Alzheimer's disease(AD) is a progressive neurodegenerative disorder and one of the most common causes of dementia in the elderly.Acetylcholine esterase inhibitors(AChEI) are the main drugs used in the treatment of...Alzheimer's disease(AD) is a progressive neurodegenerative disorder and one of the most common causes of dementia in the elderly.Acetylcholine esterase inhibitors(AChEI) are the main drugs used in the treatment of AD.In this work,docking studies have been performed in order to understand the interaction between a number of inhibitors(tacrine,rivastigmine,huperzine A,TV-3326(ladostigil),donepezil and anseculin) and acetylcholine esterase(AChE).The calculated binding affinities between inhibitors and AChE increase in the order tacrine<rivastigmine<huperzine A<TV-3326<donepezil<anseculin,which reflects the experimental inhibitory activity expressed in terms of the half maximal inhibitory concentration(the IC50 value).Of the above inhibitors,anseculin is the most useful drug for the treatment of dementia.展开更多
Hereditary angioedema （HAE） is an autosomal dominant condition that affects one in about 50 000 persons, characterized by recurrent episodes of subcutaneous or submucosal swelling involving the hands, feet, limbs, f...Hereditary angioedema （HAE） is an autosomal dominant condition that affects one in about 50 000 persons, characterized by recurrent episodes of subcutaneous or submucosal swelling involving the hands, feet, limbs, face, intestinal tract, even larynx and trachea.展开更多
Detoxification plays a crucial role in agricultural pests to withstand pesticides,and cytochrome P450s,carboxyl/choline esterases(CCEs),and glutathione-S-transferases are the main proteins responsible for their detoxi...Detoxification plays a crucial role in agricultural pests to withstand pesticides,and cytochrome P450s,carboxyl/choline esterases(CCEs),and glutathione-S-transferases are the main proteins responsible for their detoxification ability.The activity of CCEs can be upregulated,downregulated,or modified by mutation.However,few studies have examined the role of alternative splicing in altering the properties of CCEs.We identified 2 variants of TcCCE23 in Tetranychus cinnabarinus:a long version(CCE23-V1)and a short version that is 18 nucleotides shorter than CCE23-V1(CCE23-V2).Whether splicing affects the activity of TcCCE23 remains unclear.Overexpression of CCE23-V2 in fenpropathrin-resistant T.cinnabarinus revealed that splicing affected the detoxification of fenpropathrin by CCE23-V2.The mortality of mites was significantly higher when the expression of CCE23-V2 was knocked down(43.2%±3.3%)via injection of CCE23-dsRNA(double-stranded RNA)compared with the control group injected with green fluorescent protein-dsRNA under fenpropathrin exposure;however,the downregulation of CCE23-V1(61.3%±6.3%)by CCE23-small interfering RNA had no such effect,indicating CCE23-V2 plays a greater role in xenobiotic metabolism than CCE23-V1.The tolerance of flies overexpressing CCE23-V2 to fenpropathrin(50%lethal dose[LD_(50)]=19.47μg/g)was significantly higher than that of Gal4/UAS-CCE23-V1 transgenic flies(LD_(50)=13.11μg/g).Molecular docking analysis showed that splicing opened a“gate”that enlarges the substrate binding cavity of CCE23-V2,might enhance the ability of CCE23-V2 to harbor fenpropathrin molecules.These findings suggest that splicing might enhance the detoxifying capability of TcCCE23.Generally,our data improve the understanding of the diversity and complexity of the mechanisms underlying the regulation of CCEs.展开更多
基金Supported by the Specialized Research Fund for the Doctoral Program of Higher Education (Grant No. 20070183046)the Specialized Fund for the Basic Research of Jilin University (Grant No. 200810018)
文摘Alzheimer's disease(AD) is a progressive neurodegenerative disorder and one of the most common causes of dementia in the elderly.Acetylcholine esterase inhibitors(AChEI) are the main drugs used in the treatment of AD.In this work,docking studies have been performed in order to understand the interaction between a number of inhibitors(tacrine,rivastigmine,huperzine A,TV-3326(ladostigil),donepezil and anseculin) and acetylcholine esterase(AChE).The calculated binding affinities between inhibitors and AChE increase in the order tacrine<rivastigmine<huperzine A<TV-3326<donepezil<anseculin,which reflects the experimental inhibitory activity expressed in terms of the half maximal inhibitory concentration(the IC50 value).Of the above inhibitors,anseculin is the most useful drug for the treatment of dementia.
文摘Hereditary angioedema （HAE） is an autosomal dominant condition that affects one in about 50 000 persons, characterized by recurrent episodes of subcutaneous or submucosal swelling involving the hands, feet, limbs, face, intestinal tract, even larynx and trachea.
基金supported in part by the National Nature Sciences Foundation(32001935 and 31972297)the Fundamental Research Funds for the Central Universities(SWU-KR22005).
文摘Detoxification plays a crucial role in agricultural pests to withstand pesticides,and cytochrome P450s,carboxyl/choline esterases(CCEs),and glutathione-S-transferases are the main proteins responsible for their detoxification ability.The activity of CCEs can be upregulated,downregulated,or modified by mutation.However,few studies have examined the role of alternative splicing in altering the properties of CCEs.We identified 2 variants of TcCCE23 in Tetranychus cinnabarinus:a long version(CCE23-V1)and a short version that is 18 nucleotides shorter than CCE23-V1(CCE23-V2).Whether splicing affects the activity of TcCCE23 remains unclear.Overexpression of CCE23-V2 in fenpropathrin-resistant T.cinnabarinus revealed that splicing affected the detoxification of fenpropathrin by CCE23-V2.The mortality of mites was significantly higher when the expression of CCE23-V2 was knocked down(43.2%±3.3%)via injection of CCE23-dsRNA(double-stranded RNA)compared with the control group injected with green fluorescent protein-dsRNA under fenpropathrin exposure;however,the downregulation of CCE23-V1(61.3%±6.3%)by CCE23-small interfering RNA had no such effect,indicating CCE23-V2 plays a greater role in xenobiotic metabolism than CCE23-V1.The tolerance of flies overexpressing CCE23-V2 to fenpropathrin(50%lethal dose[LD_(50)]=19.47μg/g)was significantly higher than that of Gal4/UAS-CCE23-V1 transgenic flies(LD_(50)=13.11μg/g).Molecular docking analysis showed that splicing opened a“gate”that enlarges the substrate binding cavity of CCE23-V2,might enhance the ability of CCE23-V2 to harbor fenpropathrin molecules.These findings suggest that splicing might enhance the detoxifying capability of TcCCE23.Generally,our data improve the understanding of the diversity and complexity of the mechanisms underlying the regulation of CCEs.
