基于网络药理学与分子对接研究厚朴-麻黄治疗支气管哮喘的作用机制

侯学文; 孟泳; 侯从岭; 朱丹娜; 胡延申; 侯超峰

doi:10.16766/j.cnki.issn.1674-4152.002964

基于网络药理学与分子对接研究厚朴-麻黄治疗支气管哮喘的作用机制

doi: 10.16766/j.cnki.issn.1674-4152.002964

1.
河南中医药大学第二临床医学院，河南郑州 450000
2.
河南省中医院肺病科，河南郑州 450000

基金项目:

河南省中医药科学研究专项课题 2019JDZX049

详细信息

通讯作者:
孟泳，E-mail: mywd1966@sina.com

中图分类号: R562.25 R285
计量
- 文章访问数: 416
- HTML全文浏览量: 402
- PDF下载量: 19
- 被引次数: 0
出版历程
- 收稿日期: 2022-02-18
- 网络出版日期: 2023-05-31

Mechanism of Houpo-Mahuang Pair in treating bronchial asthma based on network pharmacology and molecular docking

1.
The Second Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan 450000, China

摘要

摘要: 目的通过网络药理学与分子对接研究厚朴-麻黄药对治疗支气管哮喘的作用机制, 为临床应用提供依据。方法利用中药系统药理学数据库(TCMSP)、人类基因数据库(Gene Cards)等数据库筛选出药物与疾病靶点，规范化处理后找出两者共有靶点。分别运用Cytoscape 3.7.2软件及String数据库找出主要活性成分及靶点。运用Metascape平台对数据进行基因本体论(gene ontology，GO)及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes，KEGG)富集分析，预测中药有效成分作用于疾病的分子机制。最后将主要有效活性成分与疾病核心靶点通过分子对接进行初步验证。结果厚朴-麻黄主要有效成分为槲皮素(quercetin)、山奈酚(kaempferol)、木犀草素(luteolin)、β-谷甾醇(beta-sitosterol)等；核心靶点蛋白为蛋白激酶B1(AKT1)、白介素6(IL6)、肿瘤坏死因子(TNF)、肿瘤蛋白p53(TP53)。GO功能富集得到生物过程2 044个、细胞组成70个、分子功能165个，KEGG富集分析得到329条信号通路，主要有PI3K-Akt信号通路、胆碱能突触、咖啡因代谢、腺苷酸活化蛋白激酶(AMPK)信号通路等，分子对接显示主要活性成分与核心靶点有较好的结合力。结论厚朴-麻黄药治疗支气管哮喘涉及多个信号通路及生物学过程，其中主要可能通过PI3K-Akt信号通路、胆碱能突触、咖啡因代谢、AMPK信号通路等途径，达到改善气道重塑、抑制气道炎症、调节免疫、减轻氧化应激的作用，从而治疗支气管哮喘，这对下一步临床研究及新药研发有一定的指导意义。
- 厚朴 /
- 麻黄 /
- 支气管哮喘 /
- 网络药理学 /
- 分子对接
Abstract: Objective To determine the mechanism of Houpo-Mahuang in treating bronchial asthma through network pharmacology and molecular docking and provide evidence for clinical application. Methods Traditional Chinese medicine systems pharmacology database (TCMSP) and Gene Cards databases were used to screen drug and disease targets. Common targets were found after standardised treatment. Cytoscape 3.7.2 software and String database were used to identify main active components and key target information. Gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) enrichment analysis were performed using Metascape platform to predict the molecular mechanism of effective components of traditional Chinese medicine acting on diseases. The main effective active components were preliminarily verified by molecular docking with the core targets of diseases. Results The main active ingredients of Houpo-Mahuang were quercetin, kaempferol, luteolin, β-sitosterol. The core target proteins were AKT1, IL-6, TNF and TP53. The GO function enrichment obtained 2 044 biological processes, 70 cell components and 165 molecular functions. The KEGG enrichment analysis obtained 329 signalling pathways, mainly including PI3K-Akt signalling pathway, cholinergic synapses, caffeine metabolism and AMPK signalling pathway. The molecular docking showed that the main active ingredients had good binding ability to the core target. Conclusion The Houpo-Mahuang treatment of bronchial asthma involves multiple signalling pathways and biological processes, among which the effects of improving airway remodelling, inhibiting airway inflammation, regulating immunity and reducing oxidative stress are mainly achieved through PI3K-Akt signalling pathway, cholinergic synapse, caffeine metabolism and AMPK signalling pathway. Results have certain guiding significance for further clinical research and new drug development.
- Houpo /
- Mahuang /
- Bronchial asthma /
- Network pharmacology /
- Molecular docking

