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基于网络药理学探析5种经典方剂治疗肝细胞癌的作用机制

程秋骆 刘柳 白长川 丛庆伟 朱英

程秋骆, 刘柳, 白长川, 等.基于网络药理学探析5种经典方剂治疗肝细胞癌的作用机制[J]. 临床肝胆病杂志, 2021, 37(8): 1848-1855. DOI: 10.3969/j.issn.1001-5256.2021.08.020
引用本文: 程秋骆, 刘柳, 白长川, 等.基于网络药理学探析5种经典方剂治疗肝细胞癌的作用机制[J]. 临床肝胆病杂志, 2021, 37(8): 1848-1855. DOI: 10.3969/j.issn.1001-5256.2021.08.020
CHENG QL, LIU L, BAI CC, et al. Mechanism of action of five classic prescriptions in treatment of hepatocellular carcinoma based on network pharmacology[J]. J Clin Hepatol, 2021, 37(8): 1848-1855. DOI: 10.3969/j.issn.1001-5256.2021.08.020
Citation: CHENG QL, LIU L, BAI CC, et al. Mechanism of action of five classic prescriptions in treatment of hepatocellular carcinoma based on network pharmacology[J]. J Clin Hepatol, 2021, 37(8): 1848-1855. DOI: 10.3969/j.issn.1001-5256.2021.08.020

基于网络药理学探析5种经典方剂治疗肝细胞癌的作用机制

DOI: 10.3969/j.issn.1001-5256.2021.08.020
基金项目: 

国家自然科学基金 81673728

详细信息
    通讯作者:

    朱英, zhuyingsh52@126.com

  • 中图分类号: R735.7

Mechanism of action of five classic prescriptions in treatment of hepatocellular carcinoma based on network pharmacology

Funds: 

National Natural Science Foundation of China 81673728

  • 摘要:   目的  运用网络药理学及分子对接技术探究逍遥散合四君子汤、茵陈蒿汤、龙胆泻肝汤合下瘀血汤、五皮饮合四君子汤、一贯煎治疗肝细胞癌的作用机制。  方法  运用TCMSP、TCMID、BATMAN-TCM、TCM-MESH等数据库筛选中药有效成分并预测其作用靶点, 通过TTD、Drugbank、Disgenet、Liverome、OncoDB.HCC、GEO等数据库挖掘肝癌相关靶点; 将药物和疾病靶点进行映射获得交集靶点, 通过可视化软件Cytoscape3.7.1构建核心成分-交集靶点网络以及蛋白相互作用网络, 筛选核心成分及关键基因并在GEPIA数据库进行生存分析, 将筛选出的活性成分和关键基因导入DockThor在线网站进行分子对接。此外, 利用David数据库对交集靶点进行基因本体(GO)富集分析以及基因组百科全书(KEGG)通路分析。  结果  经过筛选去重获得5种经典方剂活性成分分别为110、19、154、121、51个, 药物作用靶点分别为7426、1435、9544、6619、2427个。筛选去重后获得肝癌疾病靶点4001个。5种方剂经典方剂的成分靶点与肝癌疾病靶点的交集靶点分别为260、169、276、242、192个, 共同Hub基因在GEPIA在线网站生存分析结果为PIK3CA、SRC、MAPK1、MAPK3(P值均<0.05)、AKT1(P>0.05)。5种方剂共同活性成分是槲皮素, 其中3种经典方剂(逍遥散合四君子汤、龙胆泻肝汤合下瘀血汤、五皮饮合四君子汤)的共同活性成分是异补骨脂黄酮、Kanzonol W。分子对接结果从总体趋势来看3种成分与PIK3CA、SRC结合能力相对较好。GO富集分析显示这些靶点共同参与对药物的反应、蛋白质磷酸化、炎症反应、血管生成等生物学过程。KEGG富集分析显示共同参与的通路为癌症通路、PI3K-AKT通路、MAPK通路、Ras通路、HIF-1通路、乙型肝炎通路、丙型肝炎通路。  结论  槲皮素、异补骨脂黄酮和Kanzonol W抗肝癌具有多靶点、多通路的潜在作用机制。

     

