抗糖尿病肾病的cyperane型倍半萜的发现及作用机制研究

Diabetic nephrophathy (DN) is a major and serious complication of diabetes mellitus, which has become the most common cause of end-stage renal disease. However, clinically available drugs for DN are scarce. Several sesquiterpenoids have shown their potential in DN. However, the anti-DN activity of the overwhelming majority of carbon skeletons should be further studied, and the anti-DN mechanism as well as the structure-activity relationship are unclear. In preliminary studies, 17 new sesquiterpenoids were isolated from Chiloscyphus polyanthus var. rivularis, in which the cyperane type sesquiterpenoids can be considered as new type of anti-DN compounds via inhibiting the proliferation of high-glucose-induced mesangial cells and the expression of fibronectin and collagen Ⅳ. In this study, the chemical constituents of C. polyanthus var. rivularis and Achillea wilsoniana will be achieved to evaluate the anti-DN activity of cyperane-type sesquiterpenoids. We will also study the effect on TGF-β/Smad signaling pathway induced by active compounds. Those studies will broaden our understanding of anti-DN active sesquiterpenoids and the function of TGF-β/Smad signaling pathway in DN and lead to new strategies to overcome DN in the future.

糖尿病肾病(DN)是糖尿病的严重慢性并发症，是终末期肾病的主要病因。目前，临床上尚未有有效的治疗DN的药物。个别倍半萜化合物被证明具有抗DN的作用，但大部分的结构类型仍有待研究，且构效关系与作用机制尚不明确。在前期工作期间，我们从裂萼苔水生变种中分离获得17个新的倍半萜。其中cyperane型倍半萜可以抑制高糖刺激下大鼠肾系膜细胞的增殖，并有效控制高糖刺激下纤连蛋白和胶原蛋白Ⅳ的过度分泌，是一种新型抗DN化合物。本项目以抗DN 活性为指导，继续对裂萼苔水生变种和云南蓍中的cyperane型倍半萜进行分离和鉴定；通过体外抗DN活性评价，讨论该类倍半萜发挥抗DN作用的活性基团，揭示化学成分结构类型与植物活性的相关性；并针对TGF-β/Smad信号通路中的关键因子开展研究，探讨该类型倍半萜抗DN的作用机制。本课题的完成，将为抗DN药物的研发奠定基础。

糖尿病肾病(DN)是糖尿病的严重慢性并发症，是终末期肾病的主要病因。目前，临床上尚未有有效的治疗DN的药物。本研究在苔藓植物裂萼苔水生变种，圆叶羽苔和菊科蓍属植物短瓣蓍中发现了22个萜类化合物，包括2个新的cyperane型倍半萜，6个新的桉烷型倍半萜，和2个具有新颖骨架的香橙烷型倍半萜化合物。其中cyperane型倍半萜能够抑制高糖诱导的大鼠肾系膜细胞增殖和以纤连蛋白和胶原蛋白Ⅳ为代表的细胞外基质的累积，表现出治疗DN的潜力。本课题的完成，阐释了上述药用植物的药效物质基础，为对苔藓植物以及蓍属植物资源的开发利用与治疗或预防DN的药物研发奠定基础。