摘要
【目的】探讨启宫丸治疗多囊卵巢综合征伴胰岛素抵抗(PCOS-IR)痰湿证患者的临床疗效与安全性,同时应用网络药理学方法与分子对接技术探讨启宫丸治疗PCOS-IR的作用机制。【方法】将60例PCOS-IR痰湿证患者随机分为对照组和观察组,每组各30例。对照组给予盐酸二甲双胍片治疗,观察组在对照组的基础上联合启宫丸汤剂治疗,连续应用12周后观察2组患者的肥胖指标、性激素指标、糖脂代谢指标的变化情况及不良反应发生情况。挖掘GEO数据库,获得PCOS-IR的差异表达基因靶点与表达量,绘制火山图与热图;应用网络药理学方法获取启宫丸的活性成分与靶点,二者取交集靶点,绘制韦恩图、PPI网络图并筛选核心靶点,绘制核心靶点的箱状图,并进行基因本体(GO)生物功能和京都基因与基因组百科全书(KEGG)通路富集分析。使用Cytoscape 3.7.2分析软件构建药物-活性成分-靶点网络图并筛选核心活性成分。分子对接预测核心活性成分与核心靶点的结合活性。【结果】(1)临床研究方面,治疗后,观察组的体质量、体质量指数(BMI)、腰围(WC)、雌二醇(E2)、游离雄激素指数(FAI)、空腹胰岛素(FINS)、稳态模型胰岛抵抗指数(HOMA-IR)均较治疗前下降,性激素结合球蛋白(SHBG)、高密度脂蛋白胆固醇(HDL-C)均较治疗前上升,差异均有统计学意义(P<0.05或P<0.01),而对照组仅体质量、FINS、HOMA-IR较治疗前下降(P<0.05);组间比较,观察组的BMI、E2、FAI、FINS、HOMA-IR的下降幅度均明显优于对照组(P<0.05)。安全性方面,2组患者在研究过程中均未发现不良反应。(2)网络药理学机制方面,经筛选获得启宫丸活性成分193个,靶点759个,PCOS-IR靶点1149个,交集靶点76个,前5位核心靶点为前列腺素内过氧化物合酶2(PTGS2)、雌激素受体1(ESR1)、雄激素受体(AR)、过氧化物酶体增殖物激活受体γ(PPARG)、热休克蛋白90AA1(HSP90AA1),前5位活性成分为槲皮素、山柰酚、阿魏酸、没食子酸、金丝桃苷;GO富集分析共得到1550个条目,其中生物过程(BP)1226条、细胞组成(CC)139条、分子功能(MF)185条,BP富集为炎症反应、MF富集为与信号受体结合、CC富集在三级颗粒;KEGG通路富集分析共得到134个条目,癌症通路、糖基化终末产物与特异性受体(AGE-RAGE)信号通路占据重要位置,磷脂酰肌醇3-激酶/蛋白激酶B(PI3K-Akt)信号通路具有重要的连接作用。分子对接结果显示,启宫丸中核心活性成分与核心靶点均具有较好的结合活性。【结论】启宫丸治疗PCOS-IR临床疗效显著,启宫丸多成分通过PTGS2、AR等靶点作用于癌症通路等而发挥治疗PCOS-IR的作用,该结果可为启宫丸的临床应用及进一步深入研究提供参考。
Objective To investigate the clinical efficacy and safety of Qigong Pills in the treatment of patients with polycystic ovary syndrome accompanied by insulin resistance(PCOS-IR)of phlegm-damp syndrome,and to investigate the therapeutic mechanism of Qigong Pills for PCOS-IR by using network pharmacology methods and molecular docking techniques.Methods Sixty patients with PCOS-IR of phlegm-damp syndrome type were randomly divided into a control group and an observation group,with 30 cases in each group.The control group was given Metformin Hydrochloride Tablets orally and the observation group was treated with the decoction of Qigong Pills orally on the basis of treatment for the control group.After 12 continuous weeks of medication,the changes of obesity indicators,sex hormone levels,glucolipid metabolism indicators and the incidence of adverse reactions in the two groups were observed.The GEO database was mined to obtain the differentially-expressed gene targets of PCOS-IR and their expression levels,and then volcano plot and heat map were drawn.The network pharmacology methods were applied to obtain the active components and targets of Qigong Pills,and then their intersected targets were extracted.The Venn diagram and protein-protein interaction(PPI)network diagram were drawn for the screening of the core targets,and box plots of the core targets were drawn.The Gene Ontology(GO)biofunction and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were conducted.Cytoscape 3.7.2 analysis software was used for the construction of drug-active components-target network diagram and for the screening of core active components.Molecular docking was applied to predict the binding activity of core active components to core