基于网络药理学的熟地黄干预骨质疏松症分子机制研究

目的:运用网络药理学方法分析熟地黄干预骨质疏松症(osteoporosis,OP)的分子机制。方法:运用网络药理学方法,采用药代动力学参数(ADME)筛选标准,通过靶基因预测技术、网络构建、网络结构拓扑分析技术、GO富集分析和KEGG通路分析技术,研究熟地黄干预OP的分子机制。结果:在中药系统药理学数据库和分析平台(TCMSP)中检索到熟地黄中化合物76种,通过ADME筛选和PubMed验证、补充,最终获得熟地黄活性成分14种,利用靶基因预测技术获得靶基因128个。通过疾病数据库获取与OP相关的靶基因336个。利用网络构建软件和STRING数据库分别构建蛋白质相互作用网络。将两个网络相互映射,并经过网络拓扑分析,获得熟地黄干预OP的关键靶基因47个。基因富集结果显示,熟地黄干预OP主要通过RAS信号通路、RAP1信号通路、PI3K-AKT信号通路,同时还包括雌激素信号通路、低氧诱导因子-1(HIF-1)信号通路、甲状腺激素信号通路、催产素信号通路、血管内皮生长因子(VEGF)信号通路、性腺激素信号通路、cGMP-PKG信号通路、钙信号通路、胰岛素信号通路。结论:熟地黄干预OP具有多组分、多靶点、协同作用的特点,其通过以RAS、RAP1、PI3K-AKT为主的众多信号通路下的关键靶基因对骨代谢产生双向调控作用,促进成骨作用;同时激活大量间接靶点,通过调节人体内分泌、改变离子通道状态、影响骨周围组织代谢等途径对骨代谢产生综合影响。

Study on Molecular Mechanism of Shudihuang(Rehmanniae Radix Praeparata) in Treating Osteoporosis Based on Network Pharmacology

Objective:To analyze the molecular mechanism of Shudihuang(Rehmanniae Radix Praeparata) in treating osteoporosis(OP) based on network pharmacology. Methods:In this study,based on network pharmacology,the molecular mechanism of Shudihuang in treating OP was studied by ADME screening criteria,target gene prediction technology,network construction,network structure topology analysis,GO enrichment analysis and KEGG pathway analysis. Results:A total of 76 compounds of Shudihuang were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),14 active ingredients of Shudihuang were finally obtained through ADME screening and PubMed verification and supplementation,and 128 target genes were obtained by using target gene prediction technology.A total of 336 OP-related target genes were obtained from the disease-related database. Protein interaction networks were constructed by using network building software and STRING database. The two networks were mapped to each other and 47 key target genes of Shudihuang were obtained through network topology analysis. Gene enrichment results showed that in treating OP,Shudihuang acts mainly through RAS signaling pathway,RAP1 signaling pathway and PI3 K-AKT signaling pathway. It also includes estrogen signaling pathway,HIF-1 signaling pathway,thyroid hormone signaling pathway,oxytocin signaling pathway,VEGF signaling pathway,gonadal hormone signaling pathway,c GMP-PKG signaling pathway,calcium signaling pathway and insulin signaling pathway. Conclusion:In the intervention of OP,Shudihuang is characterized by multi-component,multi-target and synergistic effect. It can exert bi-directional regulation on bone metabolism and promote osteogenesis through key target genes in RAS signaling pathway,RAP1 signaling pathway and PI3 K-AKT signaling pathway. Meanwhile,a large number of indirect targets are activated to exert a comprehensive impact on bone metabolism by regulating endocrine,changing the state of ion channels and influencing the metabolism of the surrounding soft tissues.