近年来,快速康复外科(enhanced recovery after surgery,ERAS)越来越受到重视,其以循证医学证据为基础,通过外科、麻醉、护理、营养等多学科协作,缓解病人围术期各种应激反应,达到减少术后并发症,缩短住院时间及促进康复的目的^([1])。...近年来,快速康复外科(enhanced recovery after surgery,ERAS)越来越受到重视,其以循证医学证据为基础,通过外科、麻醉、护理、营养等多学科协作,缓解病人围术期各种应激反应,达到减少术后并发症,缩短住院时间及促进康复的目的^([1])。《中国加速康复外科临床实践指南(2021)》的推出,标志着ERAS在中国推广应用里程碑式的进展^([2])。展开更多
OBJECTIVE CYP3A4 is one of the majordrug-metabolizing enzymes in humans and is responsible for the metabolism of over 50%of the clinically used drugs.Many drugs have been proved to induce the expression of CYP3A4,whic...OBJECTIVE CYP3A4 is one of the majordrug-metabolizing enzymes in humans and is responsible for the metabolism of over 50%of the clinically used drugs.Many drugs have been proved to induce the expression of CYP3A4,which usually causes drug-drug interactions and adverse reactions.The induction by numerous inducers shows significant interindividual differ ence but genetic factors can not totally explain or esti mate the difference.Recently,Epigenetic factors have been pointed out to contribute to that difference.Since histone methylation and acethylation are important parts of epigenetics,this study aimed to explore the role o active histone marks(H3K4me3,H3 acethylation)and inactive histone mark(H3K27me3)in rifampin-induced expression of CYP3A4 in LS174T cells.METHODS Chromatin immunoprecipitation(ChI P)assay was utilized to determine the levels of histone modifications in CYP3A4 promoter.RNA interference and Co-immunopre cipitation(Co-IP)assays were performed to determine the role of PXR and interactions between PXR and his tone methyltransferase/acetylase.RESULTS We found that the induction of CYP3A4 m RNA by rifampin treat ment(10μmol·L-1)in LS174T cells was accompanied by increased levels of H3K4me3 and H3 acethylation and decreased level H3K27me3 in CYP3A4 promoter Besides,enhanced recruitment of NCOA6,a coactivato of multiple nuclear receptors and transcription factors that is associated with H3K4 methyltransferase,and p300,a histone acetylase,were observed in CYP3A4promoter.To reveal the relationship between PXR activa tion and histone methylation/acethylation,gene silence was performed by sh RNA transfection.Knockdown o PXR expression not only removed the induction o CYP3A4,but also eliminated the recruitment of NCOA6and p300 and the decreased levels of H3K4me3 and H3acethylation in CYP3A4 promoter.Moreover,co-immuno cipitation(Co-IP)assay showed that interactions between PXR and NCOA6/p300 were occurred upon rifampin stimulation.CONCLUSION Histone methylation and acethylation contribute to rifampin-mediated induction of CYP3A4 through the interactions between PXR and histone methyltransferase/acetylase.展开更多
文摘近年来,快速康复外科(enhanced recovery after surgery,ERAS)越来越受到重视,其以循证医学证据为基础,通过外科、麻醉、护理、营养等多学科协作,缓解病人围术期各种应激反应,达到减少术后并发症,缩短住院时间及促进康复的目的^([1])。《中国加速康复外科临床实践指南(2021)》的推出,标志着ERAS在中国推广应用里程碑式的进展^([2])。
基金The project supported by National Natural Science Foundation of China(81173127,81273581)
文摘OBJECTIVE CYP3A4 is one of the majordrug-metabolizing enzymes in humans and is responsible for the metabolism of over 50%of the clinically used drugs.Many drugs have been proved to induce the expression of CYP3A4,which usually causes drug-drug interactions and adverse reactions.The induction by numerous inducers shows significant interindividual differ ence but genetic factors can not totally explain or esti mate the difference.Recently,Epigenetic factors have been pointed out to contribute to that difference.Since histone methylation and acethylation are important parts of epigenetics,this study aimed to explore the role o active histone marks(H3K4me3,H3 acethylation)and inactive histone mark(H3K27me3)in rifampin-induced expression of CYP3A4 in LS174T cells.METHODS Chromatin immunoprecipitation(ChI P)assay was utilized to determine the levels of histone modifications in CYP3A4 promoter.RNA interference and Co-immunopre cipitation(Co-IP)assays were performed to determine the role of PXR and interactions between PXR and his tone methyltransferase/acetylase.RESULTS We found that the induction of CYP3A4 m RNA by rifampin treat ment(10μmol·L-1)in LS174T cells was accompanied by increased levels of H3K4me3 and H3 acethylation and decreased level H3K27me3 in CYP3A4 promoter Besides,enhanced recruitment of NCOA6,a coactivato of multiple nuclear receptors and transcription factors that is associated with H3K4 methyltransferase,and p300,a histone acetylase,were observed in CYP3A4promoter.To reveal the relationship between PXR activa tion and histone methylation/acethylation,gene silence was performed by sh RNA transfection.Knockdown o PXR expression not only removed the induction o CYP3A4,but also eliminated the recruitment of NCOA6and p300 and the decreased levels of H3K4me3 and H3acethylation in CYP3A4 promoter.Moreover,co-immuno cipitation(Co-IP)assay showed that interactions between PXR and NCOA6/p300 were occurred upon rifampin stimulation.CONCLUSION Histone methylation and acethylation contribute to rifampin-mediated induction of CYP3A4 through the interactions between PXR and histone methyltransferase/acetylase.