Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays...Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases.However,the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown.In this study,we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve.High-throughput methylated RNA immunoprecipitation sequencing res ults showed that after spared nerve injury,there were 55 m6A methylated and diffe rentially expressed genes in the spinal cord.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury.Over time,the diffe rential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell prolife ration." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance.Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes,such as "very-low-density lipoprotein particle clearance," "negative regulation of choleste rol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling.We speculate that m6A reader enzymes also have an important role in neuropathic pain.These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at diffe rent stages after injury.展开更多
4-Amino-3-mercapto-6-methyl-l,2,4-triazin-5（4H）-one 1 converted to 4-amino-6-methy-3-（methylthio）-1,2,4-triazin-5（4H）-one by methylation with methyl iodide.Controlled hydrazination of the resulting compound affo...4-Amino-3-mercapto-6-methyl-l,2,4-triazin-5（4H）-one 1 converted to 4-amino-6-methy-3-（methylthio）-1,2,4-triazin-5（4H）-one by methylation with methyl iodide.Controlled hydrazination of the resulting compound afforded 4-amino-3-hydrazinyl-6- methyl-l,2,4-triazin-5（4H）-one 2 as a building block,to the synthesis of some novel derivatives of[1,2,4]triazino- [4,3,b][1,2,4,5]tetrazepine 3-6,by the reaction with 3-chloropentane-2,4-dione,chloro acetonitrile,1,3-dichloroacetone,and methyl bromoacetate.This general synthetic procedure can be extended to the preparation of wide variety of tetrazepines using 1,2- bielectrophiles derivatives.展开更多
Reaction of 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile) (1) with methyl iodide afforded the 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-(methylthio)nicotinonitrile) (2). Th...Reaction of 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile) (1) with methyl iodide afforded the 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-(methylthio)nicotinonitrile) (2). The reaction of 2 with hydrazine hydrate followed by diazotization reaction af-forded the 1,1’-(1,4-phenylenebis(3-amino-6-methyl-1H-pyrazolo[3,4-b]pyridine-4,5-diyl))bis(e-than-1-one) (3) and 1,1’-(1,4-phenylenebis(3-(chlorodiazenyl)-6-methyl-1H-pyrazolo[3,4-b]-pyridine-4,5-diyl))bis(ethan-1-one) (4) respectively. On the other hand, reaction of 4 with malononitrile, 2-cyanoethanethioamide, ethyl acetoacetate, acetyl acetone, ethyl benzoylacetate, diethylmalonate, ethyl cyanoacetate and phenacylbromide aiming to build up pyrazolotriazine or pyrazole ring on the ring system of 4. Structures of all newly synthesized heterocyclic compounds in the present study were confirmed by considering the data of IR, 1H NMR, mass spectra as well as that of elemental analyses.展开更多
运用荧光猝灭的原理在p H 7.6的生理条件下,眼镜蛇毒蛋白与系列6-氨基-4-芳基-5-氰基-3-甲基-1-苯基吡啶[2,3-c]并吡唑化合物之间的相互作用被研究,并且筛选出6-氨基-4-对羟基苯基-5-氰基-3-甲基-1-苯基吡啶[2,3-c]并吡唑(I)进行了详细...运用荧光猝灭的原理在p H 7.6的生理条件下,眼镜蛇毒蛋白与系列6-氨基-4-芳基-5-氰基-3-甲基-1-苯基吡啶[2,3-c]并吡唑化合物之间的相互作用被研究,并且筛选出6-氨基-4-对羟基苯基-5-氰基-3-甲基-1-苯基吡啶[2,3-c]并吡唑(I)进行了详细研究。猝灭常数KSV、结合常数K以及结合位点n被获得。该实验证明眼镜蛇毒蛋白与I之间生成了新的化合物,而这一过程是静态猝灭的过程,并且它们之间存在着一定的结合。展开更多
基金National Natural Science Foundation of China,No.819 73305 (to ZQ)Science and Technology Planning Project of Guangzhou of China,No.20190401 0487 (to ZQ)+1 种基金Natural Science Foundation of Guangdong Province,China,No.2021A1515010897 (to TT)Discipline Construction Fund of Cen tral Peoples Hospital of Zhanjiang,Nos.2020A01 (to TT) and 2020A02 (to TT)。
文摘Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases.However,the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown.In this study,we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve.High-throughput methylated RNA immunoprecipitation sequencing res ults showed that after spared nerve injury,there were 55 m6A methylated and diffe rentially expressed genes in the spinal cord.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury.Over time,the diffe rential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell prolife ration." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance.Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes,such as "very-low-density lipoprotein particle clearance," "negative regulation of choleste rol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling.We speculate that m6A reader enzymes also have an important role in neuropathic pain.These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at diffe rent stages after injury.
文摘4-Amino-3-mercapto-6-methyl-l,2,4-triazin-5（4H）-one 1 converted to 4-amino-6-methy-3-（methylthio）-1,2,4-triazin-5（4H）-one by methylation with methyl iodide.Controlled hydrazination of the resulting compound afforded 4-amino-3-hydrazinyl-6- methyl-l,2,4-triazin-5（4H）-one 2 as a building block,to the synthesis of some novel derivatives of[1,2,4]triazino- [4,3,b][1,2,4,5]tetrazepine 3-6,by the reaction with 3-chloropentane-2,4-dione,chloro acetonitrile,1,3-dichloroacetone,and methyl bromoacetate.This general synthetic procedure can be extended to the preparation of wide variety of tetrazepines using 1,2- bielectrophiles derivatives.
文摘Reaction of 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile) (1) with methyl iodide afforded the 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-(methylthio)nicotinonitrile) (2). The reaction of 2 with hydrazine hydrate followed by diazotization reaction af-forded the 1,1’-(1,4-phenylenebis(3-amino-6-methyl-1H-pyrazolo[3,4-b]pyridine-4,5-diyl))bis(e-than-1-one) (3) and 1,1’-(1,4-phenylenebis(3-(chlorodiazenyl)-6-methyl-1H-pyrazolo[3,4-b]-pyridine-4,5-diyl))bis(ethan-1-one) (4) respectively. On the other hand, reaction of 4 with malononitrile, 2-cyanoethanethioamide, ethyl acetoacetate, acetyl acetone, ethyl benzoylacetate, diethylmalonate, ethyl cyanoacetate and phenacylbromide aiming to build up pyrazolotriazine or pyrazole ring on the ring system of 4. Structures of all newly synthesized heterocyclic compounds in the present study were confirmed by considering the data of IR, 1H NMR, mass spectra as well as that of elemental analyses.
文摘运用荧光猝灭的原理在p H 7.6的生理条件下,眼镜蛇毒蛋白与系列6-氨基-4-芳基-5-氰基-3-甲基-1-苯基吡啶[2,3-c]并吡唑化合物之间的相互作用被研究,并且筛选出6-氨基-4-对羟基苯基-5-氰基-3-甲基-1-苯基吡啶[2,3-c]并吡唑(I)进行了详细研究。猝灭常数KSV、结合常数K以及结合位点n被获得。该实验证明眼镜蛇毒蛋白与I之间生成了新的化合物,而这一过程是静态猝灭的过程,并且它们之间存在着一定的结合。
