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titled“Overexpression of miR-1283 Inhibits Cell Proliferation and Invasion of Glioma Cells by Targeting ATF4”has been retracted from Oncology Research,Vol.27,No.3,2019,pp.325–334.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
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
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
Small modular reactors have received widespread attention owing to their inherent safety,low investment,and flexibility.Small pressurized water reactors(SPWRs)have become important candidates for SMRs owing to their h...Small modular reactors have received widespread attention owing to their inherent safety,low investment,and flexibility.Small pressurized water reactors(SPWRs)have become important candidates for SMRs owing to their high technological maturity.Since the Fukushima accident,research on accident-tolerant fuels(ATFs),which are more resistant to serious accidents than conventional fuels,has gradually increased.This study analyzes the neutronics and thermal hydraulics of an SPWR(ACPR50S)for different ATFs,BeO+UO_(2)−SiC,BeO+UO_(2)−FeