基于网络药理学和分子对接探讨“川芎-白芷”药对治疗鼻窦炎的作用机制

doi:10.6040/j.issn.1673-3770.0.2021.270

摘要/Abstract

摘要： 目的基于网络药理学和分子对接技术,探讨川芎-白芷配伍治疗鼻窦炎的作用靶点及分子机制。方法通过TCMSP数据库挖掘川芎和白芷的化学成分及潜在靶点,利用Genecards、Drugbank、DisGeNET和OMIM数据库筛选得到鼻窦炎的相关靶点集,将川芎-白芷与鼻窦炎的交集靶点通过Cytoscape3.8.0软件构建药物-成分-靶点网络图,运用STRING平台构建PPI网络并进行网络拓扑学分析得到川芎-白芷治疗鼻窦炎的关键靶点,对其进行GO及KEGG通路富集分析,并构建成分-靶点-通路网络图,筛选出核心靶点,最后使用Autodock软件对核心成分及靶点进行分子对接验证。结果研究筛选出川芎-白芷活性成分10个,成分与疾病交集靶点35个。其核心活性成分为β-谷甾醇、杨梅酮、豆甾醇、亚油酸乙酯、别欧前胡素这五种,其核心靶点为CASP3、JUN、PTGS2、HSP90AA1、MAPK14、PIK3CG这六个。KEGG富集分析得出川芎-白芷可能通过肿瘤坏死因子、神经营养因子、血管内皮生长因子、神经活性配体-受体相互作用、钙等信号通路发挥对鼻窦炎的治疗作用。结论通过网络药理学研究发现川芎-白芷药对可以多成分、多靶点、多通路的治疗鼻窦炎,并且分子对接结果显示其核心活性成分与核心靶点形成有效的分子结合,为进一步研究作用机制及实验验证提供理论基础。

关键词: 网络药理学, 分子对接, 川芎, 白芷, 鼻窦炎, 作用机制

Abstract: Objective Using network pharmacology and molecular docking technology, we explored the target(s)and molecular mechanism(s)of combination therapy with Ligusticum and Chuanxiong-Baizhi medicine to treat sinusitis. Methods The chemical components and potential drug targets of Ligusticum Chuanxiong-Baizhi were extracted from the TCMSP database. Drug targets relevant to sinusitis were screened for using Genecards, Drugbank, DisGeNET, and OMIM databases. Cytoscape 3.8.0 software and the STRING platform were used to construct drug-component-target and PPI network diagrams of intersecting targets, To further identify key targets, we conducted GO and KEGG pathway enrichment analyses, constructed a component-target-pathway network diagram, screened for core targets, and finally, used Autodock software to verify molecular docking. Results This study identified 10 chemical constituents of Ligusticum Chuanxiong-Baizhi, and 35 targets at the intersection of constituents and diseases. The core active ingredients of Ligusticum Chuanxiong-Baizhi are β-sitosterol, myricanone, stigmasterol, mandenol, and prangenidin. Its core targets are CASP3, JUN, PTGS2, HSP90AA1, MAPK14, and PIK3CG. KEGG enrichment analysis showed that Ligusticum Chuanxiong-Baizhi may display efficacy in treating sinusitis through signal pathways including TNF, neurotrophic factors, VEGF, neuroactive ligand-receptor interactions, and calcium. Conclusion Network pharmacology research indicates that the Ligusticum Chuanxiong-Baizhi drug combination supplies multiple active components to treat sinusitis via multiple targets and multiple pathways. Molecular docking results show that its core active ingredients form effective molecular complexes with core targets, providing a theoretical basis for further research into mechanism, and experimental verification.

Key words: Network pharmacology, Molecular docking, Chuanxiong, Baizhi, Sinusitis, Mechanism

中图分类号:

R765.41

王露,谢慧,卢美迪,邓新星,李清韵. 基于网络药理学和分子对接探讨“川芎-白芷”药对治疗鼻窦炎的作用机制[J]. 山东大学耳鼻喉眼学报, 2022, 36(3): 154-164.

WANG Lu, XIE Hui, LU Meidi, DENG Xinxing, LI Qingyun. Based on network pharmacology and molecular docking to explore the mechanism of “Chuanxiong-Baizhi” medicine in the treatment of sinusitis[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2022, 36(3): 154-164.

