肠道屏障缺损与溃疡性结肠炎（UC）的发生发展紧密相关，黏膜屏障保护剂是治疗UC的最新手段。牛蒡子为散风除热解毒之要药，可用于治疗UC等热毒入侵所致疾患，其抗UC的效应成分牛蒡子苷元属于植物雌激素，可显著改善结肠上皮损伤，选择性上调雌激素受体ERβ的靶基因表达，并兼备一定的抗炎和免疫抑制活性。本项目从激活ERβ受体，促进结肠紧密连接相关蛋白和黏蛋白表达的角度，阐明牛蒡子苷元增强上皮紧密连接和黏液屏障的机制。主要研究内容包括：在UC模型小鼠和结肠上皮细胞，考察苷元对上皮完整性、结肠通透性及黏液分泌的影响，探明其屏障保护作用和特点；明确苷元为ERβ激动剂，并采用特异性拮抗剂和基因沉默等手段，证实ERβ是其保护屏障的关键中介；体内外研究苷元对上皮连接相关蛋白和黏蛋白表达的影响及其信号途径，揭示其活化ERβ调控关键信号通路的分子机制。研究成果为牛蒡子苷元作为黏膜屏障保护剂用于UC的治疗提供理论依据。

Defective gut barrier is deeply involved in the initiation and development of ulcerative colitis (UC), and mucosal barrier protector has been thought to be an innovative approach in the management of UC. Arctium lappa L. fruit is a traditional Chinese medicine with efficiencies of dispelling wind, expelling heat and removing toxicity, and can be used in the treatment of diseases induced by toxic heat invasion, such as UC. Arctigenin, the major effective constituent of A. lappa, belongs to phytoestrogen. It could attenuate the epithelial damage of the colon, selectively up-regulated the expressions of the target genes of estrogen receptor β (ERβ), and showed moderate anti-inflammatory and immunosuppressive activities. The purpose of this project is to clarify the underlying mechanism of arctigenin for strengthening the tight junctions and mucus barrier in view of enhancement of the expressions of junction-related proteins and mucins via activation of ERβ. In colitis mice and colonic epithelial cells, the effects of arctigenin on epithelial integrity, permeability and mucus secretion should be studied to confirm its barrier protective effect. Next, we will clarify whether arctigenin is an agonist of ERβ, and reveal the key role that ERβ plays in the arctigenin-mediated protection of the barrier using specific antagonists and RNA interference technique. Finally, we investigate the effects and signal pathways of arctigenin on the expressions of tight junction-related proteins and mucins, and elucidate the molecular mechanisms by which it activates ERβ and consequently regulates the key signal pathway. The findings will provide evidence for the development of arctigenin as a mucosal barrier protector to treat UC.