马齿苋经CMPK2/NLRP3/Caspase-1通路抑制IL-1β治疗慢性溃疡性结肠炎的作用机制及药效物质研究

马齿苋为治疗溃疡性结肠炎（UC）常用中药，但其作用机制及药效物质尚不明确。本课题组研究马齿苋12年，已分得150个化合物，49个为新化合物，并发现其新生物碱可显著抑制IL-1β等炎症因子，下调NF-κB、MAPK通路多种蛋白或基因表达。基于前期基础及文献分析，提出假说：参与UC病变的重要炎症因子IL-1β前体的成熟、释放与CMPK2/NLRP3/Caspase-1通路多靶点激活密切相关，马齿苋可通过生物碱等多组分协同调控该信号通路多靶点而发挥治疗UC作用。本项目将建立葡聚糖硫酸钠诱导的慢性UC小鼠模型，阐明马齿苋经CMPK2/NLRP3/Caspase-1通路抑制IL-1β产生而治疗UC的作用靶点；建立脂多糖诱导的RAW264.7巨噬细胞炎症模型，以体内实验阐明的作用靶点验证候选单体化合物的活性，通过体内-外关联实验研究，揭示马齿苋治疗UC的药效物质，为马齿苋及其单体新药研制提供科学依据。

Portulaca oleracea L. is a common Chinese medicine for the treatment of ulcerative colitis (UC) in clinical, but its mechanism and pharmacodynamic substances have not been gotten clearly. In the past 12 years, 150 compounds including 49 new compounds have been isolated from P. oleracea by our research group, and we found that some new alkaloids in P. oleracea can significantly inhibited IL-1β and other inflammatory factors, down-regulate many proteins or genes expression of the NF-κB and MAPK signaling pathways. Based on the previous foundation and literature analysis, the hypothesis was proposed: the maturation and release of the precursor of IL-1β (pro-IL-1β), an important inflammatory factor involved in UC pathology, are closely related to the activation of multiple targets of CMPK2/NLRP3/Caspase-1 signaling pathway, and P. oleracea plays the role in treatment of UC via its alkaloids and other components synergistically regulating the multiple targets of CMPK2/NLRP3/Caspase-1 signaling pathway. This project will establish a chronic UC mouse model induced by dextran sodium sulfate (DSS) to in vivo clarify the mechanism of P. oleracea in the treatment of UC via CMPK2/NLRP3/Caspase-1 signaling pathway inhibiting the produce of IL-1β, to verify the activities of the candidate monomeric compounds isolated from P. oleracea in our lab based on the action targets elucidated in the vivo assay on the inflammatory model of RAW264.7 cells induced by lipopolysaccharide (LPS) , and to elucidate the pharmacodynamic substances of P. oleracea in the treatment of UC via in vivo and in vitro correlation experimental study. The project will provide scientific basis for the research and development of the target drugs of P. oleracea and its monomeric compounds in the treatment of UC.