目的从富锌硒绿茶中筛选蛋白质二硫异构酶(PDI)的抑制剂,探讨抑制剂对血小板聚集的抑制作用。方法从PDB(protein data bank)下载PDI的晶体结构(PDB ID:4EKZ);建立绿茶的化合物数据库;通过分子模拟软件MOE对化合物库进行PDI抑制剂的虚拟...目的从富锌硒绿茶中筛选蛋白质二硫异构酶(PDI)的抑制剂,探讨抑制剂对血小板聚集的抑制作用。方法从PDB(protein data bank)下载PDI的晶体结构(PDB ID:4EKZ);建立绿茶的化合物数据库;通过分子模拟软件MOE对化合物库进行PDI抑制剂的虚拟筛选,挑选出6个命中的化合物进行对PDI酶活性抑制作用的测试,然后对有抑制活性的化合物进行抗血小板聚集作用的测定。结果 6个虚拟筛选命中的化合物中,表儿茶素没食子酸酯(ECG)和表没食子儿茶素没食子酸酯(EGCG)对PDI蛋白酶具有抑制作用。其次,两个化合物对ADP诱导的血小板聚集也有抑制作用。结论绿茶活血化瘀的作用,与抑制PDI酶活性有关,ECG和EGCG是有效活性成分。展开更多
Creutzfeldt-Jakob disease(CJD)is a rare neurodegenerative disorder characterized by abnormalities in the prion protein(PrP),the most common form of human prion disease.Although Genome-Wide Association Studies(GWAS)hav...Creutzfeldt-Jakob disease(CJD)is a rare neurodegenerative disorder characterized by abnormalities in the prion protein(PrP),the most common form of human prion disease.Although Genome-Wide Association Studies(GWAS)have identified numerous risk genes for CJD,the mechanisms underlying these risk loci remain poorly understood.This study aims to elucidate novel genetically prioritized candidate proteins associated with CJD in the human brain through an integrative analytical pipeline.Utilizing datasets from Protein Quantitative Trait Loci(pQTL)(NpQTL1=152,NpQTL2=376),expression QTL(eQTL)(N=452),and the CJD GWAS(NCJD=4110,NControls=13569),we implemented a systematic analytical pipeline.This pipeline included Proteome-Wide Association Study(PWAS),Mendelian randomization(MR),Bayesian colocalization,and Transcriptome-Wide Association Study(TWAS)to identify novel genetically prioritized candidate proteins implicated in CJD pathogenesis within the brain.Through PWAS,we identified that the altered abundance of six brain proteins was significantly associated with CJD.Two genes,STX6 and PDIA4,were established as lead causal genes for CJD,supported by robust evidence(False Discovery Rate<0.05 in MR analysis;PP4/(PP3+PP4)≥0.75 in Bayesian colocalization).Specifically,elevated levels of STX6 and PDIA4 were associated with an increased risk of CJD.Additionally,TWAS demonstrated that STX6 and PDIA4 were associated with CJD at the transcriptional level.展开更多
基金Supportedby Major State Basic Research Development Program of China(973 Program,No.2006CB101700)National High Technology Research and Development Programof China(863 Program,No.20060110Z1141)National Natural Science Foundation of China(No.30571133)~~
文摘目的从富锌硒绿茶中筛选蛋白质二硫异构酶(PDI)的抑制剂,探讨抑制剂对血小板聚集的抑制作用。方法从PDB(protein data bank)下载PDI的晶体结构(PDB ID:4EKZ);建立绿茶的化合物数据库;通过分子模拟软件MOE对化合物库进行PDI抑制剂的虚拟筛选,挑选出6个命中的化合物进行对PDI酶活性抑制作用的测试,然后对有抑制活性的化合物进行抗血小板聚集作用的测定。结果 6个虚拟筛选命中的化合物中,表儿茶素没食子酸酯(ECG)和表没食子儿茶素没食子酸酯(EGCG)对PDI蛋白酶具有抑制作用。其次,两个化合物对ADP诱导的血小板聚集也有抑制作用。结论绿茶活血化瘀的作用,与抑制PDI酶活性有关,ECG和EGCG是有效活性成分。
文摘Creutzfeldt-Jakob disease(CJD)is a rare neurodegenerative disorder characterized by abnormalities in the prion protein(PrP),the most common form of human prion disease.Although Genome-Wide Association Studies(GWAS)have identified numerous risk genes for CJD,the mechanisms underlying these risk loci remain poorly understood.This study aims to elucidate novel genetically prioritized candidate proteins associated with CJD in the human brain through an integrative analytical pipeline.Utilizing datasets from Protein Quantitative Trait Loci(pQTL)(NpQTL1=152,NpQTL2=376),expression QTL(eQTL)(N=452),and the CJD GWAS(NCJD=4110,NControls=13569),we implemented a systematic analytical pipeline.This pipeline included Proteome-Wide Association Study(PWAS),Mendelian randomization(MR),Bayesian colocalization,and Transcriptome-Wide Association Study(TWAS)to identify novel genetically prioritized candidate proteins implicated in CJD pathogenesis within the brain.Through PWAS,we identified that the altered abundance of six brain proteins was significantly associated with CJD.Two genes,STX6 and PDIA4,were established as lead causal genes for CJD,supported by robust evidence(False Discovery Rate<0.05 in MR analysis;PP4/(PP3+PP4)≥0.75 in Bayesian colocalization).Specifically,elevated levels of STX6 and PDIA4 were associated with an increased risk of CJD.Additionally,TWAS demonstrated that STX6 and PDIA4 were associated with CJD at the transcriptional level.