  • 图  1  5种经典方剂活性成分靶点与肝癌靶点映射图

    注: a, 逍遥散合四君子汤; b, 茵陈蒿汤; c, 龙胆泻肝汤合下瘀血汤; d, 五皮饮合四君子汤; e, 一贯煎。

    图  2  5个靶蛋白基因表达与肝癌预后关系

    图  3  5种方剂关键活性成分与关键靶点分子对接评分统计图

    图  4  GO富集分析柱状图

    注: a, 逍遥散合四君子汤; b, 茵陈蒿汤; c, 龙胆泻肝汤合下瘀血汤; d, 五皮饮合四君子汤; e, 一贯煎。

    图  5  KEGG通路富集分析气泡图

    注: a, 逍遥散合四君子汤; b, 茵陈蒿汤; c, 龙胆泻肝汤合下瘀血汤; d, 五皮饮合四君子汤; e, 一贯煎。

    表  1  5种经典方剂度值靠前成分及其MOLID编号

    项目 逍遥散合四君子汤 茵陈蒿汤 龙胆泻肝汤合下瘀血汤 五皮饮合四君子汤 一贯煎
    自由度中位数 30 36 35 28 18
    成分MOLID编号及度值 MOL004945
    异补骨脂黄酮
    (度值: 43)
    MOL001406
    藏花酸
    (度值: 42)
    MOL000552
    Tenaxin I
    (度值: 44)
    MOL004945
    异补骨脂黄酮
    (度值: 43)
    MOL005384
    苏奇内酯
    (度值: 43)
    MOL004820
    Kanzonol W
    (度值: 42)
    MOL008041
    Eupatolitin
    (度值: 41)
    MOL002932
    Panicolin
    (度值: 44)
    MOL004820
    Kanzonol W
    (度值: 42)
    MOL000098
    槲皮素
    (度值: 38)
    MOL001689
    刺槐素
    (度值: 42)
    MOL008040
    泽兰素
    (度值: 41)
    MOL004945
    异补骨脂黄酮
    (度值: 43)
    MOL000098
    槲皮素
    (度值: 41)
    MOL002056
    蛇菰宁
    (度值: 37)
    MOL002881
    香叶木素
    (度值: 41)
    MOL000354
    异鼠李素
    (度值: 41)
    MOL002925
    5, 7, 2′, 6′-四羟基黄酮
    (度值: 43)
    MOL009650
    莨菪碱
    (度值: 28)
    MOL000098
    槲皮素
    (度值: 38)
    MOL000098
    槲皮素
    (度值: 38)
    MOL004820
    Kanzonol W
    (度值: 42)
    MOL008647
    N-反式-阿魏酸酪胺
    (度值: 28)
    MOL000098
    槲皮素
    (度值: 41)
    下载: 导出CSV

    表  2  5种经典方剂PPI网络中Hub基因度值

    方剂 逍遥散合四君子汤 茵陈蒿汤 龙胆泻肝汤合下瘀血汤 五皮饮合四君子汤 一贯煎
    靶点 PIK3CA (度值: 51) SRC (度值: 36) PIK3CA (度值: 49) SRC (度值: 48) MAPK1 (度值: 36)
    MAPK1 (度值: 48) PIK3CA (度值: 36) MAPK1 (度值: 48) PIK3CA (度值: 48) PIK3CA (度值: 35)
    SRC (度值: 48) MAPK1 (度值: 34) SRC (度值: 45) MAPK1 (度值: 43) AKT1 (度值: 34)
    AKT1 (度值: 43) MAPK3 (度值: 28) MAPK3 (度值: 44) MAPK3 (度值: 42) SRC (度值: 34)
    MAPK3 (度值: 43) AKT1 (度值: 26) AKT1 (度值: 43) AKT1 (度值: 42) MAPK3 (度值: 31)
    下载: 导出CSV

    表  3  5种经典方剂关键活性成分与关键基因的分子对接结果

    序号 活性成分 相对分子质量(g/mol) 基因(蛋白库编号)
    PIK3CA(3ZIM) MAPK1(3W55) MAPK3(4QTB) SRC(3EL7) LOXL2(5ZE3)
    1 槲皮素 302.2 -7.384 -7.220 -6.522 -8.484 -6.460
    2 异补骨脂黄酮 324.4 -7.398 -7.203 -7.109 -7.433 -7.219
    3 Kanzonol W 336.3 -7.901 -7.454 -7.330 -9.191 -7.567
    下载: 导出CSV
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