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中国精品科技期刊2020

基于网络药理学分析咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制

李玲玉 朱文卿 朱姗姗 张利 张鹏 郑振佳

李玲玉,朱文卿,朱姗姗,等. 基于网络药理学分析咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制[J]. 食品工业科技,2021,42(14):16−24. doi:  10.13386/j.issn1002-0306.2021010111
引用本文: 李玲玉,朱文卿,朱姗姗,等. 基于网络药理学分析咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制[J]. 食品工业科技,2021,42(14):16−24. doi:  10.13386/j.issn1002-0306.2021010111
LI Lingyu, ZHU Wenqing, ZHU Shanshan, et al. Mechanism of Caffeoylquinic Acids in the Treatment of Type II Diabetes Based on Network Pharmacology[J]. Science and Technology of Food Industry, 2021, 42(14): 16−24. (in Chinese with English abstract). doi:  10.13386/j.issn1002-0306.2021010111
Citation: LI Lingyu, ZHU Wenqing, ZHU Shanshan, et al. Mechanism of Caffeoylquinic Acids in the Treatment of Type II Diabetes Based on Network Pharmacology [J]. Science and Technology of Food Industry, 2021, 42(14): 16−24. (in Chinese with English abstract). doi:  10.13386/j.issn1002-0306.2021010111

基于网络药理学分析咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制

doi: 10.13386/j.issn1002-0306.2021010111
基金项目: 山东省自然科学基金(ZR2019BC100);2020年度山东省重点扶持区域引进急需紧缺人才项目;山东省高等学校青创人才引育计划;山东省重大科技创新工程项目(2019JZZY011020)
详细信息
    作者简介:

    李玲玉(1996−),女,硕士研究生,研究方向:农产品精深加工,E-mail:sdnydxlly@163.com

    通讯作者:

    郑振佳(1985-),男,博士,副教授,研究方向:农产品精深加工,E-mail:zhengzhenjia@sdau.edu.cn

  • 中图分类号: R285.5

Mechanism of Caffeoylquinic Acids in the Treatment of Type II Diabetes Based on Network Pharmacology

  • 摘要: 目的:基于网络药理学方法分析咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制。方法:通过文献挖掘和数据库检索获取咖啡酰奎宁酸类化合物作用靶点以及与II型糖尿病相关的疾病靶点,绘制咖啡酰奎宁酸类化合物的“成分-疾病-靶点”功效作用网络,对其进行基因本体论(GO)分析和京都基因与基因组百科全书(KEGG)通路分析,并将核心靶点蛋白与关键成分进行分子对接验证。结果:咖啡酰奎宁酸类化合物对应靶点483个,II型糖尿病相关靶点2214个,交集靶点211个,关键靶点37个。咖啡酰奎宁酸类化合物治疗II型糖尿病的作用机制主要涉及细胞外基质降解、基质金属蛋白酶的激活、胶原蛋白降解等多条通路,主要涉及AKT1、MMP3、MMP9、HIF1AIGF1RMAPK8等基因,这些基因主要通过调控葡萄糖代谢以及调节相关蛋白质发挥作用。化合物与分子靶点对接结果良好,验证了网络构建预测的准确性。结论:本研究预测了咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点与作用机制,为深入开展咖啡酰奎宁酸类化合物治疗II型糖尿病的分子机制研究提供了科学依据。
  • 图  1  “咖啡酰奎宁酸类化合物-靶点”网络图

    Figure  1.  Network diagram of "caffeoylquinic acids-target"

    图  2  咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点网络

    Figure  2.  Key target network of caffeoylquinic acids in the treatment of type II diabetes

    图  3  咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点GO分析

    Figure  3.  GO analysis of key targets of caffeoylquinic acids in the treatment of type II diabetes

    图  4  咖啡酰奎宁酸类化合物治疗II型糖尿病的关键靶点KEGG通路富集分析

    Figure  4.  KEGG pathway enrichment analysis of key targets of caffeoylquinic acids in the treatment of type II diabetes

    图  5  咖啡酰奎宁酸类化合物治疗II型糖尿病的作用通路与其相关靶点网络分析

    Figure  5.  Network analysis of the pathways of caffeoylquinic acids in the treatment of type II diabetes and their related targets

    图  6  IGF1R、JAK1、RPS6KB1与3个关键成分的最佳对接构象

    Figure  6.  Optimal docking conformation of IGF1R, JAK1, RPS6KB1 and the three key components

    注:(a). IGF1R与绿原酸的最佳对接构象;(b). JAK1与异绿原酸A的最佳对接构象;(c). RPS6KB1与1,3,5-O-三咖啡酰奎宁酸的最佳对接构象。

    表  1  咖啡酰奎宁酸类化合物治疗II型糖尿病的37个关键靶点信息表

    Table  1.   37 key targets information table of caffeoylquinic acids in the treatment of type II diabetes

