基于网络药理学和分子对接技术探究苍术香连散治疗猪湿热泄泻的作用机制

doi:10.16431/j.cnki.1671-7236.2023.12.035

摘要/Abstract

摘要： 【目的】基于网络药理学和分子对接技术探究苍术香连散治疗猪湿热泄泻的作用机制。【方法】通过中药系统药理学数据库(TCMSP)、文献收集获取苍术香连散的活性成分和相关作用靶点;通过GeneCards、OMIM和DisGeNET数据库获取猪湿热泄泻的相关靶点。利用Cytoscape 3.9.1软件绘制苍术香连散成分-靶点网络图。通过STRING数据库进行交集靶点蛋白互作(PPI)分析,用Cytoscape 3.9.1软件构建PPI网络并进行拓扑分析获取核心靶点;通过DAVID数据库进行GO功能和KEGG信号通路富集分析。在AutoDock Vina软件上对药物关键活性成分与核心潜在作用靶点进行分子对接模拟。【结果】经过筛选共获得药物有效成分靶点149个,疾病靶点1 246个,其交集靶点50个。PPI网络分析结果显示,肿瘤坏死因子(TNF)、细胞肿瘤抗原p53(TP53)、白细胞介素-6(IL6)、血管内皮生长因子A(VEGFA)、基质金属蛋白酶-9(MMP9)等为药物作用于疾病的关键靶点。GO功能分析显示,生物过程有129个条目,细胞组分有7个条目,分子功能有17个条目。KEGG富集分析结果显示,该药物主要通过影响IL17、Toll样受体、TNF等信号通路发挥治疗作用。分子对接结果显示,药物核心有效成分与疾病关键靶点蛋白结合能均＜－5.0 kJ/mol。【结论】苍术香连散可能通过槲皮素、汉黄芩素、R-四氢小檗碱等成分作用于TNF、TP53、IL6、VEGFA等靶点影响TNF、IL17等主要炎症相关信号通路治疗猪湿热泄泻。

关键词: 苍术香连散; 网络药理学; 分子对接; 湿热泄泻

Abstract: 【Objective】 This study was aimed to investigate the mechanism of action of Cangzhuxiangliansan in the treatment of damp-heat diarrhea in swine based on network pharmacology and molecular docking techniques.【Method】 The active ingredients and related targets of Cangzhuxiangliansan were obtained through the Traditional Chinese Medicine Systematic Pharmacology Database (TCMSP) and literature collection.The related targets of damp-heat diarrhea in swine were obtained through GeneCards,OMIM and DisGeNET databases.The composition-target network of Cangzhuxiangliansan was mapped by Cytoscape 3.9.1 software. Protein-protein interaction (PPI) analysis of intersecting targets was carried out by STRING database,PPI network was constructed and topology analysis was performed by Cytoscape 3.9.1 software to obtain core targets.GO function and KEGG signaling pathway enrichment analysis were carried out by DAVID database.Molecular docking simulations of key active ingredients of drugs with core potential targets of action were performed using AutoDock Vina software.【Result】 A total of 149 active ingredient targets,1 246 disease targets and 50 intersecting targets were obtained after screening.The results of the PPI network analysis showed that tumor necrosis factor (TNF),tumor antigen p53 (TP53),interleukin-6 (IL6),vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase-9 (MMP9) were the key targets for drug action in the disease.GO functional analysis showed that there were 129 entries in biological processe,7 entries in cell component,and 17 entries in molecular function.The results of KEGG enrichment analysis showed that the drug exerted its therapeutic effects mainly through affecting IL17 signaling pathway,Toll-like receptor signaling pathway and TNF signaling pathway.The molecular docking results showed that the binding energy of the core active ingredient to the key target protein of the disease was ＜－5.0 kJ/mol.【Conclusion】 Cangzhu xiangliansan might act on targets such as TNF,TP53,IL6 and VEGFA through components such as quercetin,wogonin,and R-tetrahydroberberine,affecting the main inflammatory signaling pathways such as TNF and IL17 in the treatment of damp-heat diarrhea in swine.

Key words: Cangzhuxiangliansan; network-based pharmacology; molecular docking; damp-heat diarrhea

中图分类号:

S859.7

胡宇豪, 苏进博, 杨洋, 熊宇明, 曾企辉, 王磊, 殷光文, 黄志坚, 邓莉萍, 王登峰. 基于网络药理学和分子对接技术探究苍术香连散治疗猪湿热泄泻的作用机制[J]. 中国畜牧兽医, 2023, 50(12): 5136-5147.

