Feng Chaoqun, Zhao Min, Jiang Leiming, Hu Ziang, Fan Xiaohong
Department of Orthopedics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
Evid Based Complement Alternat Med. 2021 Feb 12;2021:6680637. doi: 10.1155/2021/6680637. eCollection 2021.
This study aimed to explore the mechanism of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis via a combination of network pharmacology and molecular docking.
The main chemical components and corresponding targets of Modified Danggui Sini Decoction were searched and screened in TCMSP database. The disease targets of knee osteoarthritis were summarized in GeneCards, OMIM, PharmGkb, TTD, and DrugBank databases. The visual interactive network of "drugs-active components-disease targets" was drawn by Cytoscape 3.8.1 software. The protein-protein interaction network was constructed by STRING database. Then, GO function and KEGG pathway enrichment were analyzed by Bioconductor/R, and the pathway of the highest degree of correlation with knee osteoarthritis was selected for specific analysis. Finally, molecular docking was used to screen and verify core genes by AutoDockTools software.
Seventy-one main components of Modified Danggui Sini Decoction and 116 potential therapeutic targets of knee osteoarthritis were selected. The KEGG pathway and the GO function enrichment analysis showed that the targets of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis were mainly concentrated on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, apoptosis signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation signaling pathway, HIF-1 signaling pathway, and NF-B signaling pathway. It mainly involved inflammatory reaction, regulation of apoptotic signaling pathway, cellular response to regulation of inflammatory response, cellular response to oxidative stress, and other biological processes. The molecular docking results showed that ESR1-wogonin, MAPK1-quercetin, RELA-wogonin, RELA-baicalein, TP53-baicalein, TP53-quercetin, and RELA-quercetin have strong docking activities.
Modified Danggui Sini Decoction has the hierarchical network characteristics of "multicomponent, multitarget, multifunction, and multipathway" in the treatment of knee osteoarthritis. It mainly regulates the proliferation and apoptosis of chondrocytes by regulating the PI3K-Akt signaling pathway and establishes cross-talk with many downstream inflammatory-related pathways to reduce the overall inflammatory response. Meanwhile, HIF-1 expression was used to ensure the normal function and metabolism of knee joint under hypoxia condition, and the above processes play a key role in the treatment of knee osteoarthritis.
本研究旨在通过网络药理学和分子对接相结合的方法，探讨加味当归四逆汤治疗膝关节骨关节炎的作用机制。
在中药系统药理学数据库与分析平台（TCMSP）中检索并筛选加味当归四逆汤的主要化学成分及相应靶点。在基因卡片（GeneCards）、在线人类孟德尔遗传数据库（OMIM）、药物基因组学知识库（PharmGkb）、治疗靶点数据库（TTD）和药物银行（DrugBank）数据库中总结膝关节骨关节炎的疾病靶点。利用Cytoscape 3.8.1软件绘制“药物-活性成分-疾病靶点”可视化交互网络。通过STRING数据库构建蛋白质-蛋白质相互作用网络。然后，利用Bioconductor/R软件进行基因本体（GO）功能和京都基因与基因组百科全书（KEGG）通路富集分析，并选择与膝关节骨关节炎相关性最高的通路进行具体分析。最后，使用AutoDockTools软件通过分子对接筛选并验证核心基因。
筛选出加味当归四逆汤71种主要成分和膝关节骨关节炎116个潜在治疗靶点。KEGG通路和GO功能富集分析表明，加味当归四逆汤治疗膝关节骨关节炎的靶点主要集中在磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）信号通路、肿瘤坏死因子（TNF）信号通路、白细胞介素-17（IL-17）信号通路、凋亡信号通路、Toll样受体信号通路、辅助性T细胞17（Th17）细胞分化信号通路、低氧诱导因子-1（HIF-1）信号通路和核因子-κB（NF-κB）信号通路。主要涉及炎症反应、凋亡信号通路调控、细胞对炎症反应调控的应答、细胞对氧化应激的应答等生物学过程。分子对接结果显示，雌激素受体1（ESR1）-汉黄芩素、丝裂原活化蛋白激酶1（MAPK1）-槲皮素、信号转导和转录激活因子1（RELA）-汉黄芩素、RELA-黄芩苷、肿瘤蛋白p53（TP53）-黄芩苷、TP53-槲皮素和RELA-槲皮素具有较强的对接活性。
加味当归四逆汤在治疗膝关节骨关节炎方面具有“多成分、多靶点、多功能、多途径”的层次网络特征。它主要通过调节PI3K-Akt信号通路来调控软骨细胞的增殖和凋亡，并与许多下游炎症相关通路建立相互作用，以降低整体炎症反应。同时，利用HIF-1表达确保缺氧条件下膝关节的正常功能和代谢，上述过程在膝关节骨关节炎的治疗中起关键作用。
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