title: Toxicoproteomic analysis of a mouse model of nonsteroidal anti-inflammatory drug-induced gastric ulcers.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are valuable agents; however, their use has been limited by their association with mucosal damage in the upper gastrointestinal tract. NSAIDs inhibit cyclooxygenase and consequently block the synthesis of prostaglandins, which have cytoprotective effects in gastric mucosa; these effects on prostaglandins have been thought to be major cause of NSAID-induced ulceration. However, studies indicate that additional NSAID-related mechanisms are involved in formation of gastric lesions. Here, we used a toxicoproteomic approach to understand cellular processes that are affected by NSAIDs in mouse stomach tissue during ulcer formation. We used fluorogenic derivatization-liquid chromatography-tandem mass spectrometry (FD-LC-MS/MS)-which consists of fluorogenic derivatization, separation and fluorescence detection by LC, and identification by LC-tandem mass spectrometry-in this proteomic analysis of pyrolic stomach from control and diclofenac (Dic)-treated mice. FD-LC-MS/MS results were highly sensitive; 10 differentially expressed proteins were identified, and all 10 were more highly expressed in Dic-treated mice than in control mice. Specifically, expression levels of 78 kDa glucose-regulated protein (GRP78), heat shock protein beta-1 (HSP27), and gastrin were more than 3-fold higher in Dic-treated mice than in control mice. This study represents a first step to ascertain the precise actors of early NSAID-induced ulceration.
authors.affiliation: Department of Environmental and Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. k-ohyama@nagasaki-u.ac.jp
authors.forename: Kaname
authors.initials: K
authors.lastname: Ohyama
authors.forename: Akina
authors.initials: A
authors.lastname: Shiokawa
authors.forename: Kosei
authors.initials: K
authors.lastname: Ito
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Masuyama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichibangase
authors.forename: Naoya
authors.initials: N
authors.lastname: Kishikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Imai
authors.forename: Naotaka
authors.initials: N
authors.lastname: Kuroda
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D002853:Chromatography, Liquid / Q000379:methods; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005456:Fluorescent Dyes / Q000032:analysis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D005755:Gastrins / Q000032:analysis / Q000096:biosynthesis; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D040901:Proteomics / Q000379:methods*; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; D005456:Fluorescent Dyes; D005755:Gastrins; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D004008:Diclofenac