细胞凋亡
结肠炎
PI3K/AKT/mTOR通路
蛋白激酶B
炎症性肠病
癌症研究
促炎细胞因子
化学
肠道通透性
药理学
细胞生物学
医学
免疫学
炎症
生物
内科学
疾病
生物化学
作者
Zhijun Geng,Lugen Zuo,Jing Li,L.X. Yin,Jingjing Yang,Taisen Duan,Lian Wang,Xiaofeng Zhang,Xue Song,Yue‐Yue Wang,Jianguo Hu
标识
DOI:10.1096/fj.202400211rr
摘要
Abstract Excessive apoptosis of intestinal epithelial cells leads to intestinal barrier dysfunction, which is not only one of the pathological features of inflammatory bowel disease (IBD) but also a therapeutic target. A natural plant extract, Ginkgetin (GK), has been reported to have anti‐apoptotic activity, but its role in IBD is unknown. This study aimed to explore whether GK has anti‐colitis effects and related mechanisms. An experimental colitis model induced by dextran sulfate sodium (DSS) was established, and GK was found to relieve colitis in DSS‐induced mice as evidenced by improvements in weight loss, colon shortening, Disease Activity Index (DAI), macroscopic and tissue scores, and proinflammatory mediators. In addition, in DSS mice and TNF‐α‐induced colonic organoids, GK protected the intestinal barrier and inhibited intestinal epithelial cell apoptosis, by improving permeability and inhibiting the number of apoptotic cells and the expression of key apoptotic regulators (cleaved caspase 3, Bax and Bcl‐2). The underlying mechanism of GK's protective effect was explored by bioinformatics, rescue experiments and molecular docking, and it was found that GK might directly target and activate EGFR, thereby interfering with PI3K/AKT signaling to inhibit apoptosis of intestinal epithelial cells in vivo and in vitro. In conclusion, GK inhibited intestinal epithelial apoptosis in mice with experimental colitis, at least in part, by activating EGFR and interfering with PI3K/AKT activation, explaining the underlying mechanism for ameliorating colitis, which may provide new options for the treatment of IBD.
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