title: Redox signaling in the gastrointestinal tract.
abstract: Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Pérez
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Taléns-Visconti
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Rius-Pérez
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain.
authors.forename: Isabela
authors.initials: I
authors.lastname: Finamor
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain. Electronic address: juan.sastre@uv.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Sastre
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D005767:Gastrointestinal Diseases / Q000378:metabolism* / Q000473:pathology; D041981:Gastrointestinal Tract / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D019255:NADPH Oxidases
keywords: APE1/Ref1; Barrett's esophagus; Celiac disease; Colorectal cancer; Dual oxidase 2; GPx2; Gastric cancer; Inflammatory bowel disease; Intestinal epithelium; MnSOD; NADPH oxidase 1; Nrf2; Peptic ulcer