Network Pharmacology Study on the Antibacterial Activity of Caffeoylquinic Acids
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摘要: 目的：基于网络药理学方法探讨咖啡酰奎宁酸类化合物抑菌的作用机制。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对应靶点、抑菌相关靶点及两者交集靶点，将交集靶点构建蛋白互作（protein-protein interaction network，PPI）网络，并进行基因本体（Gene Ontology，GO）分析及京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genome，KEGG）分析。结果：咖啡酰奎宁酸类化合物对应靶点483个，抑菌相关靶点805个，咖啡酰奎宁酸类化合物抑菌作用靶点75个，起关键作用的为TNF、AKT1、ALB、MMP9、EGFR、MAPK8等靶点。GO功能分析及KEGG通路富集分析结果显示，咖啡酰奎宁酸类化合物抑菌的作用机制主要涉及应激反应、代谢过程、生物调节、多细胞生物过程、细胞讯息传递等生物过程，并通过细胞外基质组织、胶原蛋白降解、基质金属蛋白酶的激活和神经生长因子信号通路等多条通路共同发挥作用。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：本研究揭示了咖啡酰奎宁酸类化合物抑菌具有多靶点、多途径的特点，为其分子机制的进一步研究奠定了基础。
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关键词:
- 咖啡酰奎宁酸类化合物 /
- 网络药理学 /
- 抑菌活性 /
- 作用机制
Abstract: Objective:To explore the antibacterial mechanism of caffeoylquinic acids based on network pharmacology. Methods: Through literature mining and database search, the corresponding targets of caffeoylquinic acids, antibacterial related targets, and the common targets of them were obtained. The common targets were used to construct a protein-protein interaction (PPI) network, and perform Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis. Results: Caffeoylquinic acids correspond to 483 targets, 805 antibacterial related targets, and 75 antibacterial targets of caffeoylquinic acids, and the key targets were TNF、AKT1、ALB、MMP9、EGFR and MAPK8. GO analysis and KEGG pathway enrichment analysis results showed that the antibacterial mechanism of caffeoylquinic acids mainly involves biological processes such as response to stimulus, metabolic processes, biological regulation, multicellular biological processes, cell communication, and work together through pathways such as extracellular matrix organization, collagen degradation, activation of matrix metalloproteinases and nerve growth factor signalling. The results of molecular docking verification between compounds and molecular targets were good, which verified the accuracy of the prediction of network construction. Conclusion: This study reveals that the antibacterial activity of caffeoylquinic acids has the characteristics of multiple targets and multiple pathways, which lays the foundation for further research on its molecular mechanism. -
图 3 咖啡酰奎宁酸类化合物与抑菌作用靶点Venn图
Figure 3. Venn diagram of caffeoylquinic acids and antibacterial related targets
图 4 咖啡酰奎宁酸类化合物抑菌的PPI网络
Figure 4. PPI network of the antibacterial effect of caffeoylquinic acids
图 5 咖啡酰奎宁酸类化合物抑菌作用靶点GO分析
Figure 5. GO analysis of antibacterial targets of caffeoylquinic acids
图 6 咖啡酰奎宁酸类化合物抑菌关键靶点KEGG通路富集分析
Figure 6. KEGG pathway enrichment analysis of key antibacterial targets of caffeoylquinic acids
图 7 咖啡酰奎宁酸类化合物抑菌作用靶点与作用通路网络分析
Figure 7. Caffeoylquinic acids antibacterial targets and pathway network analysis
图 8 TNF、AKT1与关键成分的最佳对接构象
Figure 8. Optimal docking conformation of TNF, AKT1 and key components
注：A. TNF与绿原酸的最佳对接构象；B. TNF与异绿原酸A的最佳对接构象；C. AKT1与 1,3,5-O-三咖啡酰奎宁酸的最佳对接构象。
表 1 Degree值排名前30位靶点信息表
