Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilizationinduced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1(Prmt1) in thi...Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilizationinduced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1(Prmt1) in this process.Methods: 8-week-old male C57BL/6J mice were carried out combined exercise for 10 weeks. One week before the end of the intervention, mice underwent cast immobilization. Additionally, to investigate the potential mechanism in exercise-induced protection of skeletal muscle, mice in the exercise preconditioning group were administered TC-E-5003(an inhibitor of Prmt1 enzymatic activity). Exercise performance, muscle mass, and the cross-sectional area(CSA) of muscle fibers were analyzed. Besides, Prmt1 and Sestrin1(Sesn1) were either overexpressed or inhibited in C2C12 myotubes to elucidate the underlying mechanism.Results: Exercise preconditioning not only significantly improved muscle mass and motor ability in immobilized mice but also inhibited excessive activation of degradation pathways and enhanced protein synthesis. Importantly, Prmt1 mediated the protective effects of exercise preconditioning on muscle atrophy. Mechanistically,Prmt1 regulated the p38 mitogen-activated protein kinase(p38)/activating transcription factor 2(ATF2)pathway, which modulates Sesn1 expression. Sesn1 acts as a downstream of Prmt1 and ATF2, contributing to the myoblast differentiation and skeletal muscle regeneration through AMP-Activated protein kinase α2(AMPKα2)/transcriptional co-activator PPAR-γ co-activator-1 α(PGC-1α) signaling pathway.Conclusions: Taken together, our results highlighted the effectiveness of exercise preconditioning in preventing muscle atrophy via the Prmt1-Sesn1 pathway.展开更多
The published article titled“Overexpression of miR-1283 Inhibits Cell Proliferation and Invasion of Glioma Cells by Targeting ATF4”has been retracted from Oncology Research,Vol.27,No.3,2019,pp.325–334.
Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper th...Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper the clinical application.Numerous evidences support macrophages as the key immune cells during bone remodeling.Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2;R26GFP lineage tracing system.Fluorescence staining,flow cytometry analysis,and western blot determined the significantly enhanced expression of binding immunoglobulin protein(BiP)and emphasized the activation of sensor activating transcription factor 6(ATF6)in macrophages.Then,we verified that macrophage specific ATF6 deletion(ATF6f/f;CX3CR1CreERT2 mice)decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy.In contrast,macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement.In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6.At the mechanism level,RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfαpromotor and augmenting its transcription.Additionally,molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element(ERSE).Taken together,ATF6 may aggravate orthodontic bone remodeling by promoting Tnfαtranscription in macrophages,suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.展开更多
Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression...Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression Omnibus(GEO)datasets showed that ZFP36 was a differentially expressed gene(DEG)in OS.Western blot and immunohistochemistry results showed that ZFP36 was downregulated in OS tumors and cell lines.ZFP36 overexpression plasmids and small interfering RNAs(siRNAs)were respectively transfected into OS cells.ZFP36 overexpression restrained proliferation,migration,and invasion in MG63 and U2OS cells,while ZFP36 knockdown displayed the opposite results.Moreover,ZFP36 overexpression increased the levels of intracellular Fe2t,reactive oxygen species(ROS),and malondialdehyde(MDA),and decreased the levels of glutathione(GSH),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11).ZFP36 overexpression disturbed mitochondrial membrane potential(MMP)and mitochondrial morphology in OS cells.However,ZFP36 knockdown had the opposite results.Mechanistic studies indicated that ZFP36 promoted E2F transcription factor 1(E2F1)messenger RNA(mRNA)degradation by binding to the AU-rich elements(AREs)within E2F130 untranslated region(30UTR)in OS cells.E2F1 overexpression abrogated the effects of ZFP36 overexpression on malignant progression,ferroptosis,and mitochondrial dysfunction in OS cells.Furthermore,E2F1 promoted the transcription activation of activating transcription factor 4(ATF4)by binding to ATF4 promoter.E2F1 knockdown inhibited malignant progression,and promoted ferroptosis and mitochondrial dysfunction in OS cells,which was abrogated by ATF4 overexpression.Additionally,MG63 cells transfected with lentivirus ZFP36 overexpression vector(Lv-ZFP36)were injected into nude mice and tumor growth was monitored.ZFP36 overexpression significantly suppressed OS tumor growth under in vivo settings.In conclusion,ZFP36 overexpression promoted ferroptosis and mitochondrial dysfunction and inhibited malignant progression in OS by regulating the E2F1/ATF4 axis.We may provide the promising ZFP36 target for OS treatment.展开更多
Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulat...Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.展开更多
基金funded by research grants from the National Natural Science Foundation of China (32171135 and 32371168)。
文摘Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilizationinduced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1(Prmt1) in this process.Methods: 8-week-old male C57BL/6J mice were carried out combined exercise for 10 weeks. One week before the end of the intervention, mice underwent cast immobilization. Additionally, to investigate the potential mechanism in exercise-induced protection of skeletal muscle, mice in the exercise preconditioning group were administered TC-E-5003(an inhibitor of Prmt1 enzymatic activity). Exercise performance, muscle mass, and the cross-sectional area(CSA) of muscle fibers were analyzed. Besides, Prmt1 and Sestrin1(Sesn1) were either overexpressed or inhibited in C2C12 myotubes to elucidate the underlying mechanism.Results: Exercise preconditioning not only significantly improved muscle mass and motor ability in immobilized mice but also inhibited excessive activation of degradation pathways and enhanced protein synthesis. Importantly, Prmt1 mediated the protective effects of exercise preconditioning on muscle atrophy. Mechanistically,Prmt1 regulated the p38 mitogen-activated protein kinase(p38)/activating transcription factor 2(ATF2)pathway, which modulates Sesn1 expression. Sesn1 acts as a downstream of Prmt1 and ATF2, contributing to the myoblast differentiation and skeletal muscle regeneration through AMP-Activated protein kinase α2(AMPKα2)/transcriptional co-activator PPAR-γ co-activator-1 α(PGC-1α) signaling pathway.Conclusions: Taken together, our results highlighted the effectiveness of exercise preconditioning in preventing muscle atrophy via the Prmt1-Sesn1 pathway.
