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
Objective:Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer.However,its clinical application is often limited by adverse effects on normal tissues,especially...Objective:Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer.However,its clinical application is often limited by adverse effects on normal tissues,especially the kidneys.Understanding the molecular mechanisms of cisplatin-induced nephrotoxicity is crucial for developing strategies to mitigate its side effects.In this study,we aimed to elucidate the molecular mechanisms underlying cisplatin-induced DNA damage and apoptosis in human renal epithelial cells,with a focus on key signaling pathways and mediators that drive nephrotoxicity.Methods:To explore these mechanisms,human proximal tubule epithelial cells(HK-2)were treated with cisplatin.The study assessed DNA damage response(DDR)and stress-related protein expression,cell cycle distribution,and apoptosis.Activation of mitogen-activated protein kinases(MAPKs),particularly Extracellular signal-regulated Kinase(ERK),was analyzed,along with the expression and functional role of activating transcription factor 3(ATF3)and tumor protein p53(p53).Results:Cisplatin treatment upregulated DDR and stress response proteins,induced S phase arrest,and increased the SubG1 population,indicating apoptotic cell death.ERK was identified as a critical mediator of cisplatin-induced DNA damage and stress responses.ATF3 expression was significantly elevated in an ERK-dependent manner and required p53 activation.Knockdown of ATF3 reduced cisplatin-induced DNA damage,highlighting its role in the cytotoxic response.Conclusions:Cisplatin induces nephrotoxicity through ERK-and p53-dependent upregulation of ATF3,which is associated with DNA damage and cell death,suggesting a modulatory role in the cellular stress response.These findings provide novel insights into the molecular basis of cisplatin-induced renal injury and suggest potential therapeutic targets to alleviate its adverse effects.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
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.
基金supported by the research grant of Gyeongsang National University in 2023supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(RS-2025-00516213)+3 种基金the Brain Pool Program of the National Research Foundation(NRF)of Korea funded by theKorea government(MSIT)(RS-2025-25439144)AKorea Basic Science Institute(National Research Facilities and Equipment Center)grant funded by the Ministry of Education(2022R1A6C10B724)supported by the Regional Innovation System&Education(RISE)programthrough the RISE Center,Gyeongsangnam-do Provincial Government,Republic of Korea(2025-RISE-16-001)Learning&Academic research institution for Master’s⋅PhD students,and Postdocs(LAMP)Program of the National Research Foundation of Korea(NRF)grant funded by the Ministry of Education(RS-2023-00301974 and RS-2023-00301914).
文摘Objective:Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer.However,its clinical application is often limited by adverse effects on normal tissues,especially the kidneys.Understanding the molecular mechanisms of cisplatin-induced nephrotoxicity is crucial for developing strategies to mitigate its side effects.In this study,we aimed to elucidate the molecular mechanisms underlying cisplatin-induced DNA damage and apoptosis in human renal epithelial cells,with a focus on key signaling pathways and mediators that drive nephrotoxicity.Methods:To explore these mechanisms,human proximal tubule epithelial cells(HK-2)were treated with cisplatin.The study assessed DNA damage response(DDR)and stress-related protein expression,cell cycle distribution,and apoptosis.Activation of mitogen-activated protein kinases(MAPKs),particularly Extracellular signal-regulated Kinase(ERK),was analyzed,along with the expression and functional role of activating transcription factor 3(ATF3)and tumor protein p53(p53).Results:Cisplatin treatment upregulated DDR and stress response proteins,induced S phase arrest,and increased the SubG1 population,indicating apoptotic cell death.ERK was identified as a critical mediator of cisplatin-induced DNA damage and stress responses.ATF3 expression was significantly elevated in an ERK-dependent manner and required p53 activation.Knockdown of ATF3 reduced cisplatin-induced DNA damage,highlighting its role in the cytotoxic response.Conclusions:Cisplatin induces nephrotoxicity through ERK-and p53-dependent upregulation of ATF3,which is associated with DNA damage and cell death,suggesting a modulatory role in the cellular stress response.These findings provide novel insights into the molecular basis of cisplatin-induced renal injury and suggest potential therapeutic targets to alleviate its adverse effects.
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.
