整合网络药理学和生物信息学分析便可通片抗便秘性肠易激综合征分子机制  

Mechanism Analysis of Bianketong Tablet in Treatment of Constipation-predominant Irritable Bowel Syndrome Based on Network Pharmacology and Bioinformatics

作　　者：万丹[1] 梁雪娟[1] 何丹 唐纯玉 邹笃准 唐代凤 肖娟[1] WAN Dan;LIANG Xue-juan;HE Dan;TANG Chun-yu;ZOU Du-zhun;TANG Dai-feng;XIAO Juan(Hunan Provincial Institute of Traditional Chinese Medicine,Changsha 410013,China;Hunan Times Sunshine Pharmaceutical Co.Ltd.,Yongzhou 425000,China)

机构地区：[1]湖南省中医药研究院,长沙410013 [2]湖南时代阳光药业股份有限公司,湖南永州425000

出　　处：《中国实验方剂学杂志》2021年第20期152-161,共10页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：国家重大新药创制“科技重大专项”(2018ZX09731-015);湖南省自然科学基金项目(2020JJ9046)。

摘　　要：目的:采用网络药理学联合生物信息学的分析方法,探讨便可通片治疗便秘性肠易激综合征(C-IBS)的潜在作用机制。方法:构建便可通片归经络网,分析方中9味药合用的治疗规律。依托中药系统药理学数据库与分析平台(TCMSP)数据库,以口服生物利用度(OB)和类药性(DL)为标准筛选便可通的活性成分及靶点。通过GeneCards,人类孟德尔遗传数据库(OMIM),DrugBank和DisGeNet数据库获得C-IBS治疗相关靶标集,并构建蛋白质-蛋白质相互作用(PPI)网络,利用Cytoscape 3.7.2进行网络可视化,筛选关键靶点,在DAVID平台进行基因本体(GO)注释和京都基因与基因组百科全书(KEGG)富集分析。采用冰水灌胃法制备C-IBS小鼠模型,通过酶联免疫吸附测定法(ELISA)和免疫组化法验证整合分析中便可通片抗C-IBS关键靶点的表达。结果:大肠经为便可通片治疗的主要病位。便可通片中70个潜在活性成分,可作用于227个交集靶点,通过辅助性T细胞17(Th17)细胞分化,Toll样受体,肿瘤坏死因子等多条信号通路参与炎症反应、免疫调控、肠神经调节、激素调节和氧化应激反应,发挥治疗C-IBS的作用。在体实验发现便可通片可显著提高小肠推进率,上调C-IBS小鼠血清和结肠组织血管活性肠肽(VIP)的表达;且便可通片可降低血清及结肠组织中网络预测关键蛋白核转录因子-κB(NF-κB),白细胞介素-6(IL-6),Toll样受体2(TLR2)的表达,证实了整合分析的可靠性。结论:便可通片通过"多成分,多靶点,多途径"发挥协同抗C-IBS的作用,此研究为深入阐释便可通治疗C-IBS的临床研究及进一步实验验证提供了思路。Objective:To explore the potential mechanism of Bianketong tablet(BKT)in the treatment of constipation-predominant irritable bowel syndrome(C-IBS) based on network pharmacology and bioinformatics. Method: The BKT-meridian network was constructed for analyzing the combined effect of the nine Chinese herbs in BKT. The active components and targets of BKT were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and then screened according to the oral bioavailability(OB)and drug likeness(DL)criteria. Following the acquisition of C-IBS target set from GeneCards,Online Mendelian Inheritance in Man(OMIM),Drugbank and DisGeNet,the protein-protein interaction(PPI) network was constructed. Cytoscape 3.7.2 was utilized for network visualization. The screened key targets were subjected to gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis using DAVID platform. The C-IBS mouse model was established via intragastric administration of ice water,and the key targets of BKT against C-IBS were verified by enzyme linked immunosorbent assay(ELISA)and immunohistochemistry. Result:The large intestinal meridian was the main site where BKT acted. There were 70 potential active components in BKT,which acted on 227 intersection targets. Through T helper cell 17(Th17)differentiation,Toll-like receptor(TLR),tumor necrosis factor and other signaling pathways,BKT participated in inflammatory response,immune regulation,intestinal nerve regulation,hormonal regulation,and oxidative stress response,thus exerting the therapeutic effects against C-IBS. As reveled by in vivo experiments,BKT significantly improved the small intestinal propulsion rate,upregulated the expression of vasoactive intestinal peptide(VIP)in serum and colon tissue of C-IBS mice,and down-regulated the expression of nuclear transcription factor-κB(NF-κB),interleukin(IL)-6,and TLR2 in serum and colon tissue,which confirmed the reliability of integration analysis. Conclusion: BKT inhibits C

关 键 词：便可通片 肠易激综合征 网络药理学 炎症反应 免疫调节 

分 类 号：R284.2[医药卫生—中药学] R289[医药卫生—中医学]