基于网络药理学和分子对接探讨郁金散加减方治疗猪传染性胃肠炎的作用机制

doi:10.16431/j.cnki.1671-7236.2024.02.037

摘要/Abstract

摘要： 【目的】基于网络药理学和分子对接技术探讨郁金散加减方治疗猪传染性胃肠炎(TGE)的作用靶点及机制。【方法】在中药系统药理学数据库与分析平台(TCMSP)搜索郁金散加减方的活性成分及靶点并经UniProt平台转换,在比较毒理基因组学数据库(CTD)中搜索TGE相关靶点,将两者交集靶点导入Cytoscape 3.9.1软件中构建郁金散加减方-成分-靶点-疾病网络关系图,在STRING数据库和Cytoscape 3.9.1软件中进行蛋白互作(PPI)网络分析,在DAVID数据库中进行GO功能和KEGG信号通路富集分析,用AutoDock软件进行分子对接。【结果】共收集到郁金散加减方包括槲皮素、芒柄花黄素在内的126个活性成分,得到郁金散加减方治疗TGE的相关靶点74个。郁金散加减方-成分-靶点-疾病网络关系图结果显示,郁金散加减方治疗TGE的核心成分为槲皮素、山奈酚等;PPI结果表明,郁金散加减方治疗TGE的核心靶点为抑癌基因P53(TP53)、癌基因FOS、肿瘤坏死因子(TNF)、基质金属蛋白酶9(MMP9)及胱天蛋白酶3(CASP3)等;GO功能和KEGG信号通路分析结果显示,郁金散加减方治疗TGE的作用机制涉及到免疫反应、抗炎等过程,并调控MAPK、IL17、TNF、TH-17细胞分化、抗炎症性肠病和NF-κB等信号通路。核心成分与关键受体氨肽酶N(APN)分子对接表明,郁金散加减方与APN具有良好的结合能力。【结论】郁金散加减方主要是利用槲皮素、4'-甲氧基光甘草定、芒柄花黄素等核心成分作用于TP53、FOS、TNF、MMP9、CASP3等靶点,调控MAPK、IL7、TNF、TH-17细胞分化、抗炎症性肠病、NF-κB等信号通路来发挥对TGE的治疗作用。

关键词: 网络药理学; 分子对接; 郁金散加减方; 猪传染性胃肠炎; 作用机制

Abstract: 【Objective】 Based on network pharmacology and molecular docking technology, the target and the mechanism of modified Yujin San in the treatment of transmissible gastroenteritis(TGE) in pigs were studied.【Method】 The active ingredients and targets of modified Yujin San were searched by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and converted by UniProt platform.TGE related targets were searched in CTD database.The intersection targets of modified Yujin San and TGE were imported into Cytoscape 3.9.1 software to construct the modified Yujin San-component target-disease network diagram.Protein-protein interaction (PPI) network analysis was carried out in STRING database and Cytoscape 3.9.1 software.GO function and KEGG signaling pathway were analyzed in the DAVID database.Molecular docking was performed with AutoDock software.【Result】 A total of 126 active ingredients of modified Yujin San were collected, including quercetin and formononetin, and 74 related targets of modified Yujin San were obtained.The results of the network diagram of modified Yujin San-ingredient-target-disease showed that the core components of modified Yujin San for TGE were quercetin, kaempferol, etc.PPI results showed that the core targets of modified Yujin San were tumor suppressor gene P53 (TP53), tumor gene FOS, tumor necrosis factor (TNF), matrix metalloproteinase 9 (MMP9) and Caspase 3 (CASP3), etc.GO function and KEGG signaling pathway analysis results showed that the mechanism of modified Yujin San in the treatment of TGE involved immune response, anti-inflammatory and other processes, and regulated MAPK, IL17, TNF, TH-17 cell differentiation, anti-inflammatory bowel disease, NF-κB signaling pathways and so on.The molecular docking between the core components and the key receptor aminopeptidase N (APN) indicated that modified Yujin San had good binding ability with APN.【Conclusion】 Modified Yujin San mainly used core ingredients quercetin, 4'-methoxyglabridin, frmononetin and other core components to act on TP53, FOS, TNF, MMP9, CASP3 and other targets, and regulated signaling pathways such as MAPK, IL7, TNF, TH-17 cell differentiation, inflammatory bowel disease, and NF-κB to treat TGE.

