基于网络药理学研究六君子汤治疗年龄相关性黄斑变性的机制

The Mechanism of Liujunzi Decoction for Treatment of Age-Related Macular Degeneration Based on Network Pharmacology

  • 摘要:
      目的  通过网络药理学分析六君子汤治疗年龄相关性黄斑变性(AMD)的靶点和信号通路,并探讨其作用机制。
      方法  从中药网络药理学数据和分析平台(TCMSP)搜索六君子汤6味中药的化学成分,并筛选出可能活性成分;在Swiss Target Prediction数据库查询活性成分的对应靶点;使用DrugBank、TTD和OMIM数据库收集AMD的疾病靶点;Venny分析得到活性成分和疾病的共同靶点;从String数据库获取共同靶点的蛋白相互作用信息,使用Cytoscape软件构建蛋白相互作用网络和活性成分-靶点相互作用网络;通过David数据库进行共同靶点基因功能GO和KEGG通路富集分析;采用SD大鼠制备含药血清,通过ARPE-19细胞,验证六君子汤对关键信号通路的影响。
      结果  获得六君子汤活性成分154个、对应靶点934个,AMD疾病靶点266个,两者共同靶点92个;蛋白相互作用网络分析得到37个主要靶点,活性成分-靶点网络分析获得39个关键活性成分;GO分析获得277个生物过程条目,主要富集在转录因子结合、丝氨酸/苏氨酸激酶活性、蛋白质磷酸化、蛋白激酶C活性、蛋白激酶活性、蛋白脱乙酰酶活性、蛋白自磷酸化、肽-丝氨酸磷酸化、NAD依赖的组蛋白脱乙酰酶活性、MAP激酶活性等。KEGG通路分析产生107个条目,主要富集在VEGF信号通路、Toll样受体信号通路、肿瘤坏死因子信号通路、NOD样受体信号通路、催乳素信号通路、神经营养素信号通路、MAPK信号通路、炎症介质对TRP通道的调节等;六君子汤对氧化损伤ARPE-19细胞有保护作用,能下调VEGF、AKT、ERK1/2及p38蛋白表达。
      结论  六君子汤是通过多组分、多途径、多靶点发挥治疗AMD的作用,潜在机制是影响细胞增殖和迁移、细胞凋亡、血管形成、炎症过程。

     

    Abstract:
      OBJECTIVE  To analyze the targets and signal pathways of Liujunzi decoction in the treatment of age-related macular degeneration (AMD) by network pharmacology, and explore the mechanism of action.
      METHODS  The chemical constituents of six herbs of Liujunzi Decoction were searched from the TCMSP, and the active ingredients were screened out. The corresponding targets of the active ingredients were searched from the Swiss Target Prediction database, the disease targets of AMD were collected through Drugbank, TTD and OMIM databases, the common targets of the active ingredients and disease were determined by Venny analysis. The protein interaction information of common targets was obtained from String database, the target protein interaction network and active ingredient-targets interaction network were constructed with Cytoscape software, the gene function GO and KEGG pathway enrichment analysis were carried out by David database.
      RESULTS  Liujunzi decoction contains 154 active ingredients and 934 corresponding targets, AMD has 266 disease targets, common targets are 92. 37 major targets were obtained by protein interaction network, 39 key active ingredients were obtained by active ingredients-target network. The gene function GO enrichment yielded 277 biological processes entries, mainly involving in transcription factor binding, serine/threonine kinase activity, protein phosphorylation, protein kinase C activity, protein kinase activity, protein deacetylase activity, protein autophosphorylation, peptidyl-tyrosine phosphorylation, NAD-dependent histone deacetylase activity, and MAP kinase activity. KEGG pathway enrichment generated 107 signal pathways, mainly involving in VEGF signaling pathway, Toll-like receptor signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, prolactin signaling pathway, neurotrophin signaling pathway, MAPK signaling pathway and inflammatory mediator regulation of TRP channels. The serum containing Liujunzi decoction could protect ARPE-19 cells from oxidative injury, and down-regulate the expressions of VEGF, Akt, ERK1/2 and p38.
      CONCLUSION  Liujunzi decoction plays an active role through multi-component, multi-target and multi-pathway. The underlying mechanism in treatment of AMD may be to regulate cell proliferation and migration, apoptosis, angiogenesis and inflammation.

     

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