参考文献

[1] Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, et al. Clinical practice guideline(update): adult sinusitis[J]. Otolaryngol Head Neck Surg, 2015, 152(2 suppl): S1-S39. doi:10.1177/0194599815572097.
[2] Rosenfeld RM. CLINICAL PRACTICE. acute sinusitis in adults[J]. N Engl J Med, 2016, 375(10): 962-970. doi:10.1056/nejmcp1601749.
[3] 中华耳鼻咽喉头颈外科杂志编辑委员会鼻科组, 中华医学会耳鼻咽喉头颈外科学分会鼻科学组. 中国慢性鼻窦炎诊断和治疗指南(2018)[J]. 中华耳鼻咽喉头颈外科杂志, 2019, 54(2): 81-100. doi: 10.3760/cma.j.issn.1673-0860.2019.02.001.
[4] 郭清华, 刘玉, 颜延凤, 等. 对“胆移热于脑,则辛頞鼻渊”的认识[J]. 国际中医中药杂志, 2017,39(2):163-164. doi: 10.3760/cma.j.issn.1673-4246.2017.02.019
[5] 李莉, 刘艳丽, 熊大经. 熊大经教授治疗鼻窦炎经验谈[J]. 四川中医, 2004, 22(3): 4-5. doi:10.3969/j.issn.1000-3649.2004.03.002.
[6] Mahdavinia M, Suh LA, Carter RG, et al. Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia[J]. J Allergy Clin Immunol, 2015, 135(2): 576-579. doi:10.1016/j.jaci.2014.08.031.
[7] Chee L, Graham SM, Carothers DG, et al. Immune dysfunction in refractory sinusitis in a tertiary care setting[J]. Laryngoscope, 2001, 111(2): 233-235. doi:10.1097/00005537-200102000-00008.
[8] 姚和梅, 李红英, 赵勇, 等. 慢性鼻窦炎鼻息肉的遗传调查[J]. 中国现代医生, 2008, 46(5):78. doi: 10.3969/j.issn.1673-9701.2008.05.049.
[9] Shi JB, Fu QL, Zhang H, et al. Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities[J]. Allergy, 2015, 70(5): 533-539. doi:10.1111/all.12577.
[10] Bachert C, Zhang L, Gevaert P. Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis[J]. J Allergy Clin Immunol, 2015, 136(6): 1431-1440. doi:10.1016/j.jaci.2015.10.010.
[11] Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for U.S. adults: national health interview survey, 2012[J]. Vital Health Stat 10,2014(260):1-161. doi: 10.1016/S0033-3506(96)80082-5.
[12] Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe: an underestimated disease. A GA2LEN study[J]. Allergy, 2011, 66(9): 1216-1223. doi:10.1111/j.1398-9995.2011.02646.x.
[13] 郭娟娟. 基于关联规则明代治疗头痛方剂用药规律的研究[D]. 济南: 山东中医药大学, 2016.
[14] 国家药典委员会. 中华人民共和国药典: 2020年版分辑号: 一部[M]. 北京: 中国医药科技出版社, 2020: 42.
[15] 徐军, 李仪奎, 陈蔚琳, 等. 川芎白芷药对(都梁丸)的药理作用研究[J]. 中药药理与临床, 1992, 8(3): 12-14. doi: 10.13412/j.cnki.zyyl.1992.03.006. XU Jun, LI Yikui, CHEN Weilin, et al. Pharmacology study on Chuanxiong-Baizhi(duliang wan)[J]. Pharmacol Clin Chin Mater Med, 1992, 8(3): 12-14. doi: 10.13412/j.cnki.zyyl.1992.03.006.
[16] 陈海彬, 周红光, 李文婷, 等. 网络药理学——中药复方作用机制研究新视角[J]. 中华中医药杂志, 2019,34(7): 2873-2876. CHEN Haibin, ZHOU Hongguang, LI Wenting, et al. Network pharmacology——a new perspective of mechanism research of traditional Chinese medicine formula[J]. China J Tradit Chin Med Pharm, 2019,34(7): 2873-2876.
[17] Yang M, Chen JL, Xu LW, et al. Navigating traditional Chinese medicine network pharmacology and computational tools[J]. Evid Based Complement Alternat Med, 2013, 2013: 731969. doi:10.1155/2013/731969.