Table 1. Information table of the top 30 targets with Degree value
编号 目标基因 目标蛋白质 Degree 靶向蛋白的生物学活性 参考文献 1 TNF Tumor necrosis factor 46 杀伤转化细胞和某些病毒感染的细胞 [27] 2 AKT1 RAC-alpha serine/threonine-protein kinase; 45 调控细胞存活和凋亡 [29] 3 ALB Serum albumin 40 调节血液的胶体渗透压 [30] 4 MMP9 Matrix metalloproteinase-9 36 在细胞外基质的蛋白水解和白细胞迁移中起重要作用 [31] 5 EGFR Epidermal growth factor receptor 36 参与细胞功能的调节 [32] 6 MAPK8 Mitogen-activated protein kinase 8 35 调控细胞增殖、分化、迁移及凋亡 [35] 7 CASP3 Caspase-3 34 调控细胞凋亡 [36] 8 MAPK1 Mitogen-activated protein kinase 1 33 参与细胞生长、粘附、存活和分化 [35] 9 MMP2 72 kDa type IV collagenase 30 参与血管系统重塑、血管生成、组织修复、肿瘤浸润及炎症反应 [31] 10 MAPK14 Mitogen-activated protein kinase 14 27 刺激促炎性细胞因子及激活转录因子 [37] 11 ESR1 Estrogen receptor 24 转录因子 [38] 12 SIRT1 NAD-dependent protein deacetylase sirtuin-1 23 调控细胞凋亡、生存及分化 [33] 13 IL-2 Interleukin-2 21 对病原微生物的防御和清除起到重要作用 [34] 14 XIAP E3 ubiquitin-protein ligase XIAP 20 调控细胞增殖、凋亡 [39] 15 MMP1 interstitial collagenase 20 降解细胞外基质 [31] 16 MCL1 Induced myeloid leukemia cell differentiation protein Mcl-1 20 调控细胞凋亡 [40] 17 PLG Plasminogen 19 参与组织重塑和肿瘤侵袭过程 [41] 18 CASP1 Caspase-1 19 参与多种炎症过程 [42] 19 ELANE Neutrophil elastase 18 参与多种炎症过程 [43] 20 AGTR1 Type-1 angiotensin II receptor 18 调控血压和液体稳态 [44] 21 MMP7 Matrilysin 17 激活胶原蛋白原酶 [31] 22 PARP1 Poly [ADP-ribose] polymerase 1 16 调控细胞生长、分化 [45] 23 CXCR2 C-X-C chemokine receptor type 2 16 参与炎症反应 [46] 24 ADAM17 Disintegrin and metalloproteinase domain-containing protein 17 14 参与细胞粘附、融合、迁移及信号传导 [47] 25 BCL2 Apoptosis regulator Bcl-2 14 调控细胞凋亡 [48] 26 CDK4 Cyclin-dependent kinase 4 14 调控细胞周期 [49] 27 MMP8 Neutrophil collagenase 13 降解I、II、III型胶原纤维 [50] 28 CTSK Cathepsin K 13 参与细胞外基质降解 [51] 29 SELE E-selectin 13 参与免疫粘附过程 [52] 30 MAPK10 Mitogen-activated protein kinase 10 13 刺激促炎性细胞因子 [53] 
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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 基因数 Intrinsic Pathway for Apoptosismembrane AKT1, BCL2, CASP3, MAPK8, XIAP 1.06455E-05 5 Activation of BH3-only proteins AKT1, BCL2, MAPK8 0.001116903 3 Signaling by ERBB4 ADAM17, EGFR, ESR1 0.003400526 3 Antigen processing-Cross presentation CTSL, CTSS, HLA-A, IKBKB 0.00495417 4 Endosomal/Vacuolar pathway CTSL, CTSS, HLA-A 4.98677E-05 3 Collagen degradation ADAM17, CTSK, CTSL, ELANE, FURIN, MMP1, MMP2, MMP7, MMP8, MMP9 1.44433E-11 10 Degradation of the extracellular matrix ADAM17, CASP3, CTSK, CTSL, CTSS, ELANE, FURIN, MMP1, MMP2, MMP7, MMP8, MMP9, PLG, TPSAB1 4.44466E-13 14 Extracellular matrix organization ADAM17, CASP3, CTSK, CTSL, CTSS, ELANE, FURIN, MMP1, MMP2, MMP7, MMP8, MMP9, PLG, TPSAB1 1.30521E-08 14 Collagen formation CTSL, CTSS, MMP7, MMP9 0.003399094 4 Activation of Matrix Metalloproteinases CTSK, ELANE, FURIN, MMP1, MMP2, MMP7, MMP8, MMP9, PLG, TPSAB1 1.04463E-14 10 Toll Like Receptor 4 (TLR4) Cascade IKBKB, IRAK4, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 3.28081E-05 7 Activated TLR4 signalling IKBKB, IRAK4, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 1.58446E-05 7 MyD88:Mal cascade initiated on plasma IKBKB, IRAK4, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 4.33043E-06 7 