Dipeptidyl peptidase 4(DPP4)is recognised as an attractive anti-diabetic drug target,and several DPP4 inhibitors are already on the market.As members of the same gene family,dipeptidyl peptidase 8(DPP8)and dipeptidyl ...Dipeptidyl peptidase 4(DPP4)is recognised as an attractive anti-diabetic drug target,and several DPP4 inhibitors are already on the market.As members of the same gene family,dipeptidyl peptidase 8(DPP8)and dipeptidyl peptidase 9(DPP9)share high sequence and structural homology as well as functional activity with DPP4.However,the inhibition of their activities was reported to cause severe toxicities.Thus,the development of DPP4 inhibitors that do not have DPP8 and DPP9 inhibitory activity is critical for safe anti-diabetic therapy.To achieve this goal,we established a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins expressed by Rosetta cells.In this method,we used purified recombinant 120 kDa DPP8 or DPP9 protein from the Rosetta expression system.The optimum concentrations of the recombinant DPP8 and DPP9 proteins were 30 ng/mL and 20 ng/mL,respectively,and the corresponding concentrations of their substrates were both 0.2 mmol/L.This method was highly reproducible and reliable for the evaluation of the DPP8 and DPP9 selectivity for DPP4 inhibitor candidates,which would provide valuable guidance in the development of safe DPP4 inhibitors.展开更多
Numerous studies on the formation and consolidation of memory have shown that memory processes are characterized by phase-dependent and dynamic regulation.Memory retrieval,as the only representation of memory content ...Numerous studies on the formation and consolidation of memory have shown that memory processes are characterized by phase-dependent and dynamic regulation.Memory retrieval,as the only representation of memory content and an active form of memory processing that induces memory reconsolidation,has attracted increasing attention in recent years.Although the molecular mechanisms specifc to memory retrievalinduced reconsolidation have been gradually revealed,an understanding of the time-dependent regulatory mechanisms of this process is still lacking.In this study,we applied a transcriptome analysis of memory retrieval at diferent time points in the recent memory stage.Diferential expression analysis and Short Time-series Expression Miner(STEM)depicting temporal gene expression patterns indicated that most diferential gene expression occurred at 48 h,and the STEM cluster showing the greatest transcriptional upregulation at 48 h demonstrated the most significant diference.We then screened the diferentially-expressed genes associated with that met the expression patterns of those cluster-identifed genes that have been reported to be involved in learning and memory processes in addition to dipeptidyl peptidase 9(DPP9).Further quantitative polymerase chain reaction verifcation and pharmacological intervention suggested that DPP9 is involved in 48-h fear memory retrieval and viral vector-mediated overexpression of DPP9 countered the 48-h retrieval-induced attenuation of fear memory.Taken together,our fndings suggest that temporal gene expression patterns are induced by recent memory retrieval and provide hitherto undocumented evidence of the role of DPP9 in the retrieval-induced reconsolidation of fear memory.展开更多
Genome-wide association analysis allows the identification of potential candidate genes involved in the development of severe coronavirus disease 2019(COVID-19).Hence,it seems that genetics matters here,as well.Nevert...Genome-wide association analysis allows the identification of potential candidate genes involved in the development of severe coronavirus disease 2019(COVID-19).Hence,it seems that genetics matters here,as well.Nevertheless,the virus's nature,including its RNA structure,determines the rate of mutations leading to new viral strains with all epidemiological and clinical consequences.Given these observations,we herein comment on the current hypotheses about the possible role of the genes in association with COVID-19 severity.We discuss some of the major candidate genes that have been identified as potential genetic factors associated with the COVID-19 severity and infection susceptibility:HLA,ABO,ACE2,TLR7,ApoE,TYK2,OAS,DPP9,IFNAR2,CCR2,etc.Further study of genes and genetic variants will be of great benefit for the prevention and assessment of the individual risk and disease severity in different populations.These scientific data will serve as a basis for the development of clinically applicable diagnostic and prognostic tests for patients at high risk of COVID-19.展开更多
基金We greatly appreciate Prof.Haihong Huang and Dr.Bei Han for the chemical synthesis of UAMC00132sitagliptin.This work was supported by a fund from National Mega-project for Innova-tive Drugs(2012ZX09301002-004,China).