Key words: network pharmacology; molecular docking; modified Yujin San; transmissible gastroenteritis of swine; mechanism

中图分类号:

S853.74

郭紫艳, 宋延平, 年霞, 苏敏. 基于网络药理学和分子对接探讨郁金散加减方治疗猪传染性胃肠炎的作用机制[J]. 中国畜牧兽医, 2024, 51(2): 809-819.

GUO Ziyan, SONG Yanping, NIAN Xia, SU Min. Mechanism of Modified Yujin San in Treatment of Transmissible Gastroenteritis of Swine Based on Network Pharmacology and Molecular Docking[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(2): 809-819.

参考文献

[1] 吕荞,赵钟毅,尹德玮,等.猪传染性胃肠炎病毒荧光RT-RAA方法的建立及初步应用[J].畜牧兽医学报,2023,54(5):2208-2214. LYU Q,ZHAO Z Y,YIN D W,et al.Establishment and preliminary application of a Real-time RT-RAA for detection of Transmissible gastroenteritis virus[J]. Acta Veterinaria et Zootechnica Sinica,2023,54(5):2208-2214.(in Chinese)
[2] LIU Q,WANG H Y.Porcine enteric coronaviruses:An updated overview of the pathogenesis,prevalence,and diagnosis[J].Veterinary Research Communications,2021,45(2-3):75-86.
[3] YAN Q,WU K,ZENG W,et al.Historical evolutionary dynamics and phylogeography analysis of Transmissible gastroenteritis virus and Porcine deltacoronavirus:Findings from 59 suspected swine viral samples from China[J].International Journal of Molecular Sciences,2022,23(17):9786.
[4] 樊俊洋,吴文义,张云天,等.基于网络药理学探究乌梅散加减方治疗猪传染性胃肠炎的作用机制[J].中国畜牧兽医,2022,49(11):4447-4456. FAN J Y,WU W Y,ZHANG Y T,et al.Exploration on the mechanism of modified Wumei powder in the treatment of porcine transmissible gastroenteritis based on network pharmacology[J].China Animal Husbandry&Veterinary Medicine,2022,49(11):4447-4456.(in Chinese)
[5] 张丽鑫.舒兰市猪传染性胃肠炎流行病学调查及防治研究[D].呼和浩特:内蒙古农业大学,2022. ZHANG L X.Epidemiological investigation and control of porcine transmissible gastroenteritis in Shulan city[D].Hohhot:Inner Mongolia Agricultural University,2022.(in Chinese)
[6] 宋春洁,吉梅,徐佳,等.郁金散加减方对长白猪传染性胃肠炎治疗效果的研究[J].中国畜牧兽医,2019,46(2):600-607. SONG C J,JI M,XU J,et al.Study on the therapeutic effect of modified Yujin powder on transimissible gastroenteritis in Landrace pigs[J].China Animal Husbandry&Veterinary Medicine,2019,46(2):600-607.(in Chinese)
[7] XIAO L J,TAO R.Traditional Chinese medicine (TCM) therapy[J].Advances in Experimental Medicine and Biology,2017,1010:261-280.
[8] 崔恩慧,智晓艳,范云鹏,等.郁金散拆方的抑菌与抗炎作用[J].西北农业学报,2015,24(1):43-48. CUI E H,ZHI X Y,FAN Y P,et al.Antibacterial and anti-inflammatory effects of Yujinsan's disassembled prescription[J].Acta Agriculturae Boreali-Occidentalis Sinica,2015,24(1):43-48.(in Chinese)
[9] 李秀云,章新友,吴地尧,等.中药复方网络药理学研究的文献分析[J].中国药房,2021,32(2):182-189. LI X Y,ZHANG X Y,WU D Y,et al.Literature analysis for network pharmacology research of TCM compound prescription[J]. Chinese Pharmacy,2021,32(2):182-189.(in Chinese)
[10] 陶嘉磊,汪受传,陈彦臻,等.中药复方网络药理学研究述评[J].中华中医药杂志,2019,34(9):3903-3907. TAO J L,WANG S C,CHEN Y Z,et al.Review on the research in network pharmacology of traditional Chinese medicine compound[J].China Journal of Traditional Chinese Medicine and Pharmacy,2019,34(9):3903-3907.(in Chinese)