文摘The published article titled“Overexpression of miR-1283 Inhibits Cell Proliferation and Invasion of Glioma Cells by Targeting ATF4”has been retracted from Oncology Research,Vol.27,No.3,2019,pp.325–334.
基金supported by the National Natural Science Foundation of China(82071143,82371000,82270361)Key Research and Development Program of Jiangsu Province(BE2022795)+2 种基金the Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_1801)the Jiangsu Province Capability Improvement Project through the Science,Technology and Education-Jiangsu Provincial Research Hospital Cultivation Unit(YJXYYJSDW4)Jiangsu Provincial Medical Innovation Center(CXZX202227).
文摘Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper the clinical application.Numerous evidences support macrophages as the key immune cells during bone remodeling.Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2;R26GFP lineage tracing system.Fluorescence staining,flow cytometry analysis,and western blot determined the significantly enhanced expression of binding immunoglobulin protein(BiP)and emphasized the activation of sensor activating transcription factor 6(ATF6)in macrophages.Then,we verified that macrophage specific ATF6 deletion(ATF6f/f;CX3CR1CreERT2 mice)decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy.In contrast,macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement.In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6.At the mechanism level,RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfαpromotor and augmenting its transcription.Additionally,molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element(ERSE).Taken together,ATF6 may aggravate orthodontic bone remodeling by promoting Tnfαtranscription in macrophages,suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
基金funding support from the hospital-level project of Taizhou People's Hospital(Project No.:ZL201944).
文摘Zinc finger protein 36(ZFP36)was found to be downregulated in osteosarcoma(OS)tumor tissues.We aimed to investigate the roles and mechanisms of ZFP36 in ferroptosis regulation during OS development.Two Gene Expression Omnibus(GEO)datasets showed that ZFP36 was a differentially expressed gene(DEG)in OS.Western blot and immunohistochemistry results showed that ZFP36 was downregulated in OS tumors and cell lines.ZFP36 overexpression plasmids and small interfering RNAs(siRNAs)were respectively transfected into OS cells.ZFP36 overexpression restrained proliferation,migration,and invasion in MG63 and U2OS cells,while ZFP36 knockdown displayed the opposite results.Moreover,ZFP36 overexpression increased the levels of intracellular Fe2t,reactive oxygen species(ROS),and malondialdehyde(MDA),and decreased the levels of glutathione(GSH),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11).ZFP36 overexpression disturbed mitochondrial membrane potential(MMP)and mitochondrial morphology in OS cells.However,ZFP36 knockdown had the opposite results.Mechanistic studies indicated that ZFP36 promoted E2F transcription factor 1(E2F1)messenger RNA(mRNA)degradation by binding to the AU-rich elements(AREs)within E2F130 untranslated region(30UTR)in OS cells.E2F1 overexpression abrogated the effects of ZFP36 overexpression on malignant progression,ferroptosis,and mitochondrial dysfunction in OS cells.Furthermore,E2F1 promoted the transcription activation of activating transcription factor 4(ATF4)by binding to ATF4 promoter.E2F1 knockdown inhibited malignant progression,and promoted ferroptosis and mitochondrial dysfunction in OS cells,which was abrogated by ATF4 overexpression.Additionally,MG63 cells transfected with lentivirus ZFP36 overexpression vector(Lv-ZFP36)were injected into nude mice and tumor growth was monitored.ZFP36 overexpression significantly suppressed OS tumor growth under in vivo settings.In conclusion,ZFP36 overexpression promoted ferroptosis and mitochondrial dysfunction and inhibited malignant progression in OS by regulating the E2F1/ATF4 axis.We may provide the promising ZFP36 target for OS treatment.
基金supported by the Jiangsu Provincial Medical Key Discipline(Laboratory)Cultivation Unit(JSDW202249)the Natural Science Foundation of Jiangsu Province(BK20211108)+4 种基金a Scientific Research Project of the Health Commission of Nantong(MS2023035)Nantong Natural Science Foundation(JC2023114)the Scientific Research Innovation Team of Kangda College of Nanjing Medical University(KD2022KYCXTD005)Nantong University Clinical Medicine Special Project(2022JY005)the Postgraduate Research&Practice Innovation Program of Jiangsu province(KYCX23_3416).
文摘Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.
