BACKGROUND Type 2 diabetes mellitus(T2DM)is a severe global health problem that causes prolonged disease exposure and an elevated risk for chronic complications,posing a substantial health burden.Although therapies,su...BACKGROUND Type 2 diabetes mellitus(T2DM)is a severe global health problem that causes prolonged disease exposure and an elevated risk for chronic complications,posing a substantial health burden.Although therapies,such as GLP-1 receptor agonists and SGLT2 inhibitors,have been successfully developed,new therapeutic options are still expected to offer better blood glucose control and decrease complications.AIM To elucidate the mechanism by which TERT/FOXO1 affects high glucose(HG)-induced dysfunction in isletβ-cells via the regulation of ATG9A-mediated autophagy.METHODS High-fat diet(HFD)-fed/streptozotocin(STZ)-treated mice or HG-treated MIN6 cells were used to establish T2DM models.Fasting blood glucose(FBG)and insulin levels in mice,as well as morphological changes in islet tissues,were assessed.Cell proliferation and the apoptosis rate were measured via EdU assays and flow cytometry,respectively.The expression levels of TERT,FOXO1,ATG9A and autophagy-related proteins(LC3B,p62)were analyzed via western blotting.The relationship between FOXO1 and ATG9A was assessed using dual-luciferase reporter gene assays and ChIP assays.RESULTS T2DM modeling in HFD-fed/STZ-treated mice and HG-treated MIN6 cells led to elevated TERT and FOXO1 expression and reduced ATG9A expression.Mice with T2DM were found to have decreased body weight,worsened morphology,elevated FBG and suppressed insulin levels.HG-treated MIN6 cells presented decreased viability and LC3B expression,in addition to increased p62 expression and apoptosis rates.FOXO1 knockdown both in vitro and in vivo protected mice and cells against isletβ-cell dysfunction via the activation of autophagy.The molecular mechanism involved the suppression of ATG9A expression by TERT through FOXO1 transcription activation.CONCLUSION Our results suggested that TERT/FOXO1 inhibits ATG9A expression to decrease isletβ-cell function in T2DM.展开更多
Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy bodies.Dysfunction in protein degra...Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy bodies.Dysfunction in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s disease.However,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the brain.In the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult brain.Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in glia.Atg9 is persistently in contact with these organelles.Lacking glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate degradation.This suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic degradation.Importantly,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial activation.Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s disease.These results may provide new insights on the underlying mechanism of Parkinson’s disease.展开更多
Background and Aims:125I radioactive particles implantation have demonstrated efficacy in eradicating hepatocellular carcinoma(HCC).However,progressive resistance of HCC to 125I radioactive particles has limited its w...Background and Aims:125I radioactive particles implantation have demonstrated efficacy in eradicating hepatocellular carcinoma(HCC).However,progressive resistance of HCC to 125I radioactive particles has limited its wide clinical application.Methods:We investigated the cellular responses to 125I radioactive particles treatment and autophagy-related 9B(ATG9B)silencing in HCC cell lines and Hep3B xenografted tumor model using Cell Counting Kit-8 reagent,western blotting,immunofluorescence,flow cytometry,transmission electron microscopy and immunohistochemistry.Results:In this study,we demonstrated that 125I radioactive particles induced cell apoptosis and protective autophagy of HCC in vitro and in vivo.Inhibition of autophagy enhanced the radiosensitivity of HCC to 125I radioactive particles.Moreover,125I radioactive particles induced autophagy by upregulating ATG9B,with increased expression level of LC3B and decreased expression level of p62.Furthermore,ATG9B silencing downregulated LC3B expression and upregulated p62 expression and enhanced radiosensitivity of HCC to 125I radioactive particles in vitro and in vivo.Conclusions:Inhibition of ATG9B enhanced the antitumor effects of 125I particle radiation against HCC in vitro and in vivo.Our findings suggest that 125I particle radiation plus chloroquine or/and the ATG9B inhibitor may be a novel therapeutic strategy for HCC.展开更多
基金Supported by National Natural Science Foundation of China,No.82000792General Project of Chongqing Natural Science Foundation,No.CSTB2023NSCQ-MSX0246 and No.CSTB2022NSCQ-MSX1271+1 种基金Research Project of the State Administration of Traditional Chinese Medicine on Collaborative Chronic Disease Management of Traditional Chinese Medicine and Western Medicine,No.CXZH2024087Science and Health Joint Project of Dazu District Science and Technology Bureau,No.DZKJ2024JSYJ-KWXM1002.
