基于“组-效-网”研究思路的岩黄连抗肝纤维化药效活性成分群及作用机制研究

Hepatic fibrosis is an important step in the development of malignant liver disease. Guangxi Zhuang Autonomous Region, the high incidence zone of liver disease, is crying for the therapeutic drugs for the liver disease with definite effect and clear mechanism. Corydalis saxicola Bunting (CS) is a traditional herbal medicine commonly used for the treatment of hepatitis and cirrhosis in Guangxi. CS was reported to have activities of liver-protection and anti-hepatic fibrosis, however, its active composition and therapeutic mechanism have not been clearly studied so far. Consequently, based on the “composition-effect-network” strategy by integrating multidisciplinary-technology including pharmaceutical analysis, pharmacology, mathematical statistics and molecular biology, the characteristic spectrum of the CS extract will be constructed, the active constituents contributing to the effect will be discriminated by means of correlating the changes of chemical composition and corresponding effect, and the effective basis of anti-hepatic fibrosis of CS will be elucidated preliminarily. Meanwhile, the biomarkers relating activity involved in the holistic metabolic network regulation of anti-hepatic fibrosis by CS treatment were investigated, and the action mode of anti-hepatic fibrosis of CS will be characterized by utilizing metabolomics approach, furthermore, the anti-hepatic fibrosis action mechanism of CS will be revealed by association analysis between the changes of active constituents and the fluctuation of those biomarkers relating activity. On this foundation, our study will provide scientific basis for the further research and development of Corydalis saxicola Bunting, and facilitate to improve the human health standard of living.

肝纤维化是诸多恶性肝病发展过程中的重要环节，广西作为肝病的高发区，急需找到疗效确切、作用机制清晰的治疗药物。岩黄连是广西地区用于治疗肝炎、肝硬化等疾病的常用药，具有护肝抗肝纤维化的药效，但其药效物质基础及作用机制尚未得到全面深入的研究，鉴于此，本研究以“组-效-网”的研究思路为指导，综合药物分析、药理学、数理统计、分子生物学等多学科技术和方法，通过构建不同批次岩黄连提取物的特征图谱，将组分的变化与之对应的药效指标相关联，锁定对药效贡献较大的活性成分群，初步阐明岩黄连抗肝纤维化的活性物质基础；通过代谢组学技术，阐明岩黄连在干预肝纤维化过程中对整体代谢网络调控起效的生物标志物，解析岩黄连抗肝纤维化的作用模式，将活性成分的变化与起效生物标志物的波动进行关联分析，深入阐明岩黄连药效活性组分抗肝纤维化的作用机制，从而为岩黄连的进一步开发利用提供科学依据，提高人民群众的健康生活水平。

肝纤维化是诸多恶性肝病发展过程中的重要环节，广西作为肝病的高发区，急需找到疗效确切、作用机制清晰的治疗药物。岩黄连是广西地区用于治疗肝炎、肝硬化等疾病的常用药，具有护肝抗肝纤维化的药效，但其药效物质基础及作用机制尚未得到全面深入的研究。鉴于此，本项目（1）复制CCl4诱导肝纤维化的大鼠模型，研究岩黄连对肝纤维化大鼠血清生化指标如AST、ALT、ALP、MDA和SOD的影响，明确了岩黄连对肝纤维化的改善作用；（2）采用HPLC建立了岩黄连指纹图谱，获得了15个共有峰，并对其中4个指标性成分进行了同时定量分析；（3）建立了“组-效”关系模型，选用多元统计学分析将共有峰的变化与对应的药效指标相关联，锁定了3个药效贡献较大的活性成分，阐明了岩黄连抗肝纤维化作用的药效物质基础；（4）基于核磁共振氢谱代谢组学研究方法，表征了各组大鼠血清代谢轮廓区别，确定了12个与肝纤维化密切相关的血清生物标志物，构建了岩黄连发挥抗肝纤维化作用所调控的血清综合代谢网络；（5）采用液质代谢组学研究策略对肝纤维化大鼠肝组织进行了代谢轮廓分析，筛选和鉴定了与疾病相关的6个潜在生物标志物，并以此绘制了岩黄连抗肝纤维化的肝组织代谢网络结构。本项目从血清和肝组织代谢水平层面，基于“组-效-网”研究思路揭示了岩黄连药效活性组分，初步阐明了其抗肝纤维化的潜在作用机制，为岩黄连的进一步开发利用提供了科学依据，也为挖掘天然药物药效活性成分及作用机制提供了新思路和方法。