基于网络药理学分析白头翁汤治疗猪腹泻的作用机制

doi:10.16431/j.cnki.1671-7236.2018.10.024

摘要/Abstract

摘要：

试验利用网络药理学研究方法尝试揭示白头翁汤治疗猪腹泻的活性成分、作用靶点及其基因功能、信号通路的机制。首先在中药系统药理学分析数据库中检索白头翁汤的所有化学成分、作用靶点，进而利用STRING、DAVID、NCBI数据库，Cytoscape软件构建化合物-靶点网络、蛋白质-蛋白质相互作用（PPI）网络、靶点-通路网络，研究白头翁汤治疗猪腹泻的作用机制。通过化合物的口服利用度和类药性筛选得出白头翁汤11个活性化合物，化合物-靶点网络结果显示，11个活性化合物含有63个相应靶点；白头翁汤作用于猪腹泻的PPI网络图包含45个靶点，主要靶点是雌激素受体1（estrogen receptor，ESR1）、CREB结合蛋白（CREB binding protein，CREBBP）、丝裂原活化蛋白激酶1（mitogen-activated protein kinase 1，MAPK1）、雄激素受体（androgen receptor，AR）等，与猪腹泻靶点基因直接相关的靶点是拓扑异构酶Ⅱβ（DNA topoisomerase Ⅱ，TOP2B）、ESR1、ESR2、糖皮质激素受体（glucocorticoid receptor，NR3C1）、AR和细胞核受体共激活剂2（nuclear receptor coactivator 2，NCOA2）；白头翁汤-猪腹泻PPI网络图关键靶点GO富集条目为5个，其中生物过程、分子功能、细胞组成相关的条目分别有3、1、1个；白头翁汤作用于猪腹泻PPI网络图KEGG信号通路有1条。白头翁汤可能主要通过金鱼草素、掌叶防己碱、8-异戊烯基二氢茆酚-7-葡糖苷、延胡索乙素、足叶草脂素、黄麻苷和8-羟基松脂醇等调控TOP2B、ESR1、ESR2、NR3C1、AR和NCOA2等靶点，基因功能富集于磷脂酶C激活G蛋白偶联受体信号通路、腺苷酸环化酶激活肾上腺素能受体信号通路、DNA模板转录、类固醇结合、细胞膜的组成部分，以及通过KEGG信号通路中神经活性的配体-受体相互作用信号通路来治疗猪腹泻。

关键词: 白头翁汤; 猪腹泻; 蛋白质-蛋白质互作网络(PPI); GO富集分析; KEGG信号通路

Abstract:

In the study,the network pharmacology method was used to reveal the mechanism of Baitouweng decoction in treating swine diarrhea with the active ingredient and target,gene function and signal pathway.All the chemical compounds and targets of Baitouweng decoction were searched in the pharmacological analysis database of traditional Chinese medicine (TCM).Then the compound-target network,protein-protein interaction (PPI) network and target-pathway network were constructed by STRING,DAVID,NCBI databases and Cytoscape software to study the mechanism of Baitouweng decoction in treating swine diarrhea.The results showed that 11 active compounds of Baitouweng decoction were screened through the oral availability and drug-likeness,and the results of compound-target network showed that there were 63 corresponding targets corresponding to 11 compounds.The Baitouweng decoction-swine diarrhea PPI network diagram contained 45 targets,in which the key targets were ESR1,CREBBP,MAPK1,AR and so on,TOP2B,ESR1,ESR2,NR3C1,AR and NCOA2 were directly related to the targets of swine diarrhea.There were 2 KEGG pathways and 5 gene ontology (GO) entries of which the number of biological process,molecular function and cellular component was 3,1 and 1,respectively.Baitouweng decoction could regulate the expression of TOP2B,ESR1,ESR2,NR3C1,AR and NCOA2 and other regulated genes by aureusidin,palmatine,corylifol C,fumarine,peltatin,capsularin and 8-hydroxypinoresinol.The phospholipase C activation G protein-coupled receptor signaling pathway,adenylate cyclase-activating adrenergic receptor signaling pathway,DNA template transcription,steroid binding,and cell membrane components were used to treat swine diarrhea through neuroactive ligand-receptor interaction signaling pathways.

