title: Attenuation of indomethacin-induced gastric mucosal injury by prophylactic administration of sake yeast-derived thioredoxin.
abstract: BACKGROUND
  Indomethacin is one of the group of nonsteroidal anti-inflammatory drugs, which often cause gastric mucosal injury as a side effect. Infiltration and activation of inflammatory cells, production of proinflammatory cytokines and chemokines, generation of reactive oxygen species, and activation of apoptotic signaling are involved in the pathogenesis of indomethacin-induced gastric injury. We examined whether sake yeast-derived thioredoxin (a small redox-active protein with anti-oxidative activity and various redox-regulating functions) reduced indomethacin-induced gastric injury.
  
  
  METHODS
  Gastric injury was produced by the intraperitoneal administration of indomethacin (40 mg/kg body weight) to C57BL/6 mice. Prior to the administration of indomethacin, the mice were offered food pellets containing non-genetically modified sake yeast-derived thioredoxin (thioredoxin 200 μg/g) for 3 days. Histological examinations, assessment of myeloperoxidase activity, and analysis of the gene expressions of proinflammatory cytokines and a chemokine (interleukin [IL]-1β, IL-6, and CXCL1) were statistically evaluated. Indomethacin cytotoxicity was determined by lactate dehydrogenase release from murine gastric epithelial GSM06 cells induced by 24-h treatment with 200 and 400 μM indomethacin after 1-h preincubation with 100 μg/ml sake yeast-derived thioredoxin.
  
  
  RESULTS
  Macroscopic (edema, hemorrhage, and ulcers) and histological (necrosis, submucosal edema, neutrophil infiltration) findings induced by indomethacin were significantly reduced by pretreatment with food pellets containing thioredoxin. Gastric myeloperoxidase activity and the gene expressions of proinflammatory cytokines (IL-1β and IL-6) were also significantly reduced by this pretreatment compared with findings in the mice not pretreated with thioredoxin-containing food pellets. The administration of sake yeast-derived thioredoxin significantly reduced indomethacin-induced cytotoxicity in GSM06 cells.
  
  
  CONCLUSIONS
  We conclude that oral administration of sake yeast-derived thioredoxin reduces indomethacin-induced gastric injury. Sake yeast-derived thioredoxin may have therapeutic potential against indomethacin-induced gastric injury.
authors.affiliation: Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fukui
authors.forename: Yu
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kishimoto
authors.forename: Masao
authors.initials: M
authors.lastname: Yamashina
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakayama
authors.forename: Yutaku
authors.initials: Y
authors.lastname: Sakaguchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kazushige
authors.initials: K
authors.lastname: Uchida
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishio
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D054360:Chemokine CXCL1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005656:Fungal Proteins / Q000008:administration & dosage* / Q000302:isolation & purification; D005753:Gastric Mucosa / Q000293:injuries* / Q000473:pathology; D015870:Gene Expression; D007213:Indomethacin / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000737:chemistry*; D013272:Stomach Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013879:Thioredoxins / Q000008:administration & dosage* / Q000302:isolation & purification
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054360:Chemokine CXCL1; D016207:Cytokines; D005656:Fungal Proteins; D012333:RNA, Messenger; D013879:Thioredoxins; D009195:Peroxidase; D007213:Indomethacin