HU Yuhao, SU Jinbo, YANG Yang, XIONG Yuming, ZENG Qihui, WANG Lei, YIN Guangwen, HUANG Zhijian, DENG Liping, WANG Dengfeng. Exploring the Action Mechanism of Cangzhuxiangliansan in the Treatment of Damp-heat Diarrhea in Swine Based on Network Pharmacology and Molecular Docking Techniques[J]. China Animal Husbandry and Veterinary Medicine, 2023, 50(12): 5136-5147.

参考文献

[1] 李中梓.医宗必读[M].北京:人民卫生出版社,2006. LI Z Z.Required Readings for Medical Professionals[M].Beijing:People's Medical Publishinng House,2006.(in Chinese)
[2] 于斌,邓力,张丽,等.湿邪致病现代机理研究进展[J].广州中医药大学学报,2015,32(1):174-177. YU B,DENG L,ZHANG L,et al.Advances in modern mechanisms of dampness[J]. Journal of Guangzhou University of Traditional Chinese Medicine,2015,32(1):174-177.(in Chinese)
[3] 马金鑫,唐旭东,王凤云,等.从脾论治功能性腹泻机制探析[J].中华中医药杂志,2020,35(8):3828-3830. MA J X,TANG X D,WANG F Y,et al.Analysis on the treatment mechanism of functional diarrhea from spleen[J].China Journal of Traditional Chinese Medicine and Pharmacy,2020,35(8):3828-3830.(in Chinese)
[4] 中国兽药典委员会.中华人民共和国兽药典[M].北京:中国农业出版社,2020. COMMISSION OF CHINESE VETERINARY PHARMACOPOEIA.Veterinary Pharmacopoeia of the People's Republic of China[M].Beijing:China Agriculture Press,2020(in Chinese)
[5] 邢斯嘉,赵远红.从药物归经浅议"升麻、黄连、生地黄"角药论治放射性牙周炎[J].天津中医药,2023,40(3):313-317. XING S J,ZHAO Y H.Analysis on treatment of radioactive periodontitis with Jiaoyao "Rhizoma cimicifugae,Coptis chinensis and Rehmannia glutinosa" based on meridian tropism theory[J].Tianjin Journal of Traditional Chinese Medicine,2023,40(3):313-317.(in Chinese)
[6] 王淑萍,曲妍霏,宋驰,等.木香中主要活性成分的药代动力学研究[J].现代中西医结合杂志,2019,28(12):1255-1259. WANG S P,QU Y F,SONG C,et al.Pharmacokinetics study on main components costunolide and dehydrocostuslactone after oral administration of Radix Aucklandiae extract[J].Modern Journal of Integrated Traditional Chinese and Western Medicine,2019,28(12):1255-1259.(in Chinese)
[7] HOPKINS A L.Network pharmacology[J].Nature Biotechnology,2007,25(10):1110-1111.
[8] HAN J,HOU J,LIU Y,et al.Using network pharmacology to explore the mechanism of Panax notoginseng in the treatment of myocardial fibrosis[J].Journal of Diabetes Research,2022,2022:8895950.
[9] 刘鑫煜,崔强,张兰欣,等.基于网络药理学和分子对接探究诃子鞣酸防治奶牛子宫内膜炎的作用机制[J].中国畜牧兽医,2023,50(4):1632-1641. LIU X Y,CUI Q,ZHANG L X,et al.Study on mechanism of chebulagic acid in treatment of cow endometritis based on network pharmacology and molecular docking[J]. China Animal Husbandry&Veterinary Medicine,2023,50(4):1632-1641.(in Chinese)
[10] DONG Y,TAO B,XUE X,et al.Molecular mechanism of Epicedium treatment for depression based on network pharmacology and molecular docking technology[J]. BMC Complementary Medicine and Therapies,2021,21(1):222.
[11] 邓燕君,刘博文,贺桢翔,等.基于网络药理学和分子对接法探索藿香正气口服液预防新型冠状病毒肺炎(COVID-19)活性化合物研究[J].中草药,2020,51(5):1113-1122. DENG Y J,LIU B W,HE Z X,et al.Study on active compounds from Huoxiang Zhengqi oral liquid for prevention of Coronavirus disease 2019(COVID-19) based on network pharmacology and molecular docking[J].Chinese Traditional and Herbal Drugs,2020,51(5):1113-1122.(in Chinese)
[12] 冯汉财.痢疾的中医古籍整理及临床诊疗方案的梳理[D].广州:广州中医药大学,2011. FENG H C.Literature research of Chinese ancient books on dysentery[D].Guangzhou:Guangzhou University of Chinese Medicine,2011.(in Chinese)
[13] KIM D H.Gut microbiota-mediated drug-antibiotic interactions[J]. Drug Metabolism and Disposition,2015,43(10):1581-1589.
[14] WANG X,TANG Y,LIU C,et al.Effects of restrictive-prescribing stewardship on antibiotic consumption in primary care in China:An interrupted time series analysis,2012-2017[J]. Antimicrobial Resistance and Infection Control,2020,9(1):159.