MyD88-independent TLR4 cascade IKBKB, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 6.96357E-05 6 NGF signalling ADAM17, CASP3, FURIN, IKBKB, MAPK1, MAPK14, MAPK8 0.000194394 7 Trafficking and processing of endosomal TLR CTSK, CTSL, CTSS 8.55839E-05 3 Toll Like Receptor 9 (TLR9) Cascade IKBKB, IRAK4, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 5.3083E-06 7 Toll Like Receptor 10 (TLR10) Cascade IKBKB, IRAK4, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 2.08051E-06 7 Toll Like Receptor 3 (TLR3) Cascade IKBKB, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 6.58958E-05 6 Toll Like Receptor 5 (TLR5) Cascade IKBKB, IRAK4, MAP3K7, MAPK1, MAPK10, MAPK14, MAPK8 2.08051E-06 7
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表 3 2个靶点与3个关键成分的分子对接得分
Table 3. Molecular docking scores of 2 targets and 3 key components
化合物 靶点 蛋白库编号 自由结合能（ kCal/mol） 均方根误差 绿原酸 TNF 6rmj −9.6 1.205 AKT1 3o96 −9.1 1.983 异绿原酸A TNF 6rmj −9.6 0.477 AKT1 3o96 −10.1 1.729 1,3,5-O-三咖啡酰奎宁酸 TNF 6rmj −7.0 3.494 AKT1 3o96 −10.5 1.986
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[1] Carvalho I, Henriques M, Carvalho S. New strategies to fight bacterial adhesion[M]. Spain: Formatex Research Center, 2013. [2] Liu Q, Meng X, Li Y, et al. Antibacterial and antifungal activities of spices[J]. Internatonal Journal of Molecular Sciences,2017,18(6):1283. doi: 10.3390/ijms18061283 [3] Murugavel S, Deepa S, Ravikumar C, et al. Synthesis, structural, spectral and antibacterial activity of 3, 3a, 4, 5-tetrahydro-2H-benzo[g]indazole fused carbothioamide derivatives as antibacterial agents[J]. Journal of Molecular Structure,2020,1222:128961. doi: 10.1016/j.molstruc.2020.128961 [4] 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 [5] 吴琪珍. 咖啡酰奎宁酸类化合物研究进展[J]. 中国野生植物资源,2020,39(4):48−53, 60. doi: 10.3969/j.issn.1006-9690.2020.04.011 [6] 王玲娜, 姚佳欢, 马超美. 绿原酸的研究进展[J]. 食品与生物技术学报,2017,36(11):1121−1130. doi: 10.3969/j.issn.1673-1689.2017.11.001 [7] Chen Y S, Geng S, Liu B G. Three common caffeoylquinic acids as potential hypoglycemic nutraceuticals: Evaluation of α-glucosidase inhibitory activity and glucose consumption in HepG2 cells[J]. Journal of Food Biochemistry,2020,44(9):13361. [8] Ritu K, Anurag K. In-silico design, synthesis, ADMET studies and biological evaluation of novel derivatives of chlorogenic acid against urease protein and H. Pylori bacterium[J]. BMC Chemistry,2019,13(1):41. doi: 10.1186/s13065-019-0556-0 [9] Karunanidhi A, Thomas R, Belkum A V, et al. In vitro antibacterial and antibiofilm activities of chlorogenic acid against clinical isolates of Stenotrophomonas maltophilia including the trimethoprim/sulfamethoxazole resistant strain[J]. BioMed Research International,2013,2012:392058. [10] 王虹懿, 刘芳, 孙芝兰, 等. Helveticin-M与绿原酸复配对大肠杆菌和肠炎沙门氏菌的抑菌效果及其机制[J]. 食品科学,2020,41(3):68−74. doi: 10.7506/spkx1002-6630-20190228-229 [11] Zhu X F, Zhang H X, Lo R. Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities[J]. Journal of Agricultural and Food Chemistry,2004,52(24):7272−7278. doi: 10.1021/jf0490192 [12] Lou Z X, Wang H X, Zhu S, et al. Antibacterial activity and mechanism of action of chlorogenic acid[J]. Journal of Food Science,2011,76(6):398−403. doi: 10.1111/j.1750-3841.2011.02213.x [13] 潘婉莲, 赵苗, 袁芳, 等. 