targets.Results(1)The results of clinical study showed that in the observation group,the post-treatment body mass,body mass index(BMI),waist circumference(WC),estradiol(E2),free androgen index(FAI),fasting insulin(FINS),and insulin resistance estimated with homeostasis model(HOMA-IR)were all decreased and the sex hormone-binding globulin(SHBG)and highdensity lipoprotein cholesterol(HDL-C)were all increased compared with those before treatment,and the differences were statistically significant(P<0.05 or P<0.01);in the control group,only body mass,FINS and HOMA-IR were decreased compared with those before treatment(P<0.05).The intergroup comparison showed that the decrease of BMI,E2,FAI,FINS and HOMA-IR in the observation group was significantly superior to that in the control group(P<0.05).In terms of clinical safety,no adverse reactions were found in the two groups of patients during the trial.(2)The network pharmacological results showed that 193 active components,759 targets,1149 PCOS-IR targets and 76 intersected targets of Qigong Pills were obtained after screening.The top 5 core targets were prostaglandin-endoperoxide synthase 2(PTGS2),estrogen receptor 1(ESR1),androgen receptor(AR),peroxisome proliferator-activated receptor gamma(PPARG),and heat shock protein 90AA1(HSP90AA1).The top 5 active components were quercetin,kaempferol,ferulic acid,gallic acid and hyperin.GO enrichment analysis yielded a total of 1550 entries,including 1226 for biological process(BP),139 for cellular component(CC)and 185 for molecular function(MF).The BP enrichment was characterized as inflammatory response,MF enrichment was characterized as binding to signaling receptors,and CC enrichment was characterized as tertiary granules.The KEGG pathway enrichment analysis yielded a total of 134 entries.The cancer pathway and advanced glycation end-products and their specific receptor(AGE-RAGE)signaling pathway occupied an important place,and phosphatidylinositol 3-kinase/protein kinase B(PI3K-Akt)signaling pathway had an important connection function.The molecular docking results showed that the core active components of Qigong Pills had good binding activity to the core targets.Conclusion Qigong Pills exert significant clinical efficacy in the treatment of PCOS-IR.The multiple components of Qigong Pills act on cancer pathway through PTGS2,AR and other targets to treat PCOS-IR.The results can provide reference for the clinical application and further research of Qigong Pills.
作者
张红阳
莫殿军
陈颖
赵新宇
ZHANG Hong-Yang;MO Dian-Jun;CHEN Ying;ZHAO Xin-Yu(Chifeng University,Chifeng 024000 Inner Mongolia,China;Affiliated Hospital of Chifeng University,Chifeng 024005 Inner Mongolia,China)
出处
《广州中医药大学学报》
CAS
2023年第10期2519-2530,共12页
Journal of Guangzhou University of Traditional Chinese Medicine
基金
内蒙古自治区自然科学基金项目(编号:2021LHBS08002)
内蒙古自治区卫生健康科技计划项目(编号:202201553)
赤峰学院青年科研基金项目(编号:cfxyqn202139)。
作者简介
张红阳(1992-),女,博士,主治医师,讲师,E-mail:1508664347@qq.com。