[15] YANG J H,BHARGAVA P,MCCLOSKEY D,et al.Antibiotic-induced changes to the host metabolic environment inhibit drug efficacy and alter immune function[J].Cell Host&Microbe,2017,22(6):757-765.
[16] 刘思佳,姚杰,宋雪,等.苍术属药用植物的化学成分、药理作用、临床应用概况[J].中华中医药学刊,2023,41(1):151-154. LIU S J,YAO J,SONG X,et al.Overview of chemical composition,pharmacological effects and clinical application of medicinal plants of Atractylodes DC[J]. Chinese Archives of Traditional Chinese Medicine,2023,41(1):151-154.(in Chinese)
[17] 盖晓红,刘素香,任涛,等.黄连的化学成分及药理作用研究进展[J].中草药,2018,49(20):4919-4927. GE X H,LIU S X,REN T,et al.Research progress on chemical constituents of Coptidis Rhizoma and its pharmacological activities[J]. Chinese Traditional and Herbal Drugs,2018,49(20):4919-4927.(in Chinese)
[18] 陈亮,王磊,张庆文,等.黄连非生物碱类化学成分研究[J].中国中药杂志,2012,37(9):1241-1244. CHEN L,WANG L,ZHANG Q W,et al.Non-alkaloid chemical constituents from Coptis chinensis[J]. China Journal of Chinese Materia Medica,2012,37(9):1241-1244.(in Chinese)
[19] 周瑞,项昌培,张晶晶,等.黄连化学成分及小檗碱药理作用研究进展[J].中国中药杂志,2020,45(19):4561-4573. ZHOU R,XIANG C P,ZHANG J J,et al.Research progress on chemical compositions of Coptidis Rhizoma and pharmacological effects of berberine[J].China Journal of Chinese Materia Medica,2020,45(19):4561-4573.(in Chinese)
[20] 匡艳辉,朱晶晶,王智民,等.黄连属药用植物化学成分和质量控制的研究进展[J].中国药学杂志,2008,15:1121-1125. KUANG Y H,ZHU J J,WANG Z M,et al.Advances in the chemical composition and quality control of medicinal plants of the genus Rhizoma[J]. Chinese Pharmaceutical Journal,2008,15:1121-1125.(in Chinese)
[21] 郑加梅,尚明越,王嘉乐,等.木香的化学成分、药理作用、临床应用研究进展及质量标志物预测[J].中草药,2022,53(13):4198-4213. ZHENG J M,SHANG M Y,WANG J L,et al.Research progress on chemical constituents,pharmacological effects and clinical applications of Aucklandiae Radix and prediction analysis on Q-Marker[J].Chinese Traditional and Herbal Drugs,2022,53(13):4198-4213.(in Chinese)
[22] STRZYGA L P,CZECZOT H.The role of flavonoids in the modulation of inflammation[J]. Polski Merkuriusz Lekarski,2016,40(236):134-140.
[23] MALEKI S J,CRESPO J F,CABANILLAS B.Anti-inflammatory effects of flavonoids[J]. Food Chemistry,2019,299:125124.
[24] GARCIA L A,GUILLAMON E,VILLARES A,et al.Flavonoids as anti-inflammatory agents:Implications in cancer and cardiovascular disease[J].Inflammation Research,2009,58(9):537-552.
[25] MLCEK J,JURIKOVA T,SKROVANKOVA S,et al.Quercetin and its anti-allergic immune response[J].Molecules(Basel,Switzerland),2016,21(5):623.
[26] DONG Y,HOU Q,LEI J,et al.Quercetin alleviates intestinal oxidative damage induced by H₂O₂ via modulation of GSH:In vitro screening and in vivo evaluation in a colitis model of mice[J].ACS Omega,2020,5(14):8334-8346.
[27] LUCAS C D,DORWARD D A,SHARMA S,et al.Wogonin induces eosinophil apoptosis and attenuates allergic airway inflammation[J]. American Journal of Respiratory and Critical Care Medicine,2015,191(6):626-636.
[28] LIM B O.Efficacy of wogonin in the production of immunoglobulins and cytokines by mesenteric lymph node lymphocytes in mouse colitis induced with dextran sulfate sodium[J]. Bioscience,Biotechnology,and Biochemistry,2004,68(12):2505-2511.
[29] HALLER D,ANTOINE J M,BENGMARK S,et al.Guidance for substantiating the evidence for beneficial effects of probiotics:Probiotics in chronic inflammatory bowel disease and the functional disorder irritable bowel syndrome[J].The Journal of Nutrition,2010,140(3):690-697.
[30] HABTEMARIAM S.Berberine pharmacology and the gut microbiota:A hidden therapeutic link[J].Pharmacological Research,2020,155:104722.