我国天然产物绿原酸活性及提取工艺研究进展[J]. 食品安全质量检测学报,2017,8(11):4269−4276. doi: 10.3969/j.issn.2095-0381.2017.11.032 [14] Yun J E, Lee D G. Role of potassium channels in chlorogenic acid-induced apoptotic volume decrease and cell cycle arrest in Candida albicans[J]. Biochimica Et Biophysica Acta,2017,1861(3):585−592. doi: 10.1016/j.bbagen.2016.12.026 [15] 任艳, 邓燕君, 马焓彬, 等. 网络药理学在中药领域的研究进展及面临的挑战[J]. 中草药,2020,51(18):4789−4797. doi: 10.7501/j.issn.0253-2670.2020.18.024 [16] 苏和毅, 郭振辉. 持续炎性反应-免疫抑制-分解代谢综合征治疗策略初探[J]. 中华胃肠外科杂志,2017,20(12):1444−1447. doi: 10.3760/cma.j.issn.1671-0274.2017.12.030 [17] 李彪, 林晗, 唐照琦, 等. 基于网络药理学的商陆及其拆分组分的作用机制研究[J/OL]. 中国中药杂志: 1-10[2021-02-26]. . https: //doi. org/10.19540/j. cnki. cjcmm. 20210120.401. [18] 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. [19] 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 [20] 齐云云, 温鹏, 于诗怡, 等. 五倍子抗炎、抗菌活性指导下的有效成分分离与抗口腔溃疡网络药理学评价[J]. 石河子大学学报(自然科学版),2020,38(5):620−628. [21] 袁家威, 张海涛, 揭珂, 等. 基于网络药理学研究桃红四物汤治疗假体周围感染的潜在靶点和机制[J]. 中国组织工程研究,2021,25(9):1428−1433. doi: 10.3969/j.issn.2095-4344.4012 [22] 包雅婷, 王玥, 任晓东, 等. 基于网络药理学的紫斑牡丹花、叶抗菌活性和作用机制研究[J]. 中国中药杂志,2018,43(4):779−785. [23] Hillenmeyer S, Davis L K, Gamazon E R, et al. Stams: String-assisted module search for genome wide association studies and application to autism[J]. Bioinformatics,2016,32(24):3815−3822. doi: 10.1093/bioinformatics/btw530 [24] Michael K, Sebastian W, Bettina W. Cytoscape: Software for visualization and analysis of biological networks[J]. Methods in Molecular Biology,2011,696:291−303. [25] 郑美思, 许强, 周海, 等. 基于网络药理学的金匮肾气丸治疗2型糖尿病作用机制探讨[J]. 中华中医药学刊,2020,38(11):126−131, 271-273. [26] Maere S, Heymans K, Kuiper M. Bingo: A cytoscape plugin to assess overrepresentation of Gene Ontology categories in biological networks[J]. Bioinformatics,2005,21(16):2. [27] Montfort A, Colacios C, Levade T, et al. The TNF paradox in cancer progression and immunotherapy[J]. Frontiers in Immunology,2019,10:2515. doi: 10.3389/fimmu.2019.02515 [28] Varley C D, Deodhar A A, Ehst B D, et al. Persistence of staphylococcus aureus colonization among individuals with immune-mediated inflammatory diseases treated with TNF-α inhibitor therapy[J]. Rheumatology,2014,53(2):332−337. doi: 10.1093/rheumatology/ket351 [29] 赵洁, 王欢欢, 欧阳意, 等. 基于网络药理学及质谱分析的葶苈大枣泻肺汤抗心衰的有效成分发现及作用机制[J/OL]. 中国实验方剂学杂志: 1-15[2021-03-23]. https: //doi. org/10.13422/j. cnki. syfjx. 20210414. [30] 罗艺晨, 黄利明, 杨颖, 等. 绿原酸抑制金黄色葡萄球菌机理研究[J]. 西南大学学报(自然科学版),2016,38(3):15−19. [31] Falanga V. Wound healing and its impairment in the diabetic foot[J]. The Lancet,2005,366(9484):1736−1743. [32] 余婷, 杨柱, 龙奉玺, 等. 基于网络药理学探讨黄精-百合药对抗癌作用的机制[J]. 中国实验方剂学杂志,2020,26(5):168−177. [33] Lee K S, Kim S R,Lee Y R, et al. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α[J]. Experimental & Molecular Medicine,2007,39(6):756−768. [34] Tian L, Qu X, Wang M E, et al. Selective inhibition of IL-2 mRNA blocks allograft rejection by limiting T cell clonal expansion[J]. Transplantation Proceedings,2001,33(1):330−330. [35] 万智双, 熊丁, 曹宸. MiR-433-3p靶向MAPK8对肝癌细胞MHCC97H增殖、凋亡和迁移的调控作用[J]. 