HTML全文

图 1 PPI核心网络图

Figure 1. PPI core network diagram

下载: 全尺寸图片幻灯片

图 2 GO分析功能气泡图

注：A代表生物过程，B代表分子功能，纵轴为功能富集，横轴为富集倍数，气泡大小为基因数：越大则基因数越多，颜色深浅为P值大小：由红到绿，代表P值由小到大。

Figure 2. GO analysis function bubble diagram

下载: 全尺寸图片幻灯片

图 3 KEGG通路富集分析

注：纵轴代表各个信号通路，横轴代表通路上所存在的靶点蛋白数，颜色代表P值：红色P值最小，蓝色P值最大。

Figure 3. KEGG pathway enrichment analysis

下载: 全尺寸图片幻灯片

图 4 分子对接结果

注：A为β-谷甾醇与AKT1;B为β-谷甾醇与TP53。

Figure 4. Molecular docking results

下载: 全尺寸图片幻灯片

表 1 厚朴-麻黄成分

Table 1. The ingredients of Houpo-Mahuang

编码	化学成分	OB(%)	DL值	来源
MOL005970	Eucalyptol	60.62	0.32	厚朴
MOL005980	Neohesperidin	57.44	0.27	厚朴
MOL010788	leucopelargonidin	57.97	0.24	麻黄
MOL002823	Herbacetin	36.07	0.27	麻黄
MOL010489	Resivit	30.84	0.27	麻黄
MOL000422	kaempferol	41.88	0.24	麻黄
MOL004798	delphinidin	40.63	0.28	麻黄
MOL000098	quercetin	46.43	0.28	麻黄
MOL000006	luteolin	36.16	0.25	麻黄
MOL000358	beta-sitosterol	36.91	0.75	麻黄
MOL000449	Stigmasterol	43.83	0.76	麻黄
MOL000492	(+)-catechin	54.83	0.24	麻黄
MOL001494	Mandenol	42.00	0.19	麻黄
MOL001755	24-Ethylcholest-4-en-3-one	36.08	0.76	麻黄
MOL002881	Diosmetin	31.14	0.27	麻黄
MOL004328	naringenin	59.29	0.21	麻黄
MOL004576	taxifolin	57.84	0.27	麻黄
MOL005190	eriodictyol	71.79	0.24	麻黄
MOL005573	Genkwanin	37.13	0.24	麻黄
MOL005842	Pectolinarigenin	41.17	0.30	麻黄
MOL007214	(+)-Leucocyanidin	37.61	0.27	麻黄
MOL011319	Truflex OBP	43.74	0.24	麻黄

下载: 导出CSV

参考文献(28)

