Fig. 1. Homology modeling of Helicobacter pylori SodB. Four amino acids (His 26, His 73, His 160, and Asp 156) of SodB are ferrous ion (Fe2+) coordinating residues (i.e., an ironbinding domain). ultimately yielding monochloramine (NH2Cl). NH2Cl induces mucosal cytotoxicity due to its lipophilic properties and freely penetrates biological membranes to oxidize intracellular compo- nents.(35–37) In addition, it is well known that H. pylori produces a γ- glutamyltranspeptidase (EC 2.3.2.2; GGT) in the periplasm.(38) H. pylori GGT catalyzes the transpeptidation and hydrolysis of the γ-glutamyl groups of glutamine and glutathione. Interestingly, these findings indicate that H. pylori GGT performs 2 functions. First, GGT functions in the physiological functioning of H. pylori. H. pylori is unable to take up extracellular glutamine and glutathione directly; GGT hydrolyzes these substances to gluta- mate. The glutamate is then transported into H. pylori cells via a Na+-dependent reaction and is mainly incorporated into the TCA cycle.(39) Second, GGT acts as a virulence factor by disrupting the antioxidant ability of host cells. Although glutathione has anti- oxidant potential in host cells, H. pylori GGT reduces extracellular glutathione levels. In fact, H. pylori GGT reduces the ROS resistance of the host cells and induces apoptosis or necrosis.(38,40) Excess ROS are produced in H. pylori-colonized human stomachs; this induces oxidative stress to both the gastric mucosa and H. pylori. Because H. pylori has a deft capability of detoxi- fying ROS using a variety of enzymes to establish long-term colonization,(12,13) excess ROS leads solely to host cell damage. Oxidative Stress in the Progression of Gastric Motility Disorders Gastric motility disorders can occur in many clinical settings with a wide variety in the severity of symptoms with or without gastric mucosal injuries. Gastric motility disorders are attributable to either damage within the smooth muscle itself or dysfunctions within the neuromuscular components including the enteric nerves and interstitial cells of Cajal (ICC), which regulate smooth muscle function. How oxidative stress is involved in these dysfunctions is discussed in the following situations. Gastrointestinal Complications in Sepsis Oxygen radicals are implicated as relevant mediators in sepsis and septic shock in animals including humans.(41,42) Sepsis is a systemic response caused by bacterial endotoxins such as lipo- polysaccharide, which induce the release of ROS and the genera- tion of numerous pro-inflammatory factors and nitric oxide. During sepsis, the most frequent complications within the gastrointestinal tract are gastrointestinal motility disturbances and mucosal barrier dysfunction. Experimental administration of LPS delays gastric emptying and upregulates inducible nitric oxide synthase in order H. Suzuki et al. to downregulate neuronal nitric oxide synthase (nNOS) and synthesize PGs.(43) It is also reported that SOD reverses the endotoxin-induced delay in gastric emptying and diminishes the presence of nitrotyrosine, 4-hydroxy-2-nonenal in gastric mucosa, and inducible nitric oxide synthase-positive residential macro- phages in the external musculature; these suggest the involvement of oxidative and nitrosative stresses in the pathogenesis of lipopolysaccharide-induced gastrointestinal dysmotility.(44) Gastrointestinal Complications in Ischemia/Reperfusion Injury The gastrointestinal tract is one of the most susceptible organ systems to ischemia. Previous investigations demonstrate that ischemia/reperfusion is a major contributor to gastric mucosal injury caused by stresses such as burn stress or hemorrhagic shock, NSAIDs, and H. pylori infection. In addition to mucosal injuries, delayed gastric emptying is also reported after gastric ischemia/reperfusion associated with disruption of the ICC network and nNOS-positive neurons.(45) ICC play critical roles in gastro- intestinal motility in that they are the source of the electrical slow waves underlying the phasic contractions of the gastric muscula- ture and mediate excitatory and inhibitory inputs to the muscula- ture from the enteric motor neurons. Neuronal NOS generates neuronally derived NO, which is the major inhibitory neuro- transmitter in the gastrointestinal tract. ICC and nNOS-positive neurons are both important factors for gastric emptying. Oxidative stress produced by the xanthine–xanthine oxidase system after ischemia/reperfusion may play a major role in these events, although the precise mechanism is unclear. Diabetes Mellitus Oxidative stress is a strong pathogenic co-factor involved in the development of complications of diabetes. Increased glucose levels in diabetes react non-enzymatically with proteins and become advanced glycation end products (AGEs); AGEs activate endothelial NADPH oxidase and increase endothelial ROS,(46) which occurs in animal models of diabetes(47) and diabetes patients.(48) Gastric neuromuscular dysfunction occurs in up to 30– 50% of patients after 10 years of type 1 or 2 diabetes associated with histological changes including the loss of nNOS and ICC in both humans and animal models. It is reported that increased oxidative stress is attributable to the loss of upregulation of heme oxygenase-1; this results in the loss of ICC, decreased nNOS expression, and delayed gastric emptying in non-obese diabetic mice. These changes can be reversed by heme oxygenase-1 induction, demonstrating an important role of oxidative stress in the development of diabetic gastroparesis.(49) Aging and Oxidative Stress Gastrointestinal function declines with aging, including delayed gastric emptying, decreased peristalsis, and slowed colonic transit; these impair quality of life and increase morbidity and mortality. Notable changes in gut neuromuscular function that accompany advanced age are reported in human and animal models.(50,51) Cowen et al.(52) report a 50% reduction in ileal myenteric neurons in 24-month-old Sprague-Dawley rats fed ad libitum; this was prevented by caloric restriction, which reduces oxidative stress.(53) In the study using progeric mice deficient in the anti-aging peptide Klotho, progeric mice exhibited a gastric phenotype resembling that of human aging involving profound ICC loss with reduced slow wave amplitude and nitrergic inhibitory junction potentials. Klotho protects ICC by preserving their precursors, limiting oxidative stress, and maintaining nutritional status and normal levels of trophic factors important for ICC differentia- tion.(54) Increased oxidative stress in combination with a decrease J. Clin. Biochem. Nutr. | January 2012 | vol. 50 | no. 1 | 37 ©2012 JCBN