基于网络药理学探讨独活寄生汤治疗骨质疏松症的药理机制

Exploring the Pharmacological Mechanism of Duhuo Jisheng Decoction in Treating Osteoporosis Based on Network Pharmacology.

作者信息

Xiong Zhencheng, Zheng Can, Chang Yanan, Liu Kuankuan, Shu Li, Zhang Chi

机构信息

Institute of Medical Technology, Peking University Health Science Center, Beijing, China.

Peking University Third Hospital, Beijing, China.

出版信息

Evid Based Complement Alternat Med. 2021 Apr 5;2021:5510290. doi: 10.1155/2021/5510290. eCollection 2021.

OBJECTIVE

The purpose of this work is to study the mechanism of action of Duhuo Jisheng Decoction (DHJSD) in the treatment of osteoporosis based on the methods of bioinformatics and network pharmacology.

METHODS

In this study, the active compounds of each medicinal ingredient of DHJSD and their corresponding targets were obtained from TCMSP database. Osteoporosis was treated as search query in GeneCards, MalaCards, DisGeNET, Therapeutic Target Database (TTD), Comparative Toxicogenomics Database (CTD), and OMIM databases to obtain disease-related genes. The overlapping targets of DHJSD and osteoporosis were identified, and then GO and KEGG enrichment analysis were performed. Cytoscape was employed to construct DHJSD-compounds-target genes-osteoporosis network and protein-protein interaction (PPI) network. CytoHubba was utilized to select the hub genes. The activities of binding of hub genes and key components were confirmed by molecular docking.

RESULTS

174 active compounds and their 205 related potential targets were identified in DHJSD for the treatment of osteoporosis, including 10 hub genes (AKT1, ALB, IL6, MAPK3, VEGFA, JUN, CASP3, EGFR, MYC, and EGF). Pathway enrichment analysis of target proteins indicated that osteoclast differentiation, AGE-RAGE signaling pathway in diabetic complications, Wnt signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, JAK-STAT signaling pathway, calcium signaling pathway, and TNF signaling pathway were the specifically major pathways regulated by DHJSD against osteoporosis. Further verification based on molecular docking results showed that the small molecule compounds (Quercetin, Kaempferol, Beta-sitosterol, Beta-carotene, and Formononetin) contained in DHJSD generally have excellent binding affinity to the macromolecular target proteins encoded by the top 10 genes.

CONCLUSION

This study reveals the characteristics of multi-component, multi-target, and multi-pathway of DHJSD against osteoporosis and provides novel insights for verifying the mechanism of DHJSD in the treatment of osteoporosis.

目的

本研究旨在基于生物信息学和网络药理学方法，探讨独活寄生汤（DHJSD）治疗骨质疏松症的作用机制。

方法

本研究从中药系统药理学数据库与分析平台（TCMSP）数据库中获取独活寄生汤各药物成分的活性化合物及其相应靶点。以“骨质疏松症”为检索词，在基因卡片（GeneCards）、疾病卡片（MalaCards）、疾病基因数据库（DisGeNET）、治疗靶点数据库（TTD）、比较毒理基因组学数据库（CTD）和在线孟德尔人类遗传数据库（OMIM）中检索，获取疾病相关基因。确定独活寄生汤与骨质疏松症的重叠靶点，然后进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。利用Cytoscape构建独活寄生汤-化合物-靶基因-骨质疏松症网络和蛋白质-蛋白质相互作用（PPI）网络。使用CytoHubba选择枢纽基因。通过分子对接确认枢纽基因与关键成分的结合活性。

结果

确定了独活寄生汤治疗骨质疏松症的174种活性化合物及其205个相关潜在靶点，包括10个枢纽基因（AKT1、ALB、IL6、MAPK3、VEGFA、JUN、CASP3、EGFR、MYC和EGF）。对靶蛋白的通路富集分析表明，破骨细胞分化、糖尿病并发症中的晚期糖基化终末产物-受体（AGE-RAGE）信号通路、Wnt信号通路、丝裂原活化蛋白激酶（MAPK）信号通路、磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号通路、Janus激酶-信号转导和转录激活因子（JAK-STAT）信号通路、钙信号通路和肿瘤坏死因子（TNF）信号通路是独活寄生汤抗骨质疏松症特异性调控的主要通路。基于分子对接结果的进一步验证表明，独活寄生汤所含小分子化合物（槲皮素、山奈酚、β-谷甾醇、β-胡萝卜素和芒柄花素）通常对前10个基因编码的大分子靶蛋白具有良好的结合亲和力。