Xia Wenxin, Lin Haochang, Zhang Jing, Bai Yawen, Wei Zhifeng, Zhao Huatou, Xia Yufeng, Dai Yue
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing 211198, China.
Department of Cardiology, Nanjing Gaochun People's Hospital, 53 Mao Shan Road, Nanjing 211300, China.
Food Funct. 2025 Jul 1;16(13):5543-5555. doi: 10.1039/d5fo00256g.
Intestinal barrier defects represent a significant contributor to the development and progression of ulcerative colitis (UC). This study examined the protective effect of hyperoside (Hyp), a naturally occurring flavonol glycoside with anti-colitis potential, on intestinal barrier, and explored the underlying mechanisms based on the expression of barrier-related proteins. In mice with dextran sulfate sodium (DSS)-induced colitis, Hyp, orally administered, maintained the intestinal barrier integrity, evidenced by reducing intestinal permeability and elevating expression of the proteins relevant to tight junction (occludin and claudin 1) and adhesion junction (E-cadherin and β-catenin). In human colonic epithelial cells, Hyp diminished lipopolysaccharide (LPS)-induced defects of epithelial barrier function, and increased the expression of tight junction- and adhesion junction-related proteins. Hyp promoted the protein degradation of snail, a co-repressor of tight junction proteins, which was reversed by treatment of chloroquine (the autophagy inhibitor) but not MG132 (the ubiquitin-proteasome inhibitor). Consistently, Hyp rescued LPS-reduced autophagy, restored the formation of autophagosomes and autophagic lysosomes, and increased the expression of Beclin-1, ATG 5, ATG7, and LC3 II/I. Combination with chloroquine significantly attenuated up-regulation of Hyp on transmembrane electrical resistance and down-regulation of epithelial permeability. In mice with colitis, the protection against intestinal barrier and the promotion of expression of tight junction and adhesion junction proteins by Hyp was nearly completely reversed by chloroquine. These findings highlight the protective role of Hyp in the colonic mucosal barrier and provide new insights into the development of innovative strategies for the treatment of UC.
肠道屏障缺陷是溃疡性结肠炎（UC）发生和发展的一个重要因素。本研究检测了具有抗结肠炎潜力的天然黄酮醇糖苷金丝桃苷（Hyp）对肠道屏障的保护作用，并基于屏障相关蛋白的表达探索其潜在机制。在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠中，口服Hyp可维持肠道屏障完整性，表现为肠道通透性降低以及紧密连接相关蛋白（闭合蛋白和Claudin 1）和黏附连接相关蛋白（E-钙黏蛋白和β-连环蛋白）表达升高。在人结肠上皮细胞中，Hyp减轻了脂多糖（LPS）诱导的上皮屏障功能缺陷，并增加了紧密连接和黏附连接相关蛋白的表达。Hyp促进了紧密连接蛋白的共抑制因子蜗牛蛋白的蛋白降解，氯喹（自噬抑制剂）处理可逆转这一作用，但MG132（泛素-蛋白酶体抑制剂）处理则不能。同样，Hyp挽救了LPS降低的自噬，恢复了自噬体和自噬溶酶体的形成，并增加了Beclin-1、ATG 5、ATG7和LC3 II/I的表达。与氯喹联合使用显著减弱了Hyp对跨膜电阻的上调作用以及对上皮通透性的下调作用。在结肠炎小鼠中，氯喹几乎完全逆转了Hyp对肠道屏障的保护作用以及对紧密连接和黏附连接蛋白表达的促进作用。这些发现突出了Hyp在结肠黏膜屏障中的保护作用，并为开发治疗UC的创新策略提供了新的见解。