Key words: Baitouweng decoction; swine diarrhea; protein-protein interaction network (PPI); gene ontology (GO) analysis; KEGG signaling pathway

中图分类号:

R285.5

白东东, 李新圃, 杨峰, 罗金印, 王旭荣, 李宏胜. 基于网络药理学分析白头翁汤治疗猪腹泻的作用机制[J]. 《中国畜牧兽医》, 2018, 45(10): 2866-2875.

BAI Dongdong, LI Xinpu, YANG Feng, LUO Jinyin, WANG Xurong, LI Hongsheng. The Mechanism Analysis of Baitouweng Decoction in Treating Swine Diarrhea Based on Network Pharmacology[J]. , 2018, 45(10): 2866-2875.

参考文献

[1] 马德春,郑晓丽.三黄加白散在幼畜腹泻中的应用[J].吉林畜牧兽医,2014,34(1):54.MA D C,ZHENG X L.Application of Sanhuangjiabai San in diarrhea of young animals[J].Jilin Animal Science and Veterinary Medicine,2014,34(1):54.(in Chinese)
[2] 王学新.白龙散治疗仔猪痢疾[J].中国兽医科技,1996,4:39.WANG X X.Treatment of piglet dysentery with Bailong San[J].Chinese Veterinary Science,1996,4:39.(in Chinese)
[3] 王孝先.黄芩汤、白头翁汤、葛根芩连汤对肠道菌株抑菌作用的实验观察[J].中国中医基础医学杂志,2001,7(1):42-44.WANG X X.Experimental observation on the bacteriostasis of Scutellaria decoction,Pulsatilla decoction of Pueraria,Scutellaria and Coptis against enteric bacilli[J].Journal of Basic Chinese Medicine,2001,7(1):42-44.(in Chinese)
[4] 胡唐玲,云云,徐志庆,等.白头翁汤正丁醇提取物抑制白念珠菌细胞膜[J].中国中药杂志,2017,42(16):3185-3190.HU T L,YUN Y,XU Z Q,et al.Butyl alcohol extract of Baitouweng decoction inhibits Candida albicans cell membrane[J].China Journal of Chinese Materia Medica,2017,42(16):3185-3190.(in Chinese)
[5] 颜贵明,张梦翔,夏丹,等.白头翁汤正丁醇提取物对热带念珠菌毒力因子的影响[J].中国中药杂志,2015,40(12):2396-2402.YAN G M,ZHANG M X,XIA D,et al.Inhibitory effects of butyl alcohol extract of Baitouweng decoction on virulence factors of Candida tropicalis[J].China Journal of Chinese Materia Medica,2015,40(12):2396-2402.(in Chinese)
[6] 韩捷.白头翁汤治疗乙酸诱发大鼠溃疡性结肠炎的实验研究[J].中国实验方剂学杂志,2002,8(3):38-40.HAN J.Experimental study on Baitouweng decoction for treating acetic acid-induced ulcerative colitis in rats[J].China Journal of Experimental Traditional Medical Formulae,2002,8(3):38-40.(in Chinese)
[7] 李薇.白头翁汤治疗大鼠溃疡性结肠炎的免疫机制探讨[J].甘肃中医,2004,17(6):38-39.LI W.Immune mechanism of Baitouweng decoction in treating ulcerative colitis in rats[J].Gansu Journal of Traditional Chinese Medicine,2004,17(6):38-39.(in Chinese)
[8] 吕锦芳,卢文超,宁康健.白头翁汤对兔离体十二指肠运动性能的影响[J].中国中医药科技,2005,12(5):279-280.LV J F,LU W C,NING K J.Effect of Baitouweng decoction on the activity of rabbits' isolated duodenum[J].Chinese Journal of Traditional Medical Science and Technology,2005,12(5):279-280.(in Chinese)
[9] 时维静,孙海明,俞浩.白头翁汤拆方抗腹泻试验研究[J].中兽医医药杂志,2007,1:30-31.SHI W J,SUN H M,YU H.Experimental study on anti-diarrhea with separated recipes of Baitouweng decoction[J].Journal of Traditional Chinese Veterinary Medicine,2007,1:30-31.(in Chinese)
