基于网络药理学的夏黄颗粒治疗阿片类药物所致便秘的作用机制研究

目的 探索夏黄颗粒治疗阿片类药物所致便秘的潜在作用机制。方法 在TCMSP数据库中查找夏黄颗粒的各药材成分和靶点信息,在Genecards数据库中以“opiod constipation”“opioid-induced bowel dysfunction”“opioid-induced constipation”为关键词搜索阿片类药物所致便秘相关靶点,与夏黄颗粒活性靶点映射筛选出共同靶点作为研究靶点;将共同靶点导入STRING数据库中构建靶点相互作用网络图,利用Cytoscape 3.3.0软件进行可视化处理,筛选出核心靶点;借助OmicsBean分析平台与STRING数据库对靶点进行基因本体论（GO）功能和基因组百科全书（KEGG）通路富集分析。结果 通过筛选得到夏黄颗粒化学成分55个,候选靶基因158个,Venny映射后的共同靶点86个,对应化学成分49个,核心靶点12个,主要化学成分19个。GO功能富集分析得到生物过程条目4 150个,涉及化学刺激性细胞反应、化学反应、生物质量调控等过程;细胞组成条目302个,涉及体元投射、细胞外间隙、全膜等过程;分子功能条目459个,涉及蛋白结合、分子转导活性、酶结合等过程。KEGG富集分析得到与夏黄颗粒作用相关的信号通路149条,涉及糖尿病并发症AGE-RAGE信号通路、肿瘤坏死因子信号通路等;构建了夏黄颗粒核心靶点的“药材-成分-靶点-通路”网络。结论 夏黄颗粒中主要化学成分柚皮素、川陈皮素、芦荟大黄素、大黄酸等可能通过作用于TNF、MAPK3、IL-6、VEGFA、PTGS2等关键蛋白,调节内分泌抵抗、肿瘤坏死因子信号通路等信号通路,发挥通便、解痉、促进胃肠运动等作用,为夏黄颗粒治疗阿片类药物所致便秘提供理论依据,同时与夏黄颗粒药效初步验证结果相吻合。

Mechanism of Xiahuang Granules in treating opioid-induced constipation based on network pharmacology

Objective To explore the potential mechanism of Xiahuang Granules in the treatment of opioid-induced constipation. Methods Various medicinal ingredients and targets information of Xiahuang Granules were found in TCMSP database. In Genecards database, "opiod constipation", "opioid-induced bowel dysfunction" and "opioid-induced constipation" were used as keywords to search for targets related to opioid-induced constipation, and the active targets mapping of Xiahuang Granules were selected as the research targets. The common targets were imported into the STRING database to build the targets interaction network diagram, and Cytoscape 3.3.0 software was used for visual processing to screen out the core targets. The OmicsBean analysis platform and STRING database were used to conduct GO function enrichment and KEGG pathway enrichment analysis on the targets. Results A total of 55 chemical constituents, 158 candidate target genes, 86 common targets after mapping Venny, 49 corresponding chemical components, 12 core targets and 19 main chemical components of Xiahuang Granules were obtained by screening. GO functional enrichment analysis showed 4 150 biological process items, involving chemical stimulus cell reactions, chemical reactions, biological quality control and other processes; A total of 302 cell composition items, involving voxel projection, extracellular space, and whole membrane processes; A total of 459 molecules function items, involving processes such as protein binding, molecular transduction activity, and enzyme binding were obtained. KEGG enrichment analysis revealed 149 signaling pathways related to the effect of Xiahuang Granules, involving the AGE-RAGE signaling pathway in diabetic complications and tumor necrosis factor signaling pathway, etc. The network of "medicinal herb-component-target-pathway" of Xiahuang Granules was established. Conclusion The main chemical components of Xiahuang Granules including naringenin, nobiletin, aloe emodin, rhein may regulate endocrine resistance and tumor necrosis factor signaling pathways by acting on key proteins such as TNF, MAPK3, IL-6, VEGFA, and PTGS2, thus play a role in laxative, antispasmodic, and promoting gastrointestinal motility, which provides theoretical basis for Xiahuang Granules to treat opioid-induced constipation and is consistent with the preliminary verification results of Xiahuang granules.