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作 者:楚欣欣 潘思雨 郭绅 陈宇静 祝田田 CHU Xinxin;PAN Siyu;GUO Shen;CHEN Yujing;ZHU Tiantian(Xinxiang Key Laboratory of Cardiovascular Remodeling Intervention and Molecular Targeted Therapy Drug R&D,Henan Provincial International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention,School of Pharmacy,Xinxiang Medical University,Xinxiang,Henan,453003 P.R.China)
机构地区:[1]新乡医学院药学院河南省心血管重构与药物干预国际联合实验室新乡市心血管重构干预与分子靶向治疗药物研发重点实验室,河南新乡453003
出 处:《华西药学杂志》2024年第5期509-514,共6页West China Journal of Pharmaceutical Sciences
基 金:河南省自然科学基金面上项目(242300421305);国家自然科学基金资助项目(批准号:81800051);河南省科技攻关项目(212102310319)。
摘 要:目的基于网络药理学和实验验证研究白杨素防治肺动脉高压(PH)的效果和作用机制。方法运用PubChem数据库收集白杨素的靶点;采用DisGeNET、GeneCards数据库联合筛选PH的靶点;运用STRING平台构建蛋白-蛋白相互作用网络;使用DAVID和Metescape数据库进行靶点GO功能富集和KEGG通路富集分析;采用AutoDock进行分子对接。构建低氧PH模型,通过考察血流动力学、肺组织肺血管重构及胶原沉积情况来研究白杨素对PH的治疗作用;用蛋白质印迹法验证白杨素对关键靶点蛋白含量表达的影响。结果表皮生长因子受体(EGFR)、前列腺素内过氧化物合成酶2(PTGS2)、劳斯肉瘤癌基因(SRC)、雌激素受体1(ESR1)、基质金属蛋白酶9(MMP9)是白杨素治疗PH的关键靶点;白杨素与5个关键靶点均能较好地结合。白杨素能明显改善PH大鼠的血流动力学、肺组织肺中小动脉重构及胶原沉积情况,缓解PH引起的SRC、ESR1、EGFR、PTGS2、MMP9蛋白表达量的变化。结论白杨素治疗PH具有“多靶点-多通路”的特点,可通过与MMP9、EGFR、ESR1等关键靶点结合从而发挥治疗PH的作用。OBJECTIVE To study the therapeutic efficacy and underlying mechanism of chrysin in the prevention and treatment of pulmonary hypertension(PH)through a merged approach of Network pharmacology and experimental validation.METHODS The PubChem database was utilized to identify the molecular targets of chrysin,while the DisGeNET and GeneCards databases were employed to select relevant PH targets.The STRING platform was employed to construct a protein-protein interaction network.Functional and pathway enrichment analyses were conducted using the DAVID and Metascape databases for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways,respectively.Molecular docking was conducted using AutoDock software.A hypoxia-induced PH model was established to evaluate the effects of chrysin on PH,focusing on hemodynamics,pulmonary vascular remodeling,and collagen deposition in the lung tissues.Furthermore,the effects of chrysin on key target protein expression were confirmed through Western blot experiments.RESULTS SRC,ESR1,EGFR,PTGS2,and MMP9 were the pivotal targets of chrysin in PH treatment.The preferential binding affinity of chrysin to these critical proteins.Chrysin demonstrated notable efficacy in ameliorating hemodynamic abnormalities,reducing small pulmonary artery remodeling and collagen accumulation in the lungs,and showed modulatory effects on the expression levels of SRC,ESR1,EGFR,PTGS2,and MMP9 in PH conditions.CONCLUSION Our findings indicate that chrysin exerts its therapeutic effects against PH through a"multi-target,multi-pathway"mechanism.Chrysin primarily interacts with key proteins including MMP9,EGFR,and ESR1.
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