Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-asso...Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.展开更多
目的:探讨UGT1A6 A541G、A552C基因多态对丙戊酸钠血药浓度的影响。方法:计算机检索PubMed、Medline、Cochrane Library、EMbase、CNKI、万方数据库,检索年限从建库至2024年4月,收集UGT1A6基因多态性与丙戊酸钠血药浓度文献,提取数据与...目的:探讨UGT1A6 A541G、A552C基因多态对丙戊酸钠血药浓度的影响。方法:计算机检索PubMed、Medline、Cochrane Library、EMbase、CNKI、万方数据库,检索年限从建库至2024年4月,收集UGT1A6基因多态性与丙戊酸钠血药浓度文献,提取数据与质量评价,采用Revman5.3软件进行Meta分析。结果:共纳入文献11篇,999例癫痫患者。Meta分析结果显示,在UGT1A6 A541G基因中,除AG vs GG[MD=0.16,95%CI(-0.39,0.70),P=0.50]外,AA vs AG[MD=0.53,95%CI(0.32,0.75),P<0.00001],AA vs GG[MD=0.67,95%CI(0.10,1.23),P=0.02],AA vs AG+GG[MD=0.61,95%CI(0.45,0.76)P<0.00001],两者差异均具有统计学意义,说明癫痫患者UGT1A6 A541G AA型丙戊酸钠血药浓度高于AG型或/和GG型。在UGT1A6 A552C中,除AC vs CC[MD=0.21,95%CI(-0.31,0.74),P=0.43]外,AA vs AC[MD=0.90,95%CI(0.77,1.03),P<0.00001],AA vs CC[MD=0.90,95%CI(0.77,1.03),P<0.00001],AA vs AC+CC[MD=1.58,95%CI(1.07,2.10),P<0.00001],两者差异均具有统计学意义,说明UGT1A6 A552C AA型丙戊酸钠血药浓度高于AC型或/和CC型。结论:癫痫患者UGT1A6 A541G和A552C基因多态性与丙戊酸钠血药浓度具有相关性,且基因突变可能导致丙戊酸钠血药浓度降低。展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
基金supported by the National Natural Science Foundation of China,Nos.82071008(to BL)and 82004001(to XJ)Medical Science and Technology Program of Health Commission of Henan Province,No.LHGJ20210072(to RQ)Science and Technology Department of Henan Province,No.212102310307(to XJ)。
文摘Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.
文摘目的:探讨UGT1A6 A541G、A552C基因多态对丙戊酸钠血药浓度的影响。方法:计算机检索PubMed、Medline、Cochrane Library、EMbase、CNKI、万方数据库,检索年限从建库至2024年4月,收集UGT1A6基因多态性与丙戊酸钠血药浓度文献,提取数据与质量评价,采用Revman5.3软件进行Meta分析。结果:共纳入文献11篇,999例癫痫患者。Meta分析结果显示,在UGT1A6 A541G基因中,除AG vs GG[MD=0.16,95%CI(-0.39,0.70),P=0.50]外,AA vs AG[MD=0.53,95%CI(0.32,0.75),P<0.00001],AA vs GG[MD=0.67,95%CI(0.10,1.23),P=0.02],AA vs AG+GG[MD=0.61,95%CI(0.45,0.76)P<0.00001],两者差异均具有统计学意义,说明癫痫患者UGT1A6 A541G AA型丙戊酸钠血药浓度高于AG型或/和GG型。在UGT1A6 A552C中,除AC vs CC[MD=0.21,95%CI(-0.31,0.74),P=0.43]外,AA vs AC[MD=0.90,95%CI(0.77,1.03),P<0.00001],AA vs CC[MD=0.90,95%CI(0.77,1.03),P<0.00001],AA vs AC+CC[MD=1.58,95%CI(1.07,2.10),P<0.00001],两者差异均具有统计学意义,说明UGT1A6 A552C AA型丙戊酸钠血药浓度高于AC型或/和CC型。结论:癫痫患者UGT1A6 A541G和A552C基因多态性与丙戊酸钠血药浓度具有相关性,且基因突变可能导致丙戊酸钠血药浓度降低。
