial permeability coupled to cyclooxygenase-1 inhibition; this increase can be restored by PGE2 administration. Heat shock proteins. Heat shock proteins, especially HSP70, provide cellular protection against stressor-induced tissue damage by refolding or degrading denatured proteins produced as a result of these stressors. Otaka et al.(9) recently used affinity chromato- graphy to identify cytoskeletal myosin and actin as the first molecules bound by HSP70 after gastric mucosal injury in rats. Transcriptional upregulation of HSPs occurs via the binding of the transcription factor, heat shock factor 1 (HSF1), to heat shock element, which is located upstream of the HSP genes. In HSF1 and HSP70-expressing transgenic mice, HSPs protect against irritant (e.g., ethanol or NSAIDs)-induced gastric lesions; more- over, geranylgeranylacetone (GGA), a gastroprotective agent, induces HSPs. Furthermore, HSP70 protects the gastric mucosa by inhibiting apoptosis, proinflammatory cytokines, and cell adhesion molecules involved in leukocyte infiltration. After induction by GGA, HSPs exhibit protective effects in mouse models of inflammatory bowel disease as well as in NSAID- induced lesions of the small intestine. Therefore, HSP inducers such as GGA may have therapeutic benefits in numerous diseases. Enlarged Fold Gastritis and Oxidative Stress H. pylori eradication therapy increases Runt domain transcrip- tion factor 3 (RUNX3) expression in glandular epithelial cells in enlarged-fold gastritis. Recently, we reported that RUNX3 is expressed in gastric epithelial cells and that H. pylori eradication significantly increases RUNX3 expression in the glandular epithelium of the corpus; however, no changes were observed in the antrum.(10) The mucosal chemiluminescence value, a marker of oxidative stress, is 4-fold higher in the corpus than in the antrum. H. pylori eradication significantly decreases the mucosal chemiluminescence values in both portions of the stomach to nearly undetectable levels. We conclude that the glandular epithelium is exposed to high levels of carcinogenic oxidative stress and expresses low levels of the tumor-suppressing mole- cule, RUNX3; however, RUNX3 expression was restored after eradication, suggesting a high risk of carcinogenesis associated with H. pylori-induced enlarged-fold gastritis of the corpus.(10) 36 Oxidative Stress during H. pylori Infection Antioxidant ability of H. pylori to establish chronic infec tion. H. pylori infection induces a strong inflammatory host response, leading to the generation of a number of ROS and reactive nitrogen species (RNS), which are mediated by neutro- phils and macrophages.(11) The generation of ROS and/or RNS is an important host immune response against persistent pathogens. Therefore, H. pylori must combat oxidative stress generated by the host immune response using an antioxidant protein in order to establish long-term colonization.(12,13) The mechanisms for ROS detoxification are of particular interest in understanding the H. pylori-associated pathogenesis. It is well known that H. pylori has a variety of enzymes acting as antioxidant systems to combat the toxic effects of ROS including catalase (KatA), iron-cofactored superoxide dismutase (SodB), and alkyl hydroperoxide reductase (AhpC).(13,14) Superoxide dismutase (SOD) catalyzes the conversion of super- oxide anions to hydrogen peroxide, which is degraded to oxygen and water by catalase.(13,15) SOD is a metalloenzyme; 3 structurally different forms have been identified depending on the metal cofactor. In general, organisms encode different sets of SOD enzymes. For example, Escherichia coli has 3 SODs: Fe-SOD (SodB) and Mn-SOD (SodA) in the cytoplasm and Cu/Zn-SOD in the periplasm.(16) On the other hand, H. pylori produces only a single SodB encoded by the sodB gene.(17,18) It was recently reported that sodB deletion in H. pylori causes the bacterium to lose its capacity for gastric mucosal colonization in mice.(19) This indicates that SodB is an important determinant of the host colonization capability of H. pylori. The regulation of sodB mRNA expression is also important for ROS detoxification. The mRNA expression of sodB in H. pylori is directly regulated by ferric uptake regulator (Fur) protein.(20) Fur functions as a global transcriptional regulator in H. pylori.(21–24) It is reported that Fur binds to ferrous iron (Fe2+) and that the genes for iron uptake are suppressed by the iron-binding form of Fur.(25,26) On the other hand, sodB expression is suppressed by the iron-free form of Fur (apo-Fur).(20) Apo-Fur binds to a specific consensus sequence called Fur-Box located on the sodB promoter, blocking the binding of RNA polymerase.(20,27,28) It was recently reported that nucleic-acid mutations in Fur-Box and/or amino-acid mutations in Fur decrease the affinity of apo-Fur for Fur-Box in H. pylori, halting the suppression of sodB mRNA expression.(29–31) In particular, stopping the suppression of sodB mRNA expression in H. pylori by amino-acid mutations in Fur (i.e., C78Y and P114S) determines the development of metronidazole (Mtz) resistance.(31) This is because, when Mtz enters cells, its antimicrobial toxicity is dependent on the reduction of its nitro group to nitro anion radicals and the generation of superoxide.(32,33) The SodB of H. pylori shares 53% sequence identity with the corresponding protein from E. coli. Interestingly, H. pylori SodB is significantly different from other Fe-SODs; its most distin- guishing characteristic is its extended C-terminal tail,(34) although the role of this tail remains unclear. The structure of SodB has been clarified; it is now known to exist as a dimer composed of 2 identical subunits.(34) Furthermore, it is identified as having 4 ferrous ion (Fe2+)-coordinating residues (i.e., an iron-binding domain; His 26, His 73, His 160, and Asp 156) (Fig. 1). In fact, SodB needs to recruit ferrous ion (Fe2+) to express its activity.(15,34) It is expected that SodB activity might be suppressed by preventing the uptake of iron ion (Fe2+ and/or Fe3+). Generation of oxidative stress as a virulence factor in H. pyloriinfected hosts. ROS released from activated neutro- phils are also potential virulence factors involved in H. pylori- infected host cells. In H. pylori-infected host cells, hypochlorous anions (OCl−) are generated from H2O2 in the presence of Cl−. The hypochlorous anions subsequently react with ammonia (NH3), which is derived from urea by urease produced by H. pylori, doi: 10.3164/jcbn.11115SR ©2012 JCBN