[18] 谢慧, 李玲珑, 窦豆, 等. 鼻渊舒口服液对慢性鼻-鼻窦炎患者鼻腔表皮葡萄球菌细菌生物膜形成的影响[J]. 中国中西医结合耳鼻咽喉科杂志, 2018,26(6): 407-411,456. doi:10.16542/j.cnki.issn.1007-4856.2018.06.002. XIE Hui, LI Linglong, DOU Dou, et al. The influence of Biyuanshu oral liquid on the bacterial biofilm formation of the nasal epidermal staphylococcal bacteria in patients with chronic rhinosinusitis[J]. Chin J Otorhinolaryngol Integr Med, 2018, 26(6): 407-411,456. doi:10.16542/j.cnki.issn.1007-4856.2018.06.002.
[19] 许必芳, 谢慧, 朱天民, 等. 鼻渊舒口服液对实验性鼻窦炎大鼠鼻黏膜的超微结构的影响[J]. 成都中医药大学学报, 2013, 36(4): 1-3. doi:10.13593/j.cnki.51-1501/r.2013.04.001. XU Bifang, XIE Hui, ZHU Tianmin, et al. Experimental research on influence of nasal mucosalultrastructure of experimental ARS rats by using Bi-Yuan-Shu oral liquid[J]. J Chengdu Univ Tradit Chin Med, 2013, 36(4): 1-3. doi:10.13593/j.cnki.51-1501/r.2013.04.001.
[20] 韩书婧, 鲁洁, 初平, 等. 慢性鼻-鼻窦炎的微生态Meta分析[J]. 山东大学耳鼻喉眼学报, 2019, 33(5): 132-138. doi: 10.6040/j.issn.1673-3770.0.2018.603. HAN Shujing, LU Jie, CHU Ping, et al. Meta analysis of the nasal cavity bacterial culture in chronic rhinosinusitis[J]. J Otolaryngol Ophthalmol Shandong Univ, 2019, 33(5): 132-138. doi: 10.6040/j.issn.1673-3770.0.2018.603.
[21] 陈元堃, 曾奥, 罗振辉, 等. β-谷甾醇药理作用研究进展[J]. 广东药科大学学报, 2021,37(1): 148-153. doi:10.16809/j.cnki.2096-3653.2020040801. CHEN Yuankun, ZENG Ao, LUO Zhenhui, et al. Advances on pharmacology of β-sitosterol[J]. J Guangdong Pharm Univ, 2021,37(1): 148-153. doi:10.16809/j.cnki.2096-3653.2020040801.
[22] 汪帅, 孙宇, 李春梅, 等. 豆甾醇的研究进展概述[J]. 中国药业, 2019, 28(23): 96-98. doi: 10.3969/j.issn.1006-4931.2019.23.031. WANG Shuai, SUN Yu, LI Chunmei, et al. Research progress of stigmasterol[J]. China Pharm, 2019, 28(23): 96-98. doi: 10.3969/j.issn.1006-4931.2019.23.031.
[23] Liu R, Hao D, Xu W, et al. Β-Sitosterol modulates macrophage polarization and attenuates rheumatoid inflammation in mice[J]. Pharm Biol, 2019, 57(1): 161-168. doi:10.1080/13880209.2019.1577461.
[24] Sun YN, Gao L, Hou W, et al. Β-sitosterol alleviates inflammatory response via inhibiting the activation of ERK/p38 and NF-κB pathways in LPS-exposed BV2 cells[J]. Biomed Res Int, 2020, 2020: 1-10. doi:10.1155/2020/7532306.
[25] 倪平敏, 赵晶晶, 李乐, 等. 鼻渊合剂对急性鼻窦炎模型大鼠鼻窦黏膜p38MAPK信号通路及IL-9/IL-10的影响[J]. 南京中医药大学学报, 2019, 35(2): 185-188. doi:10.14148/j.issn.1672-0482.2019.0185. NI Pingmin, ZHAO Jingjing, LI Le, et al. The influence of biyuan mixture on p38MAPK signaling pathway and IL-9/IL-10 of sinus mucosa of ARS in model rats[J]. J Nanjing Univ Tradit Chin Med, 2019, 35(2): 185-188. doi:10.14148/j.issn.1672-0482.2019.0185.
[26] Ahmad Khan M, Sarwar AHMG, Rahat R, et al. Stigmasterol protects rats from collagen induced arthritis by inhibiting proinflammatory cytokines[J]. Int Immunopharmacol, 2020, 85: 106642. doi:10.1016/j.intimp.2020.106642.