[10] 陆树文,刘红菊,赵伟,等.白头翁汤治疗炎症性肠病的分子机制研究[J].中国应用生理学杂志,2011,27(1):106-109.LU S W,LIU H J,ZHAO W,et al.Molecular mechanisms involved in the treatment of inflammatory bowel disease by Baitouweng decoction[J].Chinese Journal of Applied Physiology,2011,27(1):106-109.(in Chinese)
[11] 李森娟.白头翁汤对溃疡性结肠炎患者CD4⁺ CD25⁺ Treg细胞、IL-10的影响[J].浙江中医杂志,2012,47(2):107-108.LI S J.Effect of Baitouweng decoction on CD4⁺ CD25⁺ Treg cells and IL-10 in patients with ulcerative colitis[J].Zhejiang Journal of Traditional Chinese Medicine,2012,47(2):107-108.(in Chinese)
[12] 叶益平.白头翁汤治疗溃疡性结肠炎临床疗效及对血清炎症因子水平的影响[J].中华中医药学刊,2017,35(6):1627-1629.YE Y P.Clinical efficacy of Baitouweng decoction on ulcerative colitis and its influenceon serum levels of inflammatory cytokines[J].Chinese Archives of Traditional Chinese Medicine,2017,35(6):1627-1629.(in Chinese)
[13] ZHOU P Z,LIU F B,LUO Q,et al.Effect of Baitouweng decoction on intestinal miR-19a expression in MICE with ulcerative colitis[J].Journal of Southern Medical University,2012,32(11):1597-1599.
[14] 吴有彩,周宝林,沈训忠,等."白头翁汤"治疗犊牛红白痢疾效果良好[J].中国畜禽种业,2013,9(5):61.WU Y C,ZHOU B L,SHEN X Z,et al.The good effect of "Baitouweng decoction" on red or white dysentery in calves[J].The Chinese Livestock Breeding,2013,9(5):61.(in Chinese)
[15] 史生彦.白龙散及白头翁汤治疗仔猪白痢[J].青海畜牧兽医杂志,1987,6:35.SHI S Y.Treatment of white dysentery in piglets with Bailong san and Baitouweng decoction[J].Chinese Qinghai Journal of Animal and Veterinary Sciences,1987,6:35.(in Chinese)
[16] 柴朝宗.白头翁汤治疗犊牛白痢[J].中兽医学杂志,2000,4:25CHAI C Z.Treatment of white dysentery in calves with Baitouweng decoction[J].Chinese Journal of Traditional Veterinary Science,2000,4:25.(in Chinese)
[17] 张志海,刘才林,赵淑美.以中药白头翁汤为主方治疗犊牛痢疾效果好[J].黑龙江动物繁殖,2003,2:40.ZHANG Z H,LIU C L,ZHAO S M.Treating calf dysentery is effective with Baitouweng soup-based[J].Heilongjiang Journal of Animal Reproduction,2003,2:40.(in Chinese)
[18] 雷有玲,鲍玉林.试论白头翁汤在仔猪白痢治疗中的研究与应用[J].青海畜牧兽医杂志,2016,5:57.LEI Y Y,BAO Y Y.The research and application of Baitouweng decoction in the treatment of white scour of piglets[J].Chinese Qinghai Journal of Animal and Veterinary Sciences,2016,5:57.(in Chinese)
[19] 佚名.中草药在猪腹泻病防治中的应用研究进展[J].畜禽业,2014,1:51.ANONYMOUS.Research progress on application of Chinese herbal medicine in prevention and treatment of diarrhea in pigs[J].Livestock and Poultry Industry,2014,1:51.(in Chinese)
[20] 杨屏生,曾军,金慧蓉,等.白头翁汤加味治疗猪传染性腹泻的疗效观察[J].科学种养,2014,7:104-105.YANG B C,ZENG J,JIN H R,et al.Observation on the efficacy of Baitouweng decoction in the treatment of infectious diarrhea in pigs[J].Kexue Zhongyang,2014,7:104-105.(in Chinese)
