Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
J Gastroenterol. 2012 Sep;47(9):978-87. doi: 10.1007/s00535-012-0564-5. Epub 2012 Mar 9.
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.
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.
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.
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.
吲哚美辛是一类非甾体抗炎药，常作为其副作用引起胃黏膜损伤。炎症细胞浸润和激活、促炎细胞因子和趋化因子的产生、活性氧的产生以及凋亡信号的激活都参与了吲哚美辛引起的胃损伤的发病机制。我们研究了清酒酵母来源的硫氧还蛋白（一种具有抗氧化活性和各种氧化还原调节功能的小分子氧化还原活性蛋白）是否能减轻吲哚美辛引起的胃损伤。
通过腹腔注射吲哚美辛（40mg/kg 体重）在 C57BL/6 小鼠中产生胃损伤。在给予吲哚美辛之前，小鼠食用含有非基因改造的清酒酵母来源的硫氧还蛋白（硫氧还蛋白 200μg/g）的食物颗粒 3 天。对组织学检查、髓过氧化物酶活性评估以及促炎细胞因子和趋化因子（白细胞介素[IL]-1β、IL-6 和 CXCL1）的基因表达进行统计学评价。通过用 200 和 400μM 吲哚美辛处理 24 小时，然后用 100μg/ml 清酒酵母来源的硫氧还蛋白预处理 1 小时，从鼠胃上皮细胞 GSM06 中诱导出的乳酸脱氢酶释放来确定吲哚美辛的细胞毒性。
用含有硫氧还蛋白的食物颗粒预处理可显著减轻吲哚美辛引起的胃的大体（水肿、出血和溃疡）和组织学（坏死、黏膜下水肿、中性粒细胞浸润）损伤。与未用含硫氧还蛋白食物颗粒预处理的小鼠相比，这种预处理也显著降低了胃髓过氧化物酶活性和促炎细胞因子（IL-1β和 IL-6）的基因表达。清酒酵母来源的硫氧还蛋白的给予显著降低了 GSM06 细胞中吲哚美辛诱导的细胞毒性。
我们的结论是，口服清酒酵母来源的硫氧还蛋白可减轻吲哚美辛引起的胃损伤。清酒酵母来源的硫氧还蛋白可能具有治疗吲哚美辛引起的胃损伤的潜力。