[11] LI Y M,WANG J,LIU Y C,et al.Antiviral and virucidal effects of curcumin on Transmissible gastroenteritis virus in vitro[J]. The Journal of General Virology,2020,101(10):1079-1084.
[12] ZHENG L,YUN L X,QIN Y T,et al.Action mechanism underlying improvement effect of Fuzi Lizhong decoction on nonalcoholic fatty liver disease:A study based on network pharmacology and molecular docking[J].Evidence-Based Complementary and Alternative Medicine,2022,2022:1670014.
[13] MALVIYA R,SHARMA A.Sources,properties,and pharmacological effects of quercetin[J].Current Nutrition&Food Science,2022,18(5):457-465.
[14] MISHRA R,KULKARNI S.A review of various pharmacological effects of quercetin with its barriers and approaches for solubility and permeability enhancement[J].The Natural Products Journal,2022,12(4):9-21.
[15] 梅华迪,李袁飞,马现永,等.槲皮素对动物肠道黏膜屏障功能的影响及其调控机制[J].动物营养学报,2022,34(9):5475-5488. MEI H D,LI Y F,MA X Y,et al.Effects of quercetin on intestinal mucosal barrier function and its regulatory mechanism[J].Chinese Journal of Animal Nutrition,2022,34(9):5475-5488.(in Chinese)
[16] 梅华迪,陈秋雨,马现永,等.槲皮素基于内质网应激信号通路调节动物机体健康和疾病的研究进展[J].动物营养学报,2023,35(3):1413-1425. MEI H D,CHEN Q Y,MA X Y,et al.Research progress of quercetin regulating animal health and disease based on endoplasmic reticulum stress signaling pathway[J].Chinese Journal of Animal Nutrition,2023,35(3):1413-1425.(in Chinese)
[17] LI Z H,CAO H,CHENG Y F,et al.Inhibition of Porcine epidemic diarrhea virus replication and viral 3C-like protease by quercetin.[J].International Journal of Molecular Sciences,2020,21(21):8095.
[18] DUTRA J M,ESPITIA P J P,BATISTA R A.Formononetin:Biological effects and uses-A review[J].Food Chemistry,2021,359:129975.
[19] MENDONÇA M A A,RIBEIRO A R S,LIMA A K,et al.Red propolis and its dyslipidemic regulator formononetin:Evaluation of antioxidant activity and gastroprotective effects in rat model of gastric ulcer[J].Nutrients,2020,12(10):2951.
[20] NAUDHANI M,THAKUR K,NI Z J,et al.Formononetin reshapes the gut microbiota,prevents progression of obesity and improves host metabolism[J].Food&Function,202112(24):12303-12324.
[21] OLIVEIRA D C R,PONTES S G,KOSTYUK A,et al.Anticancer and immunomodulatory activities of a novel water-soluble derivative of ellipticine[J].Molecules,2020,25(9):2130.
[22] CERAMELLA J,CARUSO A,OCCHIUZZI A M,et al.Benzothienoquinazolinones as new multi-target scaffolds:Dual inhibition of human topoisomerase Ⅰ and tubulin polymerization[J].European Journal of Medicinal Chemistry,2019,181(C):111583.
[23] SAPPATI S,HASSANALI A,GEBAUER R,et al.Nuclear quantum effects in a HIV/cancer inhibitor:The case of ellipticine[J].The Journal of Chemical Physics,2016,145(20):205102.
[24] 李幸丽.玫瑰树碱抑制IL-17A和TNF-α介导的炎症反应和缓解重症急性胰腺炎[D].上海:上海交通大学,2020. LI X L.Ellipticine blocks synergistic effects of IL-17A and TNF-α in epithelial cells and alleviates severe acute pancreatitis-associated lung injury[D].Shanghai:Shanghai Jiao Tong University,2020.(in Chinese)