文摘BACKGROUND Type 2 diabetes mellitus(T2DM)is a severe global health problem that causes prolonged disease exposure and an elevated risk for chronic complications,posing a substantial health burden.Although therapies,such as GLP-1 receptor agonists and SGLT2 inhibitors,have been successfully developed,new therapeutic options are still expected to offer better blood glucose control and decrease complications.AIM To elucidate the mechanism by which TERT/FOXO1 affects high glucose(HG)-induced dysfunction in isletβ-cells via the regulation of ATG9A-mediated autophagy.METHODS High-fat diet(HFD)-fed/streptozotocin(STZ)-treated mice or HG-treated MIN6 cells were used to establish T2DM models.Fasting blood glucose(FBG)and insulin levels in mice,as well as morphological changes in islet tissues,were assessed.Cell proliferation and the apoptosis rate were measured via EdU assays and flow cytometry,respectively.The expression levels of TERT,FOXO1,ATG9A and autophagy-related proteins(LC3B,p62)were analyzed via western blotting.The relationship between FOXO1 and ATG9A was assessed using dual-luciferase reporter gene assays and ChIP assays.RESULTS T2DM modeling in HFD-fed/STZ-treated mice and HG-treated MIN6 cells led to elevated TERT and FOXO1 expression and reduced ATG9A expression.Mice with T2DM were found to have decreased body weight,worsened morphology,elevated FBG and suppressed insulin levels.HG-treated MIN6 cells presented decreased viability and LC3B expression,in addition to increased p62 expression and apoptosis rates.FOXO1 knockdown both in vitro and in vivo protected mice and cells against isletβ-cell dysfunction via the activation of autophagy.The molecular mechanism involved the suppression of ATG9A expression by TERT through FOXO1 transcription activation.CONCLUSION Our results suggested that TERT/FOXO1 inhibits ATG9A expression to decrease isletβ-cell function in T2DM.
基金supported by the National Natural Science Foundation of China,Nos.31871039 and 32170962(to MSH).
文摘Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy bodies.Dysfunction in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s disease.However,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the brain.In the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult brain.Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in glia.Atg9 is persistently in contact with these organelles.Lacking glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate degradation.This suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic degradation.Importantly,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial activation.Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s disease.These results may provide new insights on the underlying mechanism of Parkinson’s disease.
基金supported by the Science and Technology Innovation Project of Social Undertakings and Livelihood Security in Chongqing (No.cstc2016shms-ztzx0045).
文摘Background and Aims:125I radioactive particles implantation have demonstrated efficacy in eradicating hepatocellular carcinoma(HCC).However,progressive resistance of HCC to 125I radioactive particles has limited its wide clinical application.Methods:We investigated the cellular responses to 125I radioactive particles treatment and autophagy-related 9B(ATG9B)silencing in HCC cell lines and Hep3B xenografted tumor model using Cell Counting Kit-8 reagent,western blotting,immunofluorescence,flow cytometry,transmission electron microscopy and immunohistochemistry.Results:In this study,we demonstrated that 125I radioactive particles induced cell apoptosis and protective autophagy of HCC in vitro and in vivo.Inhibition of autophagy enhanced the radiosensitivity of HCC to 125I radioactive particles.Moreover,125I radioactive particles induced autophagy by upregulating ATG9B,with increased expression level of LC3B and decreased expression level of p62.Furthermore,ATG9B silencing downregulated LC3B expression and upregulated p62 expression and enhanced radiosensitivity of HCC to 125I radioactive particles in vitro and in vivo.Conclusions:Inhibition of ATG9B enhanced the antitumor effects of 125I particle radiation against HCC in vitro and in vivo.Our findings suggest that 125I particle radiation plus chloroquine or/and the ATG9B inhibitor may be a novel therapeutic strategy for HCC.
