陈皮-半夏药对治疗高脂血症作用机制的网络药理学分析与实验研究

The Hypolipidemic Mechanism of Citrus Reticulata-Arum Ternatum Thunb Based on Network Pharmacology and Experimental Verification

目的基于网络药理学研究陈皮-半夏药对治疗高脂血症的潜在作用机制,并通过动物实验进行初步验证。方法利用网络药理学获取陈皮-半夏药对有效成分及与高脂血症的共同靶点,进而利用David数据库进行基因本体(GO)与京都基因与基因组百科全书(KEGG)富集分析,分子对接技术对相关结果进行分子模拟对接,并通过动物实验对Hub基因表达量进行实验验证。结果得到陈皮有效成分5个、半夏有效成分13个,与高脂血症共同靶基因69个;GO富集分析发现,陈皮-半夏药对有效成分具有酶结合、RNA聚合酶Ⅱ转录因子调控、配体激活序列特异性DNA结合、类固醇激素受体结合等分子功能,可以参与对药物的反应、衰老、缺氧反应、胆固醇代谢过程、凋亡过程的负调控等生物过程;KEGG富集分析结果主要包括非酒精性脂肪肝信号通路、肿瘤坏死因子信号通路、脂肪细胞因子信号通路等;分子对接技术证实其中的川陈皮素、黄芩苷等有效成分与3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶的对接构象优于瑞舒伐他汀。动物实验表明,陈皮-半夏药对可以有效调控Hub基因表达量,从而起到治疗高脂血症作用,对生物富集结果进行了初步验证。结论陈皮-半夏药对中的多种活性成分具有通过多靶点、多通路协同作用于高脂血症的网络机制,而川陈皮素、黄芩苷等有效成分是其发挥降脂作用的潜在分子基础。陈皮-半夏对高脂血症小鼠血脂代谢有明显改善效果,并能有效调控相关基因的表达量。

Objective To study the potential mechanism of Citrus Reticulata-Arum Ternatum Thunb in the treatment of hyperlipidemia based on network pharmacology,and to preliminaries verify it through animal experiments.Methods Network pharmacology was used to obtain the effective components of Citrus Reticulata-Arum Ternatum Thunb,and the common targets with hyperlipidemia.Then the gene ontology(GO)and d Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were carried out using David database.Finally,the relevant results were verified by molecular docking technology.The Hub gene was verified by animal experiments.Results There were 5 active components of Citrus Reticulata,13 active components of Arum Ternatum Thunb,and 69 common targets with hyperlipidemia.GO enrichment analysis found that Citrus Reticulata-Arum Ternatum Thunb had molecular functions,such as enzyme binding,RNA polymeraseⅡtranscription factor regulation,ligand-activated sequence-specific DNA binding,steroid hormone receptor binding,etc,and it can participating in certain biological processes such as response to drug,aging,response to hypoxia,cholesterol metabolic process,negative regulation of apoptotic process.KEGG pathway enrichment analysis showed that the active components of Citrus Reticulata-Arum Ternatum Thunb could participate in non-alcoholic fatty liver disease(NAFLD),tumor necrosis factor(TNF)signaling pathway,adipocytokine signaling pathway,etc.Molecular docking technology confirmed that these docking conformations of active components with HMG-CoA reductase,such as nobiletin,baicalin,and so on,were better than that of rosuvastatin.Animal experiments showed that Citrus Reticulata-Arum Ternatum Thunb could effectively regulate the expression of Hub genes,so as to play a role in the treatment of hyperlipidemia.Conclusion The active components of Citrus Reticulata-Arum Ternatum Thunb can synergistically effect on hyperlipidemia through multiple targets and multiple pathways.Besides,the active components such as nobiletin and baicalin are the potential molecular basis for its hypolipidemic effect.Citrus Reticulata-Arum Ternatum Thunb can significantly improve lipid metabolism in hyperlipidemia mice,and can effectively regulate the expression of related genes.