[31] TAKAHARA M,TAKAKI A,HIRAOKA S,et al.Berberine improved experimental chronic colitis by regulating interferon-γ-and IL-17A-producing lamina propria CD4⁺ T cells through AMPK activation[J].Scientific Reports,2019,9(1):11934.
[32] SINGH B,SINGH J P,SHEVKANI K,et al.Bioactive constituents in pulses and their health benefits[J].Journal of Food Science and Technology,2017,54(4):858-870.
[33] WEN S,HE L,ZHONG Z,et al.Stigmasterol restores the balance of Treg/Th17 cells by activating the butyrate-PPARγ axis in colitis[J].Frontiers in Immunology,2021,12:741934.
[34] LI L,DU Y,WANG Y,et al.Atractylone alleviates ethanol-induced gastric ulcer in rat with altered gut microbiota and metabolites[J].Journal of Inflammation Research,2022,15:4709-4723.
[35] PESCE B,RIBEIRO C H,LARRONDO M,et al.TNF-α affects signature cytokines of Th1 and Th17 T cell subsets through differential actions on TNFR1 and TNFR2[J].International Journal of Molecular Sciences,2022,23(16):9306.
[36] KASTENHUBER E R,LOWE S W.Putting p53 in context[J].Cell,2017,170(6):1062-1078.
[37] AUBREY B J,STRASSER A,KELLY G L.Tumor-suppressor functions of the TP53 pathway[J].Cold Spring Harbor Perspectives in Medicine,2016,6(5):a026062.
[38] KISHIMOTO T.The biology of interleukin-6[J]. Blood,1989,74(1):1-10.
[39] TANAKA T,NARAZAKI M,KISHIMOTO T.Interleukin (IL-6) immunotherapy[J]. Cold Spring Harbor Perspectives in Biology,2018,10(8):a028456.
[40] FOLKMAN J.Angiogenesis:An organizing principle for drug discovery[J].Nature Reviews.Drug Discovery,2007,6(4):273-286.
[41] YAN X,MANAGLIA E,LIU S X,et al.Lack of VEGFR2 signaling causes maldevelopment of the intestinal microvasculature and facilitates necrotizing enterocolitis in neonatal mice[J].American Journal of Physiology.Gastrointestinal and Liver Physiology,2016,310(9):716-725.
[42] BAKIRTZI K,WEST G,FIOCCHI C,et al.The neurotensin-HIF-1α-VEGFα axis orchestrates hypoxia,colonic inflammation,and intestinal angiogenesis[J].The American Journal of Pathology,2014,184(12):3405-3414.
[43] KOU M,GUO D,LIU L,et al.Expression pattern and association analysis of porcine matrix metallopeptidase 9(MMP9) with diarrhea and performance traits in piglets[J]. Research in Veterinary Science,2020,129:53-58.
[44] JIANG X E,YANG S M,ZHOU X J,et al.Effects of mesalazine combined with bifid triple viable on intestinal flora,immunoglobulin and levels of cal,MMP-9,and MPO in feces of patients with ulcerative colitis[J].European Review for Medical and Pharmacological Sciences,2020,24(2):935-942.
[45] CHELAKKOT C,GHIM J,RYU S H.Mechanisms regulating intestinal barrier integrity and its pathological implications[J].Experimental&Molecular Medicine,2018,50(8):1-9.
[46] NAKASE H,SATO N,MIZUNO N,et al.The influence of cytokines on the complex pathology of ulcerative colitis[J]. Autoimmunity Reviews,2022,21(3):103017.
[47] KUMAR P,MONIN L,CASTILLO P,et al.Intestinal interleukin-17 receptor signaling mediates reciprocal control of the gut microbiota and autoimmune inflammation[J].Immunity,2016,44(3):659-671.
[48] ALURI J,COOPER M A,SCHUETTPELZ L G.Toll-like receptor signaling in the establishment and function of the immune system[J]. Cells,2021,10(6):1374.
[49] KALLIOLIAS G D,IVASHKIV L B.TNF biology,pathogenic mechanisms and emerging therapeutic strategies[J].Nature Reviews.Rheumatology,2016,12(1):49-62.
[50] 金韦呈,张岳峰,刘艳艳,等.基于网络药理学探究苦参止痢颗粒治疗湿热泄泻的有效成分及作用机制[J].中国兽医学报,2022,42(1):135-141. JIN W C,ZHANG Y F,LIU Y Y,et al.Investigation of the effective components and action mechanism of Kushen Zhili granules in the treatment of dampness-heat diarrhea based on network pharmacology[J].Chinese Journal of Veterinary Science,2022,42(1):135-141.(in Chinese)