Miyazaki Tsuneyuki, Shirakami Yohei, Mizutani Taku, Maruta Akinori, Ideta Takayasu, Kubota Masaya, Sakai Hiroyasu, Ibuka Takashi, Genovese Salvatore, Fiorito Serena, Taddeo Vito Alessandro, Epifano Francesco, Tanaka Takuji, Shimizu Masahito
Department of Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
Department of Pharmacy, D'Annunzio University of Chieti-Pescara, 66100, Chieti Scalo, Italy.
Sci Rep. 2021 Jan 12;11(1):492. doi: 10.1038/s41598-020-79916-5.
FXR is a member of the nuclear receptor superfamily and bile acids are endogenous ligands of FXR. FXR activation has recently been reported to inhibit intestinal inflammation and tumour development. This study aimed to investigate whether the novel FXR agonist nelumal A, the active compound of the plant Ligularia nelumbifolia, can prevent colitis and colorectal carcinogenesis. In a mouse colitis model, dextran sodium sulfate-induced colonic mucosal ulcer and the inflammation grade in the colon significantly reduced in mice fed diets containing nelumal A. In an azoxymethane/dextran sodium sulfate-induced mouse inflammation-related colorectal carcinogenesis model, the mice showed decreased incidence of colonic mucosal ulcers and adenocarcinomas in nelumal A-treated group. Administration of nelumal A also induced tight junctions, antioxidant enzymes, and FXR target gene expression in the intestine, while it decreased the gene expression of bile acid synthesis in the liver. These findings suggest that nelumal A effectively attenuates colonic inflammation and suppresses colitis-related carcinogenesis, presumably through reduction of bile acid synthesis and oxidative damage. This agent may be potentially useful for treatment of inflammatory bowel diseases as well as their related colorectal cancer chemoprevention.
法尼酯X受体（FXR）是核受体超家族的成员，胆汁酸是FXR的内源性配体。最近有报道称，FXR激活可抑制肠道炎症和肿瘤发展。本研究旨在探讨新型FXR激动剂牛磺熊去氧胆酸A（nelumal A），即植物莲叶橐吾的活性化合物，是否能预防结肠炎和结直肠癌的发生。在小鼠结肠炎模型中，给予含牛磺熊去氧胆酸A的饮食后，葡聚糖硫酸钠诱导的结肠黏膜溃疡和结肠炎症程度在小鼠中显著降低。在氧化偶氮甲烷/葡聚糖硫酸钠诱导的小鼠炎症相关结直肠癌发生模型中，牛磺熊去氧胆酸A治疗组小鼠的结肠黏膜溃疡和腺癌发病率降低。给予牛磺熊去氧胆酸A还可诱导肠道紧密连接、抗氧化酶和FXR靶基因表达，同时降低肝脏中胆汁酸合成的基因表达。这些发现表明，牛磺熊去氧胆酸A可有效减轻结肠炎症并抑制结肠炎相关的肿瘤发生，可能是通过减少胆汁酸合成和氧化损伤实现的。该药物可能对治疗炎症性肠病及其相关的结直肠癌化学预防具有潜在作用。
