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
Parkinson’s disease is a common chronic neurodegenerative disease.N-methylation can enhance the neurotoxiicity to dopaminergic neuron in the metabolic process of catechol isoquinolines and Salsolinol N-methyltransfer...Parkinson’s disease is a common chronic neurodegenerative disease.N-methylation can enhance the neurotoxiicity to dopaminergic neuron in the metabolic process of catechol isoquinolines and Salsolinol N-methyltransferases (SNMT) may play an important role in the pathogenesis of PD.A new method including SNMT purification and detecting SNMT activity was developed and displays an excellent sensitivity and stability.In addition,the SNMT activity in Wistar rats substantia nigra,striatum and cerebellum.展开更多
A new method for the quantitative determination of the enantiomers of salsolinol, an endogenous neurotoxin, was reported. Enantiomeric separation of salsolinol was obtained by capillary zone electrophoresis using hydr...A new method for the quantitative determination of the enantiomers of salsolinol, an endogenous neurotoxin, was reported. Enantiomeric separation of salsolinol was obtained by capillary zone electrophoresis using hydroxypropyl-β-cyclodextrin （HP-β-CD） as chiral selector. Coupled with UV detection, this separation was applied to the determination of R,S-salsolinol in dried banana chips, and both R- and S-salsolinol were found at 40 ktg/g level.展开更多
Objective The selective loss of dopaminergic neurons in Parkinson＇s disease is suspected to correlate with the increase of cellular iron, which may be involved in the pathogenesis of PD by promotion of oxidative stre...Objective The selective loss of dopaminergic neurons in Parkinson＇s disease is suspected to correlate with the increase of cellular iron, which may be involved in the pathogenesis of PD by promotion of oxidative stress. This research investigated dopamine-induced oxidative stress toxicity contributed by iron and the production of dopamine-derived neurotoxins in dopaminergic SH-SYSY cells. Methods After the SH-SYSY cells were pre-incubated with dopamine and Fe^2＋ for 24 h, the cell viability, hydroxyl radical, melondialdehyde, cell apoptosis, and catechol isoquinolines were measured by lactate dehydrogenase assay, salicylic acid trapping method, thiobarbuteric acid assay, Hoechst 33258 staining and HPLC-electrochemical detection （HPLC-ECD）, respectively. Results （1） Optimal dopamine （150 μmol/L） and Fe^2＋ （40 or 80 μmol/L） significantly increased the concentrations of hydroxy radicals and melondialdehyde in SH-SYSY cells. （2） Induction with dopamine alone or dopamine and Fe^2＋ （dopamine/Fe^2＋） caused cell apoptosis. （3） Compared with untreated cells, the catechol isoquinolines, salsolinol and N-methyl-salsolinol in dopamine/Fe^2＋-induced cells were detected in increasing amounts. Conclusion Due to dopamine/Fe^2＋-induced oxidative stress similar to the state in the parkinsonian substantia nigra neurons, dopamine and Fe^2＋ impaired SH-SYSY cells could be used as the cell oxidative stress model of Parkinson＇s disease. The catechol isoquinolines detected in cells may be involved in the pathogenesis of Parkinson＇s disease as potential neurotoxins.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.
文摘Parkinson’s disease is a common chronic neurodegenerative disease.N-methylation can enhance the neurotoxiicity to dopaminergic neuron in the metabolic process of catechol isoquinolines and Salsolinol N-methyltransferases (SNMT) may play an important role in the pathogenesis of PD.A new method including SNMT purification and detecting SNMT activity was developed and displays an excellent sensitivity and stability.In addition,the SNMT activity in Wistar rats substantia nigra,striatum and cerebellum.
基金accepted November 6, 2005. Project supported by the National Natural Science Foundation of China （No. 20265001）.
文摘A new method for the quantitative determination of the enantiomers of salsolinol, an endogenous neurotoxin, was reported. Enantiomeric separation of salsolinol was obtained by capillary zone electrophoresis using hydroxypropyl-β-cyclodextrin （HP-β-CD） as chiral selector. Coupled with UV detection, this separation was applied to the determination of R,S-salsolinol in dried banana chips, and both R- and S-salsolinol were found at 40 ktg/g level.
基金This work was supported by the National Natural Science Foundation of China （No. 20435020, No. 20275005, and No. 30670645）.
文摘Objective The selective loss of dopaminergic neurons in Parkinson＇s disease is suspected to correlate with the increase of cellular iron, which may be involved in the pathogenesis of PD by promotion of oxidative stress. This research investigated dopamine-induced oxidative stress toxicity contributed by iron and the production of dopamine-derived neurotoxins in dopaminergic SH-SYSY cells. Methods After the SH-SYSY cells were pre-incubated with dopamine and Fe^2＋ for 24 h, the cell viability, hydroxyl radical, melondialdehyde, cell apoptosis, and catechol isoquinolines were measured by lactate dehydrogenase assay, salicylic acid trapping method, thiobarbuteric acid assay, Hoechst 33258 staining and HPLC-electrochemical detection （HPLC-ECD）, respectively. Results （1） Optimal dopamine （150 μmol/L） and Fe^2＋ （40 or 80 μmol/L） significantly increased the concentrations of hydroxy radicals and melondialdehyde in SH-SYSY cells. （2） Induction with dopamine alone or dopamine and Fe^2＋ （dopamine/Fe^2＋） caused cell apoptosis. （3） Compared with untreated cells, the catechol isoquinolines, salsolinol and N-methyl-salsolinol in dopamine/Fe^2＋-induced cells were detected in increasing amounts. Conclusion Due to dopamine/Fe^2＋-induced oxidative stress similar to the state in the parkinsonian substantia nigra neurons, dopamine and Fe^2＋ impaired SH-SYSY cells could be used as the cell oxidative stress model of Parkinson＇s disease. The catechol isoquinolines detected in cells may be involved in the pathogenesis of Parkinson＇s disease as potential neurotoxins.
