基于网络药理学探究菟丝子黄酮缓解孕期暴露双酚A致仔鼠生殖损伤的作用机制  

Exploring of the Mechanism of Cuscuta chinensis Flavonoids in Alleviating Reproductive Damage in Offspring Rats Exposed to Bisphenol A During Pregnancy Based on Network Pharmacology

作　　者：赵千惠 刘莹 焦玉兰 史万玉[1,2] 陈福星[1,2] ZHAO Qianhui;LIU Ying;JIAO Yulan;SHI Wanyu;CHEN Fuxing(College of Veterinary Medicine,Hebei Agricultural University,Baoding 071001,China;Hebei Veterinary Biotenology Innovation Center,Baoding 071001,China;Ruipu(Baoding)Biological Pharmaceutical Co.,Ltd.,Baoding 071000,China)

机构地区：[1]河北农业大学中兽医学院,保定071001 [2]河北省兽医生物技术创新中心,保定071001 [3]瑞普(保定)生物药业有限公司,保定071000

出　　处：《中国畜牧兽医》2023年第6期2550-2561,共12页China Animal Husbandry & Veterinary Medicine

基　　金：国家自然科学基金(32172896)。

摘　　要：【目的】分析预测菟丝子黄酮缓解孕期暴露双酚A(bisphenol A,BPA)致仔鼠生殖损伤的潜在活性成分和靶点,探究其可能的作用机制,进而保护动物生殖功能。【方法】通过检索CTD数据库确定BPA潜在靶点,使用TCMSP数据库和TCMIP平台筛选菟丝子黄酮中活性成分和潜在靶点,获得菟丝子黄酮与BPA的共同靶点,利用STRING数据库构建蛋白互作(PPI)网络,使用DAVID数据库进行GO功能和KEGG通路富集分析。应用AutoDock Tools 1.5.7软件将主要活性成分与核心蛋白进行分子对接。在临床试验中用8周龄SPF小鼠制造孕期BPA暴露模型,设置对照组(妊娠1~17 d灌胃玉米油0.2 mL/d)、BPA组(妊娠1~17 d灌胃含5 mg/kg BW BPA的玉米油0.2 mL/d)和菟丝子黄酮组(妊娠1~17 d灌胃含5 mg/kg BW BPA和40 mg/kg BW菟丝子黄酮的玉米油0.2 mL/d)。仔鼠21日龄时测定血清中雌激素(estrogen,E 2)水平及卵巢中E 2受体ESR1和ESR2含量。【结果】菟丝子黄酮中主要活性成分可能为槲皮素、山奈酚和异鼠李素,其与BPA交集的潜在靶点有59个。菟丝子黄酮干预BPA的PPI网络中关联度最高的5个靶点分别为丝氨酸/苏氨酸蛋白激酶1(serine/threonine-protein kinase,AKT1)、表皮生长因子受体(epidermal growth factor receptor,EGFR)、ESR1、丝裂原活化蛋白激酶1(mitogen-activated protein kinase 1,MAPK1)和丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAPK3)。GO功能富集分析显示,潜在靶点共富集到375个条目,主要涉及磷酸化、细胞对活性氧的反应、膜、细胞质、蛋白质结合、核苷酸结合、转移酶和激酶活性等。KEGG通路富集分析显示,菟丝子黄酮干预BPA损伤过程主要在癌症通路富集,其次在雌激素信号通路、松弛素信号通路、内分泌抵抗等通路富集,这些可能是菟丝子黄酮干预BPA的主要信号通路。此外,该干预过程也与丝氨酸/苏氨酸激酶Akt信号通路(PI3K-Akt)、促性腺激素释放激素信号通�【Objective】This study was aimed to analyze and predict the potential active ingredients and targets of Cuscuta chinensis flavonoids in alleviating the reproductive damage of offspring exposed to bisphenol A(BPA)during pregnancy,to explore its possible mechanism of action,and then to protect animal reproductive function.【Method】The potential targets of BPA were determined by searching the CTD database,and then the main active ingredients and potential targets in Cuscuta chinensis flavonoids were screened through the TCMSP database and TCMIP platform to obtain common targets of drugs and pollutants BPA,and the protein-protein interaction(PPI)network was constructed by using the STRING database,and the DAVID database was used for GO function and KEGG pathway enrichment analysis.AutoDock Tools 1.5.7 software was used to connect the main active ingredients with core targets.In the clinical experiment,8-week-old SPF mice were used as the BPA exposure model during pregnancy,and the control group(gavage corn oil from 1 to 17 d of pregnancy,0.2 mL/d),BPA group(gavage corn oil containing 5 mg/kg BW BPA from 1 to 17 d of pregnancy,0.2 mL/d)and Cuscuta chinensis flavonoids group(gavage corn oil containing 5 mg/kg BW BPA and 40 mg/kg BW Cuscuta chinensis flavonoids by intragastric administration from 1 to 17 d of pregnancy,0.2 mL/d)were set up.At the age of 21 days,the level of estrogen(E 2)in serum and the contents of ESR1 and ESR2 in ovarian tissue were measured.【Result】The results suggested that the possible key ingredients of Cuscuta chinensis flavonoids were quercetin,kaempferol and isorhamna.There were 59 intersection targets of Cuscuta chinensis flavonoids and BPA.The five most highly correlated targets in the PPI network of Cuscuta flavonoids interfering with BPA were serine/threonine protein kinase 1(AKT1),epidermal growth factor receptor(EGFR),estrogen receptorα(ESR1),mitogen-activated protein kinase 1(MAPK1)and mitogen-activated protein kinase 1(MAPK3).GO functional analysis showed that potential targe

关 键 词：菟丝子黄酮 双酚A(BPA) 网络药理学 分子对接 

分 类 号：S859.7[农业科学—临床兽医学]