文摘Dipeptidyl peptidase 4(DPP4)is recognised as an attractive anti-diabetic drug target,and several DPP4 inhibitors are already on the market.As members of the same gene family,dipeptidyl peptidase 8(DPP8)and dipeptidyl peptidase 9(DPP9)share high sequence and structural homology as well as functional activity with DPP4.However,the inhibition of their activities was reported to cause severe toxicities.Thus,the development of DPP4 inhibitors that do not have DPP8 and DPP9 inhibitory activity is critical for safe anti-diabetic therapy.To achieve this goal,we established a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins expressed by Rosetta cells.In this method,we used purified recombinant 120 kDa DPP8 or DPP9 protein from the Rosetta expression system.The optimum concentrations of the recombinant DPP8 and DPP9 proteins were 30 ng/mL and 20 ng/mL,respectively,and the corresponding concentrations of their substrates were both 0.2 mmol/L.This method was highly reproducible and reliable for the evaluation of the DPP8 and DPP9 selectivity for DPP4 inhibitor candidates,which would provide valuable guidance in the development of safe DPP4 inhibitors.
基金supported by the STI2030-Major Projects(2022ZD0204900)the National Natural Science Foundation of China(32071029 and 32271080)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32020200)the Yunnan Provincial Science and Technology Department(202402AA310014).
文摘Numerous studies on the formation and consolidation of memory have shown that memory processes are characterized by phase-dependent and dynamic regulation.Memory retrieval,as the only representation of memory content and an active form of memory processing that induces memory reconsolidation,has attracted increasing attention in recent years.Although the molecular mechanisms specifc to memory retrievalinduced reconsolidation have been gradually revealed,an understanding of the time-dependent regulatory mechanisms of this process is still lacking.In this study,we applied a transcriptome analysis of memory retrieval at diferent time points in the recent memory stage.Diferential expression analysis and Short Time-series Expression Miner(STEM)depicting temporal gene expression patterns indicated that most diferential gene expression occurred at 48 h,and the STEM cluster showing the greatest transcriptional upregulation at 48 h demonstrated the most significant diference.We then screened the diferentially-expressed genes associated with that met the expression patterns of those cluster-identifed genes that have been reported to be involved in learning and memory processes in addition to dipeptidyl peptidase 9(DPP9).Further quantitative polymerase chain reaction verifcation and pharmacological intervention suggested that DPP9 is involved in 48-h fear memory retrieval and viral vector-mediated overexpression of DPP9 countered the 48-h retrieval-induced attenuation of fear memory.Taken together,our fndings suggest that temporal gene expression patterns are induced by recent memory retrieval and provide hitherto undocumented evidence of the role of DPP9 in the retrieval-induced reconsolidation of fear memory.
文摘Genome-wide association analysis allows the identification of potential candidate genes involved in the development of severe coronavirus disease 2019(COVID-19).Hence,it seems that genetics matters here,as well.Nevertheless,the virus's nature,including its RNA structure,determines the rate of mutations leading to new viral strains with all epidemiological and clinical consequences.Given these observations,we herein comment on the current hypotheses about the possible role of the genes in association with COVID-19 severity.We discuss some of the major candidate genes that have been identified as potential genetic factors associated with the COVID-19 severity and infection susceptibility:HLA,ABO,ACE2,TLR7,ApoE,TYK2,OAS,DPP9,IFNAR2,CCR2,etc.Further study of genes and genetic variants will be of great benefit for the prevention and assessment of the individual risk and disease severity in different populations.These scientific data will serve as a basis for the development of clinically applicable diagnostic and prognostic tests for patients at high risk of COVID-19.
