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
As the“fourth messenger”of epigenetic regulation,metabolites playa spatiotemporally specific regulatory role in kidney regeneration by dynamically reshaping the state of chromatin modifications.This review systemati...As the“fourth messenger”of epigenetic regulation,metabolites playa spatiotemporally specific regulatory role in kidney regeneration by dynamically reshaping the state of chromatin modifications.This review systematically expounds the coordinated mechanism of the dual axes of succinate/H3K9ac andα-ketoglutarate(α-KG)/TET enzymes:Succinate activates regeneration-related genes by regulating histone acetylation(H3K9ac),whileα-KG relieves the epigenetic repression of the Wnt pathway through TET-mediated DNA demethylation.The dynamic balance between the two maintains epigenetic plasticity.Multi-omics integration strategies(such as Gaussian graphical models and deep learning frameworks)and single-cell epigenetic tracking technologies(such as spatial metabolomics)have revealed the regulation of metabolite gradients on cellular heterogeneity and the immune microenvironment.The coordinated application of metabolite precursor supplementation(such as NAD precursors)and dynamic monitoring systems(such as isotope tracing and artifi cial intelligence models)has promoted the shift of metabolic medicine from the“static replacement”paradigm to the“dynamic reshaping”paradigm.However,technical bottlenecks(such as insuffi cient multimodal integration)and clinical translation pitfalls(such as challenges in standardized production)still need to be overcome.In the future,through the development of“metabolism-immunity”co-regulatory strategies and intelligent closed-loop systems,it is expected to achieve precise interventions for kidney regeneration and disease treatment.展开更多
The addition of effective nucleating particles in the melt to achieve grain refinement has become the most widely used method for the casting industries.In this study,a novel GNP@MgO particle with a nanocomposite stru...The addition of effective nucleating particles in the melt to achieve grain refinement has become the most widely used method for the casting industries.In this study,a novel GNP@MgO particle with a nanocomposite structure was prepared by utilizing an in-situ reaction of the carbon source gas with Mg melt.The results showed that the particles can significantly reduce the average grain size of Mg-9Al alloy from 130.4μm to 13.1μm,and achieve an ultra-high grain refinement efficiency of 90%.The refinement mechanisms are that the Al_(4)C_(3)phase can act as a heterogeneous nucleation site forα-Mg grains due to the orientation relationship as(001)_(Al_(4)C_(3))//(002)Mg.Meanwhile,the particle distribution model shows that the velocity of MgO particles is much higher than the growth rate ofα-Mg grains.Therefore,it is pushed to the vicinity of grain boundaries during solidification,effectively limiting the growth ofα-Mg grains.The remarkable grain refinement effect was achieved through the synergistic modulation of Al_(4)C_(3)and MgO particles.This work may provide new insight into designing high efficiency grain refiners for Mg-Al alloys.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funded by Medical Science Research Project of Hebei(No.20220364).
文摘As the“fourth messenger”of epigenetic regulation,metabolites playa spatiotemporally specific regulatory role in kidney regeneration by dynamically reshaping the state of chromatin modifications.This review systematically expounds the coordinated mechanism of the dual axes of succinate/H3K9ac andα-ketoglutarate(α-KG)/TET enzymes:Succinate activates regeneration-related genes by regulating histone acetylation(H3K9ac),whileα-KG relieves the epigenetic repression of the Wnt pathway through TET-mediated DNA demethylation.The dynamic balance between the two maintains epigenetic plasticity.Multi-omics integration strategies(such as Gaussian graphical models and deep learning frameworks)and single-cell epigenetic tracking technologies(such as spatial metabolomics)have revealed the regulation of metabolite gradients on cellular heterogeneity and the immune microenvironment.The coordinated application of metabolite precursor supplementation(such as NAD precursors)and dynamic monitoring systems(such as isotope tracing and artifi cial intelligence models)has promoted the shift of metabolic medicine from the“static replacement”paradigm to the“dynamic reshaping”paradigm.However,technical bottlenecks(such as insuffi cient multimodal integration)and clinical translation pitfalls(such as challenges in standardized production)still need to be overcome.In the future,through the development of“metabolism-immunity”co-regulatory strategies and intelligent closed-loop systems,it is expected to achieve precise interventions for kidney regeneration and disease treatment.
基金supported by the National Natural Science Foundation of China(grant nos.52301142,52371107,52201115)Heilongjiang Provincial Postdoctoral Science Foundation(grant no.LBH-11Z22167).
文摘The addition of effective nucleating particles in the melt to achieve grain refinement has become the most widely used method for the casting industries.In this study,a novel GNP@MgO particle with a nanocomposite structure was prepared by utilizing an in-situ reaction of the carbon source gas with Mg melt.The results showed that the particles can significantly reduce the average grain size of Mg-9Al alloy from 130.4μm to 13.1μm,and achieve an ultra-high grain refinement efficiency of 90%.The refinement mechanisms are that the Al_(4)C_(3)phase can act as a heterogeneous nucleation site forα-Mg grains due to the orientation relationship as(001)_(Al_(4)C_(3))//(002)Mg.Meanwhile,the particle distribution model shows that the velocity of MgO particles is much higher than the growth rate ofα-Mg grains.Therefore,it is pushed to the vicinity of grain boundaries during solidification,effectively limiting the growth ofα-Mg grains.The remarkable grain refinement effect was achieved through the synergistic modulation of Al_(4)C_(3)and MgO particles.This work may provide new insight into designing high efficiency grain refiners for Mg-Al alloys.
