基于Akt1/Bad信号通路探索独一味总黄酮治疗“真布病”的作用机制及药效物质基础

本项目针对抗“真布病”（相当于类风湿关节炎RA）药物药效物质基础及作用机制不明的难题，基于藏医药理论及临床实践经验，选择对“真布病”确有疗效的藏药独一味为研究对象。申请人前期基于网络药理学的研究表明，总黄酮是独一味抗RA的主要药效物质基础，抑制Akt1/Bad信号通路而诱导成纤维样滑膜细胞（FLS）凋亡可能是总黄酮抗RA的关键作用机制。然而该机制是否为独一味总黄酮抗RA的主要作用机制，其药效物质基础是什么，尚需进一步研究。据此提出假说：抑制Akt1/Bad信号通路而诱导FLS凋亡是独一味总黄酮抗“真布病”的主要作用机制，其药效物质基础由多个成分构成。项目将基于佐剂性关节炎模型大鼠、FLS，采用分子生物学、血清药理学、血清药物化学、虚拟筛选、等温滴定量热法等技术，从整体、细胞、分子水平阐明假说的科学内涵。为提供质量稳定可控、作用机制明确的独一味总黄酮用于“真布病”的防治奠定基础。

To solve the problem of unknown pharmacodynamic material basis and mechanism of drugs against “Zhenbu Disease” equivalent to rheumatoid arthritis (RA), this project selected the Tibetan medicine Lamiophlomis rotata (LR), which shows a real curative effect on “Zhenbu Disease”, as the research object based on Tibetan medicine theory and clinical practice experience. The applicant’s preliminary research based on network pharmacology showed that total flavonoids were the main pharmacodynamic material basis of LR against RA, and the key mechanism of total flavonoids against RA may be to induce apoptosis of fibroblast-like synoviocyte (FLS) by inactivating Akt1/Bad signaling pathway. However, further research needs to be carried out to clarify whether this mechanism is the main mechanism of LR total flavonoids against RA, and what is its pharmacodynamic material basis. Based on the above research foundation, a hypothesis was proposed that “Apoptosis of FLS mediated by inactivation of Akt1/Bad signaling pathway is the main mechanism of LR total flavonoids against ‘Zhenbu Disease’. And its pharmacodynamic material basis consists of multiple ingredients.” In the project, adjuvant-induced arthritis model rats and FLS were used to clarify the scientific connotation of the hypothesis from the overall, cellular and molecular levels based on multiple research methods, such as molecular biology, serum pharmacology, serum pharmacochemistry, virtual screening, and isothermal titration calorimetry. This project can lay the foundation for providing LR total flavonoids with stable and controllable quality and clear mechanism of action for the prevention and treatment of “Zhenbu Disease”.