土家药血筒总三萜抗类风湿性关节炎及NLPR3-caspase-1-GSDMD通路调控的细胞焦亡作用机制研究

类风湿性关节炎（RA）是一种自身免疫性疾病，给患者造成了极大的痛苦，其治疗仍是世界医学界亟待攻破的难题。土家药血筒具有祛风除湿、行气止痛之功效，土家医常用于治疗热书卡别列证（风湿痹症），课题组前期从血筒中分离到系列三萜类成分，且发现其醇提物对佐剂性关节炎大鼠关节滑膜炎症有显著抑制作用，能抑制炎症相关因子TNF-α、IL-1β、IL-6等的分泌，但其物质基础仍待进一步探明。焦亡是一种涉及多种免疫性疾病的高度促炎性细胞程序性死亡，诸多研究表明RA的发生发展与细胞焦亡密切相关，血筒抑制炎性因子分泌抗RA是否与血筒三萜抑制关节滑膜细胞焦亡有关？本课题拟用运用现代分离手段分离富集血筒总三萜，利用体内外筛选相结合的模式，对血筒三萜抗NLRP3-caspase-1-GSDMD介导的细胞焦亡中起关键作用的基因、蛋白和细胞因子的变化进行研究，阐明血筒抗RA的药效物质基础和作用机制，为其临床应用奠定基础。

Rheumatoid arthritis (RA) is an autoimmune chronic disease, which often leads to great suffering to the patients. Its treatment is still a difficult problem to be solved urgently worldwide. Tujia ethnomedicine “Xuetong” possesses the effects of dispelling wind, eliminating dampness, and promoting qi circulation to relieve pain, which was used to treat arthralgia and arthritis. Previous research lead to isolate serials of triterpenes, and the ethanol extract demonstrates potential anti-arthritic effects via inhibiting the production of inflammatory cytokines (TNF-α、IL-1β、IL-6) in adjuvant induced arthritis (AIA) rat model. However, its material basis still needs further exploration. Pyroptosis is a highly pro-inflammatory programmed cell death involved in many immune diseases, many studies have shown that the occurrence and development of RA are closely related to pyroptosis, Xuetong can inhibit the secretion of inflammatory factors and play the role of anti-RA, which is related to the anti-pyroptosis of synovial cell of the joint or not? In order to elucidate the pharmacodynamic substance basis and mechanism of anti-RA of Xuetong, and lay a foundation for the application of Xuetong in treating rheumatism arthralgia syndrome, in the present study, the extensive modern spectroscopic analyses and chemical techniques will be used to isolate and enrich the total triterpenoids, and a combination of in vivo and in vitro screening will be used to evaluated the anti -RA effect of triterpenes of Xuetong, the changes of key genes, proteins and cytokines that play a key role in cell pyroptosis mediated by NLRP3-caspase-1-GSDMD pathway will be studied.