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.
摘要：
肠上皮细胞过度凋亡导致肠屏障功能紊乱,这不仅是炎症性肠病（IBD）的病理特征之一，也是治疗的靶点。一种天然植物提取物，银杏素(GK),据报道具有抗凋亡活性，但其在IBD中的作用尚不清楚。本研究旨在探讨GK是否具有抗结肠炎作用及相关机制。建立葡聚糖硫酸钠(DSS)诱导的实验性结肠炎模型,发现GK可以缓解DSS诱导的小鼠的结肠炎，体重减轻的改善证明了这一点，结肠缩短,疾病活动指数（DAI），宏观和组织评分，和促炎介质。此外,在DSS小鼠和TNF-α诱导的结肠类器官中，GK保护肠屏障，抑制肠上皮细胞凋亡，通过改善通透性并抑制凋亡细胞的数量和关键凋亡调节因子（裂解的caspase3，Bax和Bcl-2）的表达。通过生物信息学探索GK的保护作用的潜在机制，救援实验和分子对接，发现GK可能直接靶向并激活EGFR，从而干扰PI3K/AKT信号传导以在体内和体外抑制肠上皮细胞的凋亡。总之,GK抑制实验性结肠炎小鼠肠上皮细胞凋亡,至少在某种程度上,通过激活EGFR和干扰PI3K/AKT激活，解释改善结肠炎的潜在机制，这为IBD的治疗提供了新的选择。
