基于网络药理学探讨大陷胸汤治疗消化道穿孔引起的急性弥漫性腹膜炎作用机制

Discussion on Mechanism of Daxianxiong Decoction in the Treatment of Acute Diffuse Peritonitis Caused by Gastrointestinal Perforation Based on Network Pharmacology

目的:基于网络药理学探讨大陷胸汤治疗消化道穿孔引起的急性弥漫性腹膜炎的作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP)数据库、化学专业数据库、中医药百科全书(ETCM)数据库获取并筛选出大黄、芒硝、甘遂的主要化学成分及其靶点。利用人类基因数据库(GeneCards)、在线人类孟德尔遗传数据库(OMIM)、DisGeNet、DrugBank数据库获取主要疾病靶点。采用STRING平台进行蛋白质相互作用分析,构建蛋白互作(PPI)网络并挖掘网络中潜在的蛋白质功能模块。利用Metascape平台分析“药物-成分-靶点”及其参与的生物过程及通路,通过Cytoscape3.7.1软件构建“成分-疾病靶点-通路”网络,采用AutoDock Tools 1.5.6进行分子对接验证。结果:大陷胸汤治疗消化道穿孔引起的急性弥漫性腹膜炎的核心活性成分为山柰酚、芦荟大黄素、白皮杉醇、甘遂素A等,核心靶点有磷脂酰肌醇-3-激酶(PIK3CA)、磷脂酰肌醇3-激酶调节亚基α (PIK3R1)、丝氨酸/苏氨酸蛋白激酶1 (AKT1)、雌激素受体(ESR1)、肿瘤蛋白P53 (TP53)等。大陷胸汤治疗消化道穿孔引起的急性弥漫性腹膜炎的生物学通路主要作用于磷脂酰肌醇3-激酶-蛋白激酶B (PI3K-Akt)信号通路、表皮生长因子受体(EGFR)-酪氨酸激酶抑制剂(TKI)耐药性通路、糖尿病并发症中的晚期糖基化终末产物及其受体(AGE-RAGE)信号通路,其功能主要为参与炎症反应、细胞稳态调节及细胞的增殖调控,在促进细胞生长、抑制细胞凋亡方面起重要作用等。分子对接结果显示,大陷胸汤中的核心化合物山柰酚、芦荟大黄素、白皮杉醇等与主要靶点AKT1、ESR1、TP53的结合活性较强。结论:大陷胸汤可通过调节PIK3CA、PIK3R1、AKT1等靶点发挥治疗消化道穿孔引起的急性弥漫性腹膜炎的功效,其作用机制与PI3K-Akt信号通路、EGFR-TKI耐药性通路、糖尿病并发症中的AGE-RAGE信号通路密切相关。

Objective:To discuss the mechanism of Daxianxiong Decoction in the treatment of acute diffuse peritonitis caused by gastrointestinal perforation based on network pharmacology. Methods: The Traditional Chinese Medicine Systems Pharmacology(TCMSP) database and analysis platform, chemistry database, and Encyclopedia of Traditional Chinese Medicine(ETCM) database were used to obtain and screen out the main chemical components and their corresponding targets of Rhei Radix et Rhizoma,Natrii Sulfas and Kansui Radix. Main disease targets were retrieved by databases including GeneCards,Online Mendelian Inheritance in Man(OMIM),DisGeNet,and DrugBank. STRING platform was used to analyze protein interaction,construct protein-protein interaction(PPI) network and mine potential protein function modules in the network. Metascape platform was applied in the analysis of the “medicine-componenttarget” network and the biological processes and pathways it involved,the “component-disease targetpathway” network was drawn by Cytoscape 3.7.1 software, and molecular docking was verified by AutoDock Tools 1.5.6. Results: The core active components of Daxianxiong Decoction in treating acute diffuse diffuse peritonitis caused by gastrointestinal perforation were kaempferol,aloe-emodin,piceatannol,and kansuinin,horin A. The core targets were phosphatidylinositol-3-kinase(PIK3CA),phosphatidylinositol3-kinase regulatory subunit alpha(PIK3R1), serine/threonine protein kinase 1(AKT1), estrogen receptor(ESR1),tumor protein P53(TP53),etc. The biological pathway of Daxianxiong Decoction in the treatment of acute diffuse peritonitis caused by gastrointestinal perforation mainly acted on the phosphatidylinositol 3kinase-protein kinase B(PI3K-Akt) signaling pathway,epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI) medicine resistance pathway,and advanced glycation end products and AGE receptor(AGE-RAGE) signaling pathway of diabetic complications. Its major functions were involving in inflammatory responses and regulating cellular homeostasis and proliferation, and it also plays an important role in stimulating cell growth and inhibiting cell apoptosis. The results of molecular docking showed that kaempferol,aloe-emodin,and piceatannol were the core compounds of Daxianxiong Decoction,which had strong binding activities with the main targets of AKT1,ESR1,and TP53. Conclusion:Daxianxiong Decoction can treat acute diffuse peritonitis caused by gastrointestinal perforation by regulating the targets,including PIK3CA, PIK3R1 and AKT1, and its mechanism is closely related to the PI3K-Akt signaling pathway, EGFR-TKI medicine resistance pathway, and AGE-RAGE signaling pathway of diabetic complications.