[27] 朱继荷. 杨梅酮对人肝细胞基因表达的影响及其抗炎功能分析[D]. 长沙: 湖南农业大学, 2017.
[28] 刘国栋, 辛兵, 黄栋, 等. 亚油酸乙酯抑制钛颗粒诱导的炎症反应及其作用机制[J]. 中国组织工程研究, 2016,20(52): 7836-7843. doi: 10.3969/j.issn.2095-4344.2016.52.012. LIU Guodong, XIN Bing, HUANG Dong, et al. Ethyl linoleate inhibits inflammatory reaction induced by titanium particles and its mechanism[J]. Chin J Tissue Eng Res, 2016,20(52): 7836-7843. doi: 10.3969/j.issn.2095-4344.2016.52.012.
[29] Park SY, Seetharaman R, Ko MJ, et al. Ethyl linoleate from garlic attenuates lipopolysaccharide-induced pro-inflammatory cytokine production by inducing heme oxygenase-1 in RAW264.7 cells[J]. Int Immunopharmacol, 2014, 19(2): 253-261. doi:10.1016/j.intimp.2014.01.017.
[30] 崔胜楠. 别欧前胡素通过激活MAPK信号通路诱导HL-60细胞凋亡[D]. 咸阳: 陕西中医药大学, 2019.
[31] 陈布衣, 张昌明. 慢性鼻窦炎黏膜组织中Eotaxin-3、Foxm1表达量与p38MAPK/NF-κB、炎症因子表达的相关性[J]. 海南医学院学报, 2017, 23(13): 1874-1876,1880. doi:10.13210/j.cnki.jhmu.20170809.037. CHEN Buyi, ZHANG Changming. Correlation of the expression of Eotaxin-3 and Foxm1 with the expression of p38MAPK/NF-κB and inflammatory factors in mucosa tissue of chronic sinusitis[J]. J Hainan Med Univ, 2017, 23(13): 1874-1876,1880. doi:10.13210/j.cnki.jhmu.20170809.037.
[32] 范隽, 赵昌敏, 刘兆芳, 等. p38MAPK信号通路调控IL-6、HIF-1α及VEGF对慢性鼻-鼻窦炎发病机制的影响[J]. 中国当代医药, 2017,24(9): 8-11,22. doi: 10.3969/j.issn.1674-4721.2017.09.003. FAN Jun, ZHAO Changmin, LIU Zhaofang, et al. The influence of p38MAPK signal pathway regulateing expression of IL-6, HIF-1α and VEGF on the chronic rhinosinusitis[J]. China Mod Med, 2017,24(9): 8-11,22. doi: 10.3969/j.issn.1674-4721.2017.09.003.
[33] 陈薇, 刘仲娟, 叶菁. 慢性鼻-鼻窦炎鼻黏膜中糖原合成酶激酶3β与PI3K/Akt及白细胞介素6间的相关性[J].中华耳鼻咽喉头颈外科杂志, 2013(2):128-134. doi: 10.3760/cma.j.issn.1673-0860.2013.02.017. CHEN Wei, LIU Zhongjuan, Yejing. Relationship among the expression of GSK3β, PDK/Akt, and IL-6 in chronic rhinosinusitis[J]. Chinese JOurnal of Otorhinolaryngology Head and Neck Surgery, 2013(2):128-134. doi: 10.3760/cma.j.issn.1673-0860.2013.02.017.
[34] Dilci A, Varol N, Kılıçcıoglu I, et al. Expression profiles of CD11b, galectin-1, beclin-1, and caspase-3 in nasal polyposis[J]. Turk J Med Sci, 2017, 47(6): 1757-1764. doi:10.3906/sag-1705-108.
[35] Papavassiliou AG, Musti AM. The multifaceted output of c-Jun biological activity: focus at the junction of CD8 T cell activation and exhaustion[J]. Cells, 2020, 9(11): 2470. doi:10.3390/cells9112470.
[36] Cho JS, Kim JA, Park JH, et al. Toll-like receptor 4-mediated expression of interleukin-32 via the c-Jun N-terminal kinase/protein kinase B/cyclic adenosine monophosphate response element binding protein pathway in chronic rhinosinusitis with nasal polyps[J]. Int Forum Allergy Rhinol, 2016, 6(10): 1020-1028. doi:10.1002/alr.21792.
