藏药方剂藏降脂胶囊血清药物化学和作用机制研究

Study on the Mechanism of Action of“Zang-Jiang-Zhi”Capsule in the Treatment of Hyperlipidemia Based on Serum Medicinal Chemistry and Network Pharmacology

目的分析藏降脂胶囊入血成分及代谢物产物,并探讨其治疗高脂血症的作用机制。方法采用UHPLC-Q-Exactive Orbitrap MS技术对藏降脂胶囊入血成分进行检测,通过比对给药血清、空白血清质谱信息,结合已有文献,鉴定入血成分及代谢物;利用SwissTargetPrediction、SuperPred数据库预测入血成分的靶点;使用STRING数据库构建PPI网络;运用Cytoscape软件构建“药物-成分-靶点-疾病”网络;通过DAVID数据库对靶点进行GO和KEGG富集分析;使用分子对接技术进行初步验证。结果从大鼠血清中共检测到13个入血成分及20个代谢物。在数据库中收集得到入血成分对应靶点556个,其中173个靶点与高脂血症靶点有交集。通过PPI、GO和KEGG分析表明,藏降脂胶囊治疗高脂血症主要的潜在作用靶点有HSP90AA1、PIK3CA、PIK3CB、AKT1、ESR1、RXRA、JAK1、JAK2等,主要涉及的信号通路有Th17细胞分化(Th17 cell differentiation)、内分泌抵抗(Endocrine resistance)、脂质和动脉粥样硬化(Lipid and atherosclerosis)、糖尿病并发症中的AGE-RAGE信号通路(AGE-RAGE signaling pathway in diabetic complications)、鞘磷脂信号通路(Sphingolipid signaling pathway)、胰岛素抵抗(Insulin resistance)。分子对接表明关键靶标与入血成分之间具有潜在的亲和力。结论藏降脂胶囊的入血成分可能是其治疗高脂血症的主要药效物质基础,其通过调节与高血脂相关的多个靶点和多条通路来发挥治疗高脂血症的作用。本研究为藏降脂胶囊的临床应用提供了更多分子水平证据。

Objective To analyse the blood entry components and metabolite products of“Zang-Jiang-Zhi”Capsule,and to investigate their mechanism of action in the treatment of hyperlipidemia.Methods The UHPLC-Q-Exactive Orbitrap MS technique was used for the determination of the blood-entry components of“Zang-Jiang-Zhi”Capsule,and the identification of the enrolled components and metabolites was carried out by comparing the mass spectral information of administered serum and blank serum,and by combining with the existing literature.Swiss Target Prediction and Super Pred databases were used to predict the targets of the entry components.Construct PPI network using STRING database.Cytoscape software was used to construct the“drug-component-target-disease”network.GO and KEGG enrichment analyses were performed on the targets using the DAVID database.The preliminary validation was carried out by molecular docking technique.Results A total of 13 components and 20 metabolites were detected in rat serum.The database was collected to obtain 556 targets corresponding to the blood entry components,of which 173 targets intersected with hyperlipidemic targets.PPI,GO,and KEGG analyses showed the main potential targets of HSP90AA1,PIK3CA,PIK3CB,AKT1,ESR1,RXRA,JAK1,JAK2.The main signaling pathways involved in the treatment of hyperlipidemia with“Zang-Jiang-Zhi”Capsule include th17 cell differentiation,endocrine resistance,lipid and atherosclerosis,AGE-RAGE signaling pathway in diabetic complications,sphingolipid signaling pathway,and insulin resistance.The molecular docking showed that there was a good affinity between the key targets and the blood-entry components.Conclusion The blood-entry components of“Zang-Jiang-Zhi”Capsule may be the main pharmacological material basis for its treatment of hyperlipidemia,and provide more molecular level evidence for its clinical application by treating hyperlipidemia through the mechanism of multi component-multi target-multi pathway.