[21] 王世宏.探讨中药方剂白头翁汤联合抗生素治疗仔猪黄痢的临床效果[J].中兽医学杂志,2017,1:64.WANG S H.Explore the clinical effect of Chinese herbal medicine Baitouweng decoction combined with antibiotics in the treatment of piglet yellow dysen-tery[J].Chinese Journal of Traditional Veterinary Science,2017,1:64.(in Chinese)
[22] 李玉芳.加味白头翁汤治疗仔猪黄痢83例临床观察[J].山东畜牧兽医,2015,36(7):33-34.LI Y F.Modified Baitouweng decoction for the treatment of 83 cases of piglet jaundice[J].Shandong Journal of Animal Science and Veterinary Medicine,2015,36(7):33-34.(in Chinese)
[23] MULLIGHAN C G,ZHANG J H,KASPER L H,et al.CREBBP mutations in relapsed acute lymphoblastic leukaemia[J].Nature,2011,471(7337):235-239.
[24] 卢燕华,唐三元.miR-217靶向MAPK1抑制胃癌细胞侵袭转移作用研究[J].中国现代医药杂志,2014,16(11):21-23.LU Y H,TANG S Y.miR-217 targeted to MAPK1 for the inhibition of metastasis and invasion of gastric cancer cell[J].Modern Medicine Journal of China,201416(11):21-23.(in Chinese)
[25] 黄宝锋,刘智皓,吴风瑞,等.雄激素受体的结构和功能[J].四川动物,2008,2:307-310.HUANG B F,LIU Z H,WU F R,et al.The structure and function of androgen receptor[J].Sichuan Journal of Zoology,2008,2:307-310.(in Chinese)
[26] 杨梅.TOP2B在蒽环类药物治疗的儿童ALL中的表达及其临床意义[D].苏州:苏州大学,2014.YANG M.The expression and clinical significance of TOP2B in children with acute lymphoblastic leukemia treated with anthracyclines[D].Suzhou:Soochow University,2014.(in Chinese)
[27] 张秋莲,陈从英,龚水萍,等.ESR1和ESR2基因遗传变异与妇女产后抑郁症的关联性[J].中国妇幼保健,2014,29(28):4634-4637.ZHANG Q L,CHEN C Y,GONG S P,et al.Correlation between ESR1 and ESR2 genetic variations and maternal postpartum depression[J].Maternal and Child Health Care of China,2014,29(28):4634-4637.(in Chinese)
[28] 梅春霞,张吉强.雌激素受体[J].生命的化学,2010,30(4):590-594.MEI C X,ZHANG J Q.Estrogen receptor[J].Chemistry of Life,2010,30(4):590-594.(in Chinese)
[29] 高天,鐔忠斌,王晓杜,等.嘉兴黑猪ESR2和FSHβ及PRLR基因多态性与繁殖性状相关性分析[J].中国畜牧杂志,2016,52(5):1-7.GAO T,CHAN Z B,WANG X D,et al.Association of SNPs in ESR2,FSHβ and PRLR genes with reproductive traits in Jiaxing Black pig[J].Chinese Journal of Animal Science,2016,52(5):1-7.(in Chinese)
[30] 闫宇翔,董晶,刘佑琴,等.NR3C1基因多态性与心血管疾病危险因素相关性[J].中国公共卫生,2015,31(4):385-389.YAN Y X,DONG J,LIU Y Q,et al.Association between polymorphism of NR3C1 gene and risk factors of cardiovascular diseases[J].Chinese Journal of Public Health,2015,31(4):385-389.(in Chinese)
[31] HABTETSION T G.NCOA2基因多态性与中国汉族人2型糖尿病的关联研究[D].长春:吉林大学,2012.HABTETSION T G.Nuclear receptor coactivator-2(NCOA2) gene polymorphism and its association with type-2 diabetes mellitus in the Chinese HAN population[D].Changchun:Jilin University,2012.(in Chinese)
[32] 潘玲珍,闫智勇,左长英,等.长期使用地西泮对神经活性配体受体相互作用信号通路的影响[J].中国药科大学学报,2011,42(5):443-446.PAN L Z,YAN Z Y,ZUO C Y,et al.Influence of long-term usage of diazepam on neuroactive ligand-receptor interaction signaling pathway[J].Journal of China Pharmaceutical University,2011,42(5):443-446.(in Chinese)