[37] Li XH, Liu YR, Jiang DH, et al. Research on the mechanism of Chinese herbal medicine Radix Paeoniae Rubra in improving chronic pelvic inflammation disease by regulating PTGS2 in the arachidonic acid pathway[J]. Biomed Pharmacother, 2020, 129: 110052. doi:10.1016/j.biopha.2020.110052.
[38] Pietruszewska W, Fendler W, Podwysocka M, et al. Expression of transcript variants of PTGS1 and PTGS2 genes among patients with chronic rhinosinusitis with nasal polyps[J]. Diagnostics, 2021, 11(1): 135. doi:10.3390/diagnostics11010135.
[39] Xu Q, Tu J, Dou C, et al. HSP90 promotes cell glycolysis, proliferation and inhibits apoptosis by regulating PKM2 abundance via Thr-328 phosphorylation in hepatocellular carcinoma[J]. Mol Cancer, 2017, 16(1): 178. doi:10.1186/s12943-017-0748-y.
[40] Choudhury A, Bullock D, Lim A, et al. Inhibition of HSP90 and activation of HSF1 diminish macrophage NLRP3 inflammasome activity in alcohol-associated liver injury[J]. Alcohol Clin Exp Res, 2020, 44(6): 1300-1311. doi:10.1111/acer.14338.
[41] Yang HW, Kim HJ, Park JH, et al. Apigenin alleviates TGF-β1-induced nasal mucosa remodeling by inhibiting MAPK / NF-kB signaling pathways in chronic rhinosinusitis[J]. PLoS One, 2018,13(8): e0201595. doi: 10.1371/journal.pone.0201595.
[42] 殷桐, 丁希艳, 王朝辉. PIK3CG在大动脉粥样硬化型脑梗死患者体内表达及临床意义[J]. 中国老年学杂志, 2020,40(13): 2721-2723. doi: 10.3969/j.issn.1005-9202.2020.13.011. YIN Tong, DING Xiyan, WANG Chaohui. Expression and clinical significance of PIK3CG in large artery atherosclerosis stroke patients[J]. Chin J Gerontol, 2020,40(13): 2721-2723. doi: 10.3969/j.issn.1005-9202.2020.13.011.
[43] Ryu G, Bae JS, Kim JH, et al. Role of IL-17A in chronic rhinosinusitis with nasal polyp[J]. Allergy Asthma Immunol Res, 2020, 12(3): 507-522. doi:10.4168/aair.2020.12.3.507.
[44] Wu DW, Mueller SK, Nocera AL, et al. Axonal guidance signaling pathway is suppressed in human nasal polyps[J]. Am J Rhinol Allergy, 2018, 32(4): 208-216. doi:10.1177/1945892418773558.
[45] 陶丹丹, 董红军, 褚云锋, 等. 慢性鼻-鼻窦炎伴鼻息肉患者组织嗜酸性粒细胞与嗅觉功能障碍的相关性研究[J]. 山东大学耳鼻喉眼学报, 2020,34(6): 16-20. doi: 10.6040/j.issn.1673-3770.0.2019.388. TAO Dandan, DONG Hongjun, CHU Yunfeng, et al. Correlation between eosinophils and olfactory dysfunction in patients with CRSwNP after nasal operation[J]. J Otolaryngol Ophthalmol Shandong Univ, 2020, 34(6): 16-20. doi: 10.6040/j.issn.1673-3770.0.2019.388.
[46] Du J, Mao H, Ouyang H, et al. Osteopontin induced vascular endothelial growth factor production in dispersed nasal polyp cells through the phosphatidylinositol 3-kinase-protein kinase B and the extracellular signal-regulated kinase 1/2 pathways[J]. Am J Rhinol Allergy, 2017, 31(4): 35-41. doi:10.2500/ajra.2017.31.4449.

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