中国免疫学杂志,2020,36(1):57−62. doi: 10.3969/j.issn.1000-484X.2020.01.011 [36] Launay O, Rosenberg A R, Rey D, et al. Long-term immune response to hepatitis B virus vaccination regimens in adults with human immunodeficiency virus 1: Secondary analysis of a randomized clinical trial[J]. Jama Internal Medicine,2016,176(5):603−610. doi: 10.1001/jamainternmed.2016.0741 [37] Madkour M M, Anbar H S, El-Gamal M I. Current status and future prospects of p38α/MAPK14 kinase and its inhibitors[J]. European Journal of Medicinal Chemistry,2021,213:113216. doi: 10.1016/j.ejmech.2021.113216 [38] Kumamoto T, Togo S, Ishibe A, et al. Role of nitric oxide synthesized by nitric oxide synthase 2 in liver regeneration[J]. Liver International,2008,28(6):865−877. doi: 10.1111/j.1478-3231.2008.01712.x [39] 李功成, 潘铁军, 田雨冬, 等. 曲古抑菌素A膀胱灌注对大鼠膀胱癌生长的抑制作用[J]. 临床泌尿外科杂志,2013,28(2):148−151. [40] Li S J, Guo W P, Wu H J. The role of post-translational modifications in the regulation of MCL1[J]. Cellular Signalling,2021,81:109933. doi: 10.1016/j.cellsig.2021.109933 [41] Klinger M H F, Jelkmann W. Role of blood platelets in infection and inflammation[J]. Journal of Interferon & Cytokine Research,2002,22(9):913−922. [42] 邓莉, 田静. 白藜芦醇抑制大肠埃希菌O104: H4诱导的结肠上皮细胞NLRP3炎症小体活化[J]. 中国临床药理学与治疗学,2021,26(2):167−173. [43] Gilberto V A, Rosalinda P S, Julian R B. Variability in genes related to SARS-CoV-2 entry into host cells (ACE2, TMPRSS2, TMPRSS11A, ELANE, and CTSL) and its potential use in association studies[J]. Life Sciences,2020,260(1):118313. [44] 杨小英, 陈春玲, 马晓聪, 等. 基于网络药理学探讨温胆汤治疗高血压的作用机制[J]. 中西医结合心脑血管病杂志,2020,18(24):4108−4116. doi: 10.12102/j.issn.1672-1349.2020.24.003 [45] Rudolph J, Roberts G, Luger K. Histone Parylation factor 1 contributes to the inhibition of PARP1 by cancer drugs[J]. Nature Communications,2021,12(1):736. doi: 10.1038/s41467-021-20998-8 [46] 尚立芝, 季书, 石龙涛, 等. 基于CXCL8-CXCR1/2轴探讨二陈汤加味对COPD大鼠的抗炎机制[J]. 中国实验方剂学杂志,2020,26(11):40−48. [47] 努尔阿米娜·依明尼亚孜, 帕力旦·艾沙, 阿依姆妮萨·阿卜杜热合曼. 奇果菌素调控miR-646/ADAM17通路对白血病细胞增殖、凋亡的影响及机制[J]. 河北医药,2020,42(24):3702−3707. doi: 10.3969/j.issn.1002-7386.2020.24.004 [48] Antonio T, Daniel R, Silvia V, et al. Prognostic value of Bcl2 and p53 in Hodgkin lymphoma: A systematic review and meta-analysis[J]. Pathology-Research and Practice,2021,219:153370. doi: 10.1016/j.prp.2021.153370 [49] 陈观平, 李明乾, 应栩华. 异鼠李素通过mTOR通路抑制肺癌增殖、侵袭及其机制研究[J/OL]. 中药材, 2021(2): 423-428[2021-03-25]. https: //doi. org/10.13863/j. issn1001-4454.2021. 02.032. [50] 郭争荣. 基质金属蛋白酶8基因治疗大鼠肝硬化的实验研究[D]. 石家庄: 河北医科大学, 2007. [51] Wei W, Ren J, Yin W W, et al. Inhibition of ctsk modulates periodontitis with arthritis via downregulation of TLR9 and autophagy[J]. Cell Proliferation,2020,53(1):e12722. [52] 高俊潇. 细胞粘附分子相关基因SELE, COL1A1, ITGAV和CAECAM1对过敏性鼻炎的影响[D]. 广州: 南方医科大学, 2020. [53] Gao Y, Wang Y F, Wang X F, et al. MiR-335-5p suppresses gastric cancer progression by targeting MAPK10[J]. Cancer Cell International,2021,21(1):71. doi: 10.1186/s12935-020-01684-z -
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