基于“肝脾同治”论研究萜烯缀合姜黄素类抗ALD的体内药效物质和“肝-肠”协同作用机制

“肝脾同治”论是依据《金匮要略》所载“见肝之病，知肝传脾，当先实脾”的中医经典理论提出，被历代医家所推崇，是治疗酒精性肝病（ALD）的中医基本治则。申请人前期从姜黄中获得抗ALD活性的萜烯缀合姜黄素类（TCC），其体内药效物质和作用机制不明。本项目拟基于“肝脾同治”论，立足申请人承担NSFC青年项目发现的TCC肝内、肠内移行成分，以“抑制LPS/TLR4/NF-κB通路”和“修复肠屏障功能”为切入点，提出科学假说：TCC给药后，体内药效物质经“护肝”与“实脾”两个显效途径“肝-肠”协同作用抗ALD。项目通过移行成分分析和代谢途径研究对TCC体内潜在药效物质进行鉴定与分离制备，从通路调控、信号传导和肠屏障修复多层面阐明“护肝”的肝内药效物质、“实脾”的肠内药效物质以及“护肝”与“实脾”的协同作用机制。本项目可揭示“肝脾同治”论的科学内涵，为中药抗ALD的体内药效物质和作用机制研究提供新思路。

The theory of “treating with liver and spleen together” is put forward according to the theory of “treating the disease of liver, knowing the pathogeny could transmit to the spleen, and the spleen should be treated first”, which is a classical clinical TCM theory recorded in Synopsis of the Golden Chamber and respected by physicians of past generations. It is the basic treatment of alcoholic liver disease (ALD) according to TCM theory. The applicant obtained terpene conjugated curcuminoids (TCC) with anti-ALD activity from Curcuma longa in previous studies. However, the in-vivo effective substances and therapeutic mechanisms of TCC have not been clarified yet. This project is based on the theory of “treating with liver and spleen together” and the previous researches of TCC transitional components detected in liver and intestine in the NSFC Youth Fund research managed by the applicant, by taking “inhibiting LPS/TLR4/NF-κB pathway” and “repairing intestinal barrier function” as the cut-in points, then the scientific hypothesis is put forward: after administration, the in-vivo effective substances of TCC could treat against ALD by synergistic effect of “liver and intestine” through two effective channels of “protecting the liver” and “strengthening the spleen”. In this project, we first identified the potential in-vivo effective substances of TCC by analyzing the transitional components and studying the metabolic pathway of TCC, and separated, purified them for preparation. Then, we elucidated the in-vivo effective substances with “protecting the liver” ability in liver and the in-vivo effective substances with “strengthening the spleen” ability in intestines, as well as the synergistic mechanisms of “protecting the liver” and “strengthening the spleen” from the aspects of pathway regulation, signal conduction and intestinal barrier repairing. Through this project, we could reveal the scientific connotation of “treating with liver and spleen together” TCM theory, and provide a new idea for the in-vivo effective substances and therapeutic mechanisms studies of Chinese herbal medicines with anti-ALD activity.