[1]	中华医学会呼吸病学分会哮喘学组. 支气管哮喘防治指南(2020年版)[J]. 中华结核和呼吸杂志, 2020, 43(12): 1023-1048. doi: 10.3760/cma.j.cn112147-20200618-00721 Asthma group of Chinese Throacic Society. Guidelines for bronchial asthma prevent and management(2020 edition) Asthma group of Chinese Throacic Society)[J]. Chinese Journal of Tuberculosis and Respiratory Diseases, 2020, 43(12): 1023-1048. doi: 10.3760/cma.j.cn112147-20200618-00721
[2]	DHARMAGE S C, PERRET J L, CUSTOVC A. Epidemiology of asthma in children and adults[J]. Front Pediatr, 2019, 7: 00246. DOI: 10.3389/fped.2019.00246.
[3]	李竹英, 王婷, 李寒梅. 外泌体在支气管哮喘发病机制中的作用[J]. 中华全科医学, 2020, 18(2): 291-294. doi: 10.16766/j.cnki.issn.1674-4152.001228 LI Z Y, WANG T, LI H M. The role of exosomes in the pathogenesis of bronchial asthma[J]. Chinese Journal of General Practice, 2020, 18(2): 291-294. doi: 10.16766/j.cnki.issn.1674-4152.001228
[4]	白震宁, 王海萍. 中西医结合治疗支气管哮喘思路探析[J]. 山西中医药大学学报, 2021, 22(2): 135-138. https://www.cnki.com.cn/Article/CJFDTOTAL-SHAN202102017.htm BAI Z N, WANG H P. Thoughts analysis on bronchial asthma treated with integrated traditional Chinese and Western medicine[J]. Journal of Shanxi University of Chinese Medicine, 2021, 22(2): 135-138. https://www.cnki.com.cn/Article/CJFDTOTAL-SHAN202102017.htm
[5]	ZHU H, SHI Y H, JIANG S S, et al. Investigation of the mechanisms of chuankezhi injection in the treatment of asthma based on the network pharmacology approach[J]. Evid-based Compl Alt, 2021, 2021: 5517041. DOI: 10.1155/2021/5517041.
[6]	刘嘉燕, 夏鑫华, 龙国豪. 邱志楠治疗哮喘经验[J]. 实用中医药杂志, 2021, 37(5): 881-882. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYAO202105093.htm LIU J Y, XIA X H, LONG G H. Qiu Zhinan's experience in treating asthma[J]. Journal of Practical Traditional Chinese Medicine, 2021, 37(5): 881-882. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYAO202105093.htm
[7]	余涛, 丁明, 喻强强, 等. 薛汉荣治疗哮喘的学术经验与临证思路[J]. 中国中医基础医学杂志, 2021, 27(4): 655-658. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYJC202104032.htm YU T, DING M, YU Q Q, et al. XUE Han-rong's Academic Experience and Clinical Thinking in Treating Asthma[J]. Journal of Basic Chinese Medicine, 2021, 27(4): 655-658. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYJC202104032.htm
[8]	任园园, 汤玉梅, 吴振起. 中医古籍哮喘用药规律的数据挖掘研究[J]. 中国中医急症, 2021, 30(3): 402-405. doi: 10.3969/j.issn.1004-745X.2021.03.007 REN Y Y, TANG Y M, WU Z Q. Medication Rule of Chinese Medicine on Asthma Based on the Data Mining of Traditional Chinese Medicine Ancient Books[J]. Journal of Emergency in Traditional Chinese Medicine, 2021, 30(3): 402-405. doi: 10.3969/j.issn.1004-745X.2021.03.007
[9]	焦蕊, 庞立健, 吕晓东. 基于网络药理学探讨三拗汤治疗咳嗽变异型哮喘的作用机制[J]. 中华全科医学, 2021, 19(7): 1218-1223. doi: 10.16766/j.cnki.issn.1674-4152.002025 JIAO R, PANG L J, LYU X D. Mechanism of San'ao Decoction in treatment of cough variant asthma on the basis of network pharmacology[J]. Chinese Journal of General Practice, 2021, 19(7): 1218-1223. doi: 10.16766/j.cnki.issn.1674-4152.002025
