地锦草皂苷VI通过EGFR/MMP9/AKT/PI3K通路治疗类风湿性关节炎的机制
Mechanism of Asperosaponin VI Related to EGFR/MMP9/AKT/PI3K Pathway in Treatment of Rheumtoid Arthritis.
作者信息
Luo Jin-Fang, Yu Yang, Liu Jian-Xin
机构信息
School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China.
Sino-Pakistan Center on Traditional Chinese Medicine, China-Pakistan International Science and Technology Innovation Cooperation Base for Ethnic Medicine Development in Hunan Province, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua City, Hunan Province, 418000, China.
出版信息
Chin J Integr Med. 2025 Feb;31(2):131-141. doi: 10.1007/s11655-024-3767-8. Epub 2024 Nov 5.
OBJECTIVE
To explore the mechanism of action of asperosaponin VI (AVI) in the treatment of rheumatoid arthritis (RA) and validate it in ex vivo experiments using network pharmacology and molecular docking methods.
METHODS
The predicted targets of AVI were obtained from PharmMaper, UniProt and SwissTarget Prediction platforms, the disease targets were collected from Online Mendelian Inheritance in Man, Therapeutic Target Database and GeneCards databases, the intersection targets of AVI and RA were obtained from Venny 2.1.0, and the protein-protein interaction (PPI) network was obtained from STRING database, which was analyzed by Cytoscape software and screened to obtain the core targets. Cytoscape software was used to analyze PPI network and screen the core targets. Based on the Database for Annotation, Visualization and Integrated Discovery database, Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed, and Cytoscape software was used to construct the "Disease-Pathway-Target-Drug" network, which was finally verified by molecular docking and animal experiments.
RESULTS
Network pharmacological studies showed that AVI was able to modulate 289 targets, with 102 targets for the potential treatment of RA, with the core pathway being the AKT/PI3K signaling pathway, and the core targets being the epidermal growth factor receptor (EGFR) and matrix metalloproteinase 9 (MMP9). Molecular docking results showed that AVI could produce strong binding with both of the 2 core targets. In vitro cellular experiments showed that AVI reduced nitric oxide, prostaglandin E, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 β levels (P<0.05) and inhibited cyclooxygenase-2, nitric oxide synthase, EGFR, MMP9, phosphorylated phosphoinositide 3-kinase (p-PI3K), and phosphorylated serine-threonine kinase (p-AKT) proteins (P<0.05). The results of in vivo studies showed that AVI improved RA score and foot swelling thickness and decreased TNF-α, IL-6, p-PI3K and p-AKT levels in RA rats (P<0.05).
CONCLUSION
AVI exerts anti-inflammatory and anti-RA effects which might be related to the EGFR/MMP9/AKT/PI3K pathway.
目的
探讨地锦草皂苷Ⅵ（AVI）治疗类风湿关节炎（RA）的作用机制，并通过网络药理学和分子对接方法在体外实验中进行验证。
方法
从PharmMaper、UniProt和SwissTarget Prediction平台获取AVI的预测靶点，从人类孟德尔遗传在线、治疗靶点数据库和GeneCards数据库收集疾病靶点，通过Venny 2.1.0获取AVI与RA的交集靶点，从STRING数据库获取蛋白质-蛋白质相互作用（PPI）网络，用Cytoscape软件进行分析并筛选以获得核心靶点。用Cytoscape软件分析PPI网络并筛选核心靶点。基于注释、可视化和综合发现数据库进行基因本体功能和京都基因与基因组百科全书通路富集分析，并用Cytoscape软件构建“疾病-通路-靶点-药物”网络，最后通过分子对接和动物实验进行验证。
结果
网络药理学研究表明，AVI能够调节289个靶点，其中有102个靶点可能用于治疗RA，核心通路为AKT/PI3K信号通路，核心靶点为表皮生长因子受体（EGFR）和基质金属蛋白酶9（MMP9）。分子对接结果表明，AVI能与这2个核心靶点都产生强烈结合。体外细胞实验表明，AVI降低了一氧化氮、前列腺素E、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和IL-1β水平（P<0.05），并抑制了环氧合酶-2、一氧化氮合酶、EGFR、MMP9、磷酸化磷脂酰肌醇3激酶（p-PI3K）和磷酸化丝氨酸-苏氨酸激酶（p-AKT）蛋白（P<0.05）。体内研究结果表明，AVI改善了RA评分和足肿胀厚度，并降低了RA大鼠的TNF-α、IL-6、p-PI3K和p-AKT水平（P<0.05）。
结论
AVI发挥抗炎和抗RA作用可能与EGFR/MMP9/AKT/PI3K通路有关。
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