[25] LI X,YE C,MULATI M,et al.Ellipticine blocks synergistic effects of IL-17A and TNF-α in epithelial cells and alleviates severe acute pancreatitis-associated acute lung injury[J].Biochemical Pharmacology,2020,177:113992.
[26] LI K,QIU H,YAN J,et al.The involvement of TNF-α and TNF-β as proinflammatory cytokines in lymphocyte-mediated adaptive immunity of Nile tilapia by initiating apoptosis[J].Developmental and Comparative Immunology,2021,115:103884.
[27] 王岚.猪传染性胃肠炎病毒(TGEV)感染IPEC-J2细胞的炎症反应及亮氨酸的调控作用[D].成都:四川农业大学,2019. WANG L.The effect of leucine on inflammatory response of IPEC-J2 cells infected with Transmissible gastroenteritis virus (TGEV) of swine[D].Chengdu:Sichuan Agricultural University,2019.(in Chinese)
[28] LI Z,WEI J,CHEN B,et al.The role of MMP-9 and MMP-9 inhibition in different types of thyroid carcinoma[J].Molecules,2023,28(9):3705.
[29] AL-SADI R,YOUSSEF M,RAWAT M,et al.MMP-9-induced increase in intestinal epithelial tight permeability is mediated by p38 kinase signaling pathway activation of MLCK gene[J].American Journal of Physiology.Gastrointestinal and Liver Physiology,2019,316(2):G278-G290.
[30] WANG K,TANG Y,WU X,et al.Eugenol attenuates Transmissible gastroenteritis virus-induced oxidative stress and apoptosis via ROS-NRF2-ARE signaling[J].Antioxidants,2022,11(9):1838.
[31] YAN Q,LIU X,SUN Y,et al.Swine enteric coronavirus:Diverse pathogen-host interactions[J].International Journal of Molecular Sciences,2022,23(7):3953.
[32] PU J,CHEN D,TIAN G,et al.All-trans retinoic acid attenuates Transmissible gastroenteritis virus-induced apoptosis in IPEC-J2 cells via inhibiting ROS-mediated p38 MAPK signaling pathway[J].Antioxidants,2022,11(2):345.
[33] MOON H,RO S W.MAPK/ERK signaling pathway in hepatocellular carcinoma[J].Cancers,2021,13(12):3026.
[34] PUA L J W,MAI C W,CHUNG F F L,et al.Functional roles of JNK and p38 MAPK signaling in nasopharyngeal carcinoma[J].International Journal of Molecular Sciences,2022,23(3):1108.
[35] ZHAO X M,BAI X Y,GUAN L J,et al.microRNA-4331 promotes Transmissible gastroenteritis virus (TGEV)-induced mitochondrial damage via targeting RB1,upregulating interleukin-1 receptor accessory protein (IL1RAP),and activating p38 MAPK pathway in vitro[J].Molecular&Cellular Proteomics,2018,17(2):190-204.
[36] DONG W,XIE W,LIU Y,et al.Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways[J].Antiviral Research,2020,173:104651.
[37] XIA L,YANG Y H,WANG J L,et al.Impact of TGEV infection on the pig small intestine[J].Virology Journal,2018,15(1):102.
[38] WANG L,QIAO X Y,ZHANG S J,et al.Porcine Tansmissible gastroenteritis virus nonstructural protein 2 contributes to inflammation via NF-κB activation[J].Virulence,2018,9(1):1685-1698.
[39] DELMAS B,GELFI J,L'HARIDON R,et al.Aminopeptidase N is a major receptor for the entero-pathogenic Coronavirus TGEV[J].Nature,1992,357(6377):417-420.