[10]	马南, 耑冰, 李萍, 等. 氧化应激失衡在支气管哮喘急性发作中的意义[J]. 中华全科医学, 2019, 17(12): 1993-1997. doi: 10.16766/j.cnki.issn.1674-4152.001110 MA N, ZHUAN B, LI P, et al. Significance of oxidative stress in acute exacerbation of bronchial asthma[J]. Chinese Journal of General Practice, 2019, 17(12): 1993-1997. doi: 10.16766/j.cnki.issn.1674-4152.001110
[11]	胡方媛, 范玉浩, 范欣生, 等. 厚朴麻黄汤对哮喘小鼠气道炎症及TRPA1, TRPV1 mRNA与蛋白表达的影响[J]. 中国实验方剂学杂志, 2020, 26(1): 37-42. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202001007.htm HU F Y, FAN Y H, FAN X S, et al. Effect of Houpu Mahuangtang on Airway Inflammation and Expression of TRPA1, TRPV1 mRNA and Protein in Asthmatic Mice[J]. Chinese Journal of Experimental Traditional Medical Formulae, 2020, 26(1): 37-42. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202001007.htm
[12]	马元, 俞琪珺, 王正霞, 等. 黄酮类化合物对支气管哮喘防治作用的研究进展[J]. 国际呼吸杂志, 2019, 39(5): 373-377. MA Y, YU Q J, WANG Z X, et al. Research progress of flavonoids on prevention and treatment of bronchial asthma[J]. International Journal of Respiration, 2019, 39(5): 373-377.
[13]	JAFARINIA M, HOSSEINI M S, KASIRI N, et al. Quercetin with the potential effect on allergic diseases[J]. Allergy Asthma Clin Immunol, 2020, 16(3): 1-7.
[14]	朱翔, 肖云斌, 易晓莲. 槲皮素对支气管哮喘小鼠气道炎症的作用及机制研究[J]. 中国现代医学杂志, 2020, 30(13): 19-22. https://www.cnki.com.cn/Article/CJFDTOTAL-ZXDY202013005.htm ZHU X, XIAO Y B, YI X L. Inhibitory effect of quercetin on airway inflammation in mice with bronchial asthma[J]. China Journal of Modern Medicine, 2020, 30(13): 19-22. https://www.cnki.com.cn/Article/CJFDTOTAL-ZXDY202013005.htm
[15]	YANG C L, YANG W K, HE Z H, et al. Kaempferol improves lung ischemia-reperfusion injury via antiinflammation and antioxidative stress regulated by SIRT1/HMGB1/NF-κB Axis[J]. Front Pharmacol, 2019, 10: 01635. DOI: 10.3389/fphar.2019.01635.
[16]	蔡蕙荞, 杨子珍, 解玉, 等. 黄酮类化合物木犀草素对哮喘影响的研究近况[J]. 世界最新医学信息文摘, 2019, 19(50): 89-90. https://www.cnki.com.cn/Article/CJFDTOTAL-WMIA201950041.htm CAI H Q, YANG Z Z, XIE Y, et al. Recent studies on the effects of flavonoids luteolin on asthma[J]. World Latest Medicine Information, 2019, 19(50): 89-90. https://www.cnki.com.cn/Article/CJFDTOTAL-WMIA201950041.htm
[17]	ROGELIO P, GABRIELA F, CELIA R, et al. Evaluation of the anti-inflammatory capacity of beta-sitosterol in rodent assays[J]. Afr J Tradit Complement Altern Med, 2017, 14(1): 123-130. http://www.ajol.info/index.php/ajtcam/article/download/151920/141516
[18]	周旋, 谭志团, 任翼, 等. 柚皮素通过抑制NF-κB信号通路减轻哮喘大鼠气道炎症反应[J]. 天津医药, 2021, 49(5): 483-489. https://www.cnki.com.cn/Article/CJFDTOTAL-TJYZ202105008.htm ZHOU X, TAN Z T, REN Y, et al. Naringenin reduces airway inflammation in asthmatic rats by inhibiting NF-κB signaling pathway[J]. Tianjin Medical Journal, 2021, 49(5): 483-489. https://www.cnki.com.cn/Article/CJFDTOTAL-TJYZ202105008.htm