    编号目标基因目标蛋白质靶向蛋白的生物学活性
    1IGF1RInsulin-like growth factor 1 receptor介导胰岛素样生长因子1
    2JAK1Tyrosine-protein kinase JAK1细胞因子信号传导过程
    3RPS6KB1Ribosomal protein S6 kinase beta-1调控细胞增殖、细胞生长和细胞周期
    4MAPK8Mitogen-activated protein kinase 8调控细胞增殖、分化及迁移
    5MTORSerine/threonine-protein kinase mTOR调节蛋白质的磷酸化
    6JAK2Tyrosine-protein kinase JAK2参与细胞生长、发育、分化及组蛋白修饰
    7HSP90AA1Heat shock protein HSP 90-alpha参与细胞周期调控及信号传导过程
    8PTPRCReceptor-type tyrosine-protein phosphatase C参与细胞生长、分化及有丝分裂等
    9SIRT1NAD-dependent protein deacetylase sirtuin-1诱导线粒体生物合成,抗炎和防止代谢下降
    10MCL1Induced myeloid leukemia cell differentiation protein Mcl-1参与调控细胞凋亡及细胞存活
    11METHepatocyte growth factor receptor调控细胞生长、生存、侵袭及转移等
    12HSPA578 kDa glucose-regulated protein促进蛋白质多聚体组装
    13ERBB2Receptor tyrosine-protein kinase erbB-2介导细胞信号转导过程
    14MMP7Matrilysin降解细胞外基质
    15ALBSerum albumin调节血浆pH和维持血浆渗透压
    16SRCProto-oncogene tyrosine-protein kinase Src编码酪氨酸蛋白激酶
    17IL2Interleukin-2调节免疫反应
    18MMP3Stromelysin-1降解纤连蛋白
    19MAPK3Mitogen-activated protein kinase 3调控细胞生长、存活及分化
    20MAPK1Mitogen-activated protein kinase 1调控细胞生长、存活及分化
    21EP300Histone acetyltransferase p300转录调节
    22MMP272 kDa type IV collagenase降解多种细胞外基质
    23PLAUUrokinase-type plasminogen activator参与细胞外基质的降解
    24MAPK14Mitogen-activated protein kinase 14参与细胞增殖、分化、转录调控等过程
    25HIF1AHypoxia-inducible factor 1-alpha转录调节
    26EGFREpidermal growth factor receptor调控细胞的生长和分化
    27MMP1Interstitial collagenase降解细胞外基质
    28PARP1Poly [ADP-ribose] polymerase 1调控细胞的增殖、分化及凋亡
    29AKT1RAC-alpha serine/threonine-protein kinase调控葡萄糖代谢
    30CASP3Caspase-3调控细胞凋亡
    31CXCR4C-X-C chemokine receptor type 4降低的细胞cAMP水平
    32CASP8Caspase-8调控细胞凋亡
    33ESR1Estrogen receptor调控细胞增殖和分化
    34VEGFAVascular endothelial growth factor A诱导内皮细胞增殖、促进内皮细胞迁移并抑制内皮细胞凋亡
    35PLGPlasminogen调控细胞增殖
    36MMP9Matrix metalloproteinase-9调控细胞外基质的局部蛋白水解和白细胞迁移
    37TNFTumor necrosis factor调控细胞的增殖与分化
    下载: 导出CSV

    表  2  KEGG通路富集分析相关基因

    Table  2.   Related genes for KEGG pathway enrichment analysis

    通路名称相关基因P-Value值基因数
    Intrinsic pathway for apoptosisAKT1, CASP3, CASP8, MAPK81.4129E-054
    MAPK3 (ERK1) activationJAK1, JAK2, MAPK34.63558E-063
    RAF-independent MAPK1/3 activationJAK1, JAK2, MAPK1, MAPK31.06568E-064
    MAPK1 (ERK2) activationJAK1, JAK2, MAPK13.25274E-063
    GPVI-mediated activation cascadeAKT1, IL-2, JAK1, JAK24.07089E-054
    Signaling by ERBB2AKT1, EGFR, erb-B2, HSP90AA1, SRC7.4417E-075
    Regulation of gene expression by Hypoxia-inducible FactorEP300, HIF-1α, VEGF-A6.35858E-063
    Regulation of Hypoxia-inducible Factor (HIF) by oxygenEP300, HIF-1α, VEGF-A0.0022311833
    Spry regulation of FGF signalingMAPK1, MAPK3, SRC2.13221E-053
    Signaling by SCF-KITJAK2, MMP9, SRC0.0004403273
    Collagen degradationMMP1, MMP2, MMP3, MMP7, MMP92.58498E-065
    Degradation of the extracellular matrixCASP3, MMP1, MMP2, MMP3, MMP7, MMP9, PLG4.28006E-077
    Activation of Matrix MetalloproteinasesMMP1, MMP2, MMP3, MMP7, MMP9, PLG1.23119E-096
    mTOR signallingAKT1, mTOR, RPS6Kb10.0003821813
    Activated TLR4 signallingCASP8, MAPK1, MAPK14, MAPK3, MAPK85.17597E-055
    MyD88: Mal cascade initiated on plasma membraneMAPK1, MAPK14, MAPK3, MAPK80.0003467254
    MyD88-independent TLR4 cascadeCASP8, MAPK1, MAPK14, MAPK3, MAPK82.5656E-055
    Toll Like Receptor 9 (TLR9) CascadeMAPK1, MAPK14, MAPK3, MAPK80.0003894744
    Toll Like Receptor 10 (TLR10) CascadeMAPK1, MAPK14, MAPK3, MAPK80.0002283634
    Toll Like Receptor 3 (TLR3) CascadeCASP8, MAPK1, MAPK14, MAPK3, MAPK82.446E-055
    下载: 导出CSV

    表  3  3个靶点与3个关键成分的分子对接得分

    Table  3.   Molecular docking scores of 3 targets and 3 key components

    化合物蛋白质PDB ID结合能(kcal/mol)RMSD
    绿原酸IGF1R2oJ9−9.20.645
    JAK15e1e−9.11.672
    RPS6KB14l3j−8.30.967
    异绿原酸AIGF1R2oJ9−9.01.367
    JAK15e1e−10.01.306
    RPS6KB14l3j−9.90.772
    1,3,5-O-三咖啡酰奎宁酸IGF1R2oJ9−9.11.304
    JAK15e1e−9.71.476
    RPS6KB14l3j−10.31.811
    下载: 导出CSV
  • [1] Borghouts L B. Exercise and type 2 diabetes[J]. Advances in Experimental Medicine and Biology,2020(1228):91−105.
    [2] Pouya S, Inga P, Paraskevi S, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the international diabetes federation diabetes atlas, 9th edition[J]. Diabetes Research and Clinical Practice,2019,157:107843. doi:  10.1016/j.diabres.2019.107843
    [3] Zheng Y, Ley S H, Hu F B. Global aetiology and epidemiology of type 2 diabetes mellitus and its caomplications[J]. Nature Reviews Endocrinology,2018,14(2):88−98. doi:  10.1038/nrendo.2017.151
    [4] Ng M L, Wadham C, Sukocheva O A. The role of sphingolipid signalling in diabetes-associated pathologies(Review)[J]. International Journal of Molecular Medicine,2017,39(2):243−252. doi:  10.3892/ijmm.2017.2855
    [5] 刘培, 孙芮芮, 张莉丹, 等. 基于网络药理学的四君子汤治疗2型糖尿病的作用机制研究[J]. 中草药,2020,51(6):1548−1558. doi:  10.7501/j.issn.0253-2670.2020.06.023
    [6] Seehusen D A, Fisher C L, Rider H A, et al. Exploring patient perspectives of prediabetes and diabetes severity: A qualitative study[J]. Psychology & Health,2019,34(11):1314−1327.
    [7] 王艳梅, 王根杰, 张树林, 等. 临床常用降糖药物的不良反应及防治策略[J]. 中国医院药学杂志,2015,35(24):2233−2236.
    [8] Yin B, Bi Y M, Fan G J, et al. Molecular mechanism of the effect of huanglianjiedu decoction on type 2 diabetes mellitus based on network pharmacology and molecular docking[J]. Journal of Diabetes Research,2020:5273914.
    [9] 席利莎, 木泰华, 孙红男. 绿原酸类物质的国内外研究进展[J]. 核农学报,2014,28(2):292−301. doi:  10.11869/j.issn.100-8551.2014.02.0292
    [10] Karthikesan K, Pari L, Menon V P. Antihyperlipidemic effect of chlorogenic acid and tetrahydrocurcumin in rats subjected to diabetogenic agents[J]. Chem-Biol Interact,2010,188(3):643−650. doi:  10.1016/j.cbi.2010.07.026
    [11] Tian Y, Cao X X, Shang H, et al. Synthesis and in vitro evaluation of caffeoylquinic acid derivatives as potential hypolipidemic agents[J]. Molecules (Basel, Switzerland),2019,24(5):964. doi:  10.3390/molecules24050964
    [12] 吴钉红. 网络药理学及其在中药领域的研究概述[J]. 广州化工,2017,45(11):216−218. doi:  10.3969/j.issn.1001-9677.2017.11.082
    [13] 李洋, 夏厚林, 周厚琴, 等. 基于分子对接技术预测人面子叶中黄酮成分抗菌作用靶点[J]. 中国医院用药评价与分析,2016,16(10):1303−1307.
    [14] Yang X, Liu H, Liu J, et al. Rational selection of the 3d structure of biomacromolecules for molecular docking studies on the mechanism of endocrine disruptor action[J]. Chemical Research in Toxicology,2016,29(9):1565−1570. doi:  10.1021/acs.chemrestox.6b00245
    [15] 赵昱, 赵军, 李湘萍, 等. 咖啡酰奎尼酸类化合物研究进展[J]. 中国中药杂志,2006(11):869−874. doi:  10.3321/j.issn:1001-5302.2006.11.001
    [16] 朱文卿, 任汉书, 徐美霞, 等. 咖啡酰奎宁酸类化合物的生物学活性及提高其生物利用度技术研究进展[J]. 食品科学,2021,42(3):321−329. doi:  10.7506/spkx1002-6630-20200102-021
    [17] 宫阿娟, 潘天荣, 付万进, 等. 基于网络药理学的方法研究桑叶活性成分对2型糖尿病治疗作用机制[J]. 医药论坛杂志,2020,41(2):30−37, 41.
    [18] Al R A, Liu B, Persaud S, et al. A novel Gymnema sylvestre extract protects pancreatic beta-cells from cytokine-induced apoptosis[J]. Phytotherapy Research,2020,34(1):161−172. doi:  10.1002/ptr.6512
    [19] Surget S, Khoury M P, Bourdon J C. Uncovering the role of p53 splice variants in human malignancy: A clinical perspective[J]. OncoTargets and Therapy,2014,2013(7):57−68.
    [20] 姜勇, 韩家淮. p38MAPK信号传导通路[J]. 生命科学,1999,11(3):102−106.
    [21] Murat K V, Yagmur D N. Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus[J]. PeerJ,2020,8:e10111. doi:  10.7717/peerj.10111
    [22] 向臣希, 欧瑜. 氧化应激在2型糖尿病发病过程中的作用[J]. 药物生物技术,2015,22(5):457−460.
    [23] Xia M H, Huang R L, Sun Y, et al. Identification of chemical compounds that induce HIF-1 alpha activity[J]. Toxicological Sciences,2009,112(1):153−163. doi:  10.1093/toxsci/kfp123
    [24] 王梦, 张泽生, 刘暄, 等. D-松醇复配Mn2+对2型糖尿病大鼠的降血糖作用及其机制的研究[J]. 食品工业科技,2019,40(9):302−307, 314.
    [25] 王馨苑, 黄夏冰, 邓鑫. 基于网络药理学和分子对接探讨黄连素治疗2型糖尿病机制研究[J]. 中国新药杂志,2020,29(24):2820−2831.
    [26] Lemus V M L, F S M E, Cervantes M R, et al. Expression of HIF-1 alpha, VEGF and EPO in peripheral blood from patients with two cardiac abnormalities associated with hypoxia[J]. Clinical Biochemistry,2010,43(3):234−239. doi:  10.1016/j.clinbiochem.2009.09.022
    [27] 吕翠岩, 张胜容, 徐暾海, 等. 糖痹康对糖尿病大鼠坐骨神经HIF-1α蛋白及HIF-1α mRNA表达的影响[J]. 中华中医药杂志,2016,31(7):2560−2563.
    [28] Lawan A, Bennett A M. Mitogen-activated protein kinase regulation in hepatic metabolism[J]. Trends in Endocrinology & Metabolism,2017,28(12):868−878.
    [29] 王超, 张会欣, 邢邯英, 等. 氧化苦参碱抑制p38MAPK通路减轻高脂喂养胰岛素抵抗小鼠氧化应激[J]. 中国中药杂志,2016,41(15):2872−2876.
    [30] 葛凌, 蔡亚军, 王章达. 槲皮素对2型糖尿病大鼠胰岛素抵抗的改善作用及FGF21/MAPK信号通路的影响[J]. 中国药师,2019,22(3):418−421. doi:  10.3969/j.issn.1008-049X.2019.03.007
    [31] Li F, Zeng O, Luo J, et al. Effects of hydrogen sulfide on myocardial fibrosis and MAPK1/3 and MMP-8 expression in diabetic rats[J]. Journal of Southern Medical University,2015,35(4):549−552.
    [32] LiuX X, HuangX Z, ChenL, et al. Mechanical stretch promotes matrix metalloproteinase-2 and prolyl-4-hydroxylase α1 production in human aortic smooth muscle cells via Akt-p38 MAPK-JNK signaling[J]. The International Journal of Biochemistry & Cell Biology,2015,62:15−23.
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  • 收稿日期:  2021-01-18
  • 网络出版日期:  2021-06-08
  • 刊出日期:  2021-07-07

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