[19]	SHI R, XU J W, XIAO Z T, et al. Naringin and naringenin relax rat tracheal smooth by regulating BKCa activation[J]. Med Food, 2019, 22(9): 963-970.
[20]	XU G, GUO J S, SUN C M. Eucalyptol ameliorates early brain injury after subarachnoid haemorrhage via antioxidant and anti-inflammatory effects in a rat model[J]. Pharm Biol, 2021, 59(1): 114-120. http://www.socolar.com/Article/Index?aid=200259187604&jid=200000001095
[21]	LIU D D, PAN J, ZHAO D Y, et al. MicroRNA-223 inhibits deposition of the extracellular matrix by airway smooth muscle cells through targeting IGF-1R in the PI3K/Akt pathway[J]. Am J Transl Res, 2018, 10(3): 744. http://ajtr.org/files/ajtr0063720.pdf
[22]	JALEESA G, JARROD W B, STEFANIE K. Targeting cytokines as evolving treatment strategies in chronic inflammatory airway diseases[J]. Int J Mol Sci, 2018, 19(11): 3402. http://www.onacademic.com/detail/journal_1000040905291310_3ef0.html
[23]	SINGH S, VERMA S K, KUMAR S, et al. Evaluation of oxidative stress and antioxidant status in chronic obstructive pulmonary disease[J]. Immunol, 2017, 85(2): 130-137. http://doc.paperpass.com/foreign/rgArti20177379340.html
[24]	刘嘉研, 李俊峰, 车楠, 等. 梓醇对哮喘小鼠气道炎症及AMPK/ROS/NF-κB信号通路的影响[J]. 郑州大学学报(医学版), 2019, 54(6): 823-827. https://www.cnki.com.cn/Article/CJFDTOTAL-HNYK201906009.htm LIU J Y, LI J F, CHE N, et al. Catalpol suppresses airway inflammation via AMPK/ROS/NF-κB signaling pathway in asthmatic mice[J]. Journal of Zhengzhou University (Medical Sciences), 2019, 54(6): 823-827. https://www.cnki.com.cn/Article/CJFDTOTAL-HNYK201906009.htm
[25]	冯晓纯, 陈琼芳, 洪天一, 等. 蝎黄解痉治哮颗粒对支气管哮喘模型小鼠肺组织PI3K/AKT通路的影响[J]. 中医杂志, 2021, 62(8): 717-722. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYZ202108017.htm FENG X C, CHEN Q F, HONG T Y, et al. Effect of Xiehuang Jiejing Zhixiao Granules on PI3K/AKT Pathway in Lung Tissues of Bronchial Asthma Model Mice[J]. Journal of Traditional Chinese Medicine, 2021, 62(8): 717-722. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYZ202108017.htm
[26]	ASHWINI R, DANIEL H, ALICE Y, et al. Cholinergic synapse pathway gene polymorphisms associated with allergen-induced late asthmatic responses[J]. ERJ Open Res, 2019, 5(4). DOI: 10.1183/23120541.00107-2019.
[27]	崔鑫洋. 茶碱类药物在支气管哮喘治疗中的合理应用[J]. 中国医药指南, 2021, 19(20): 38-39. https://www.cnki.com.cn/Article/CJFDTOTAL-YYXK202120015.htm CUI X Y. Reasonable Application of Theophylline Drugs in Bronchial Asthma Treatment[J]. Guide of China Medicine, 2021, 19(20): 38-39. https://www.cnki.com.cn/Article/CJFDTOTAL-YYXK202120015.htm
[28]	WANG W J, MAO L F, LAI H L, et al. Dolutegravir derivative inhibits proliferation and induces apoptosis of non-small cell lung cancer cells via calcium signaling pathway[J]. Pharmacol Res, 2020, 161: 105129. DOI: 10.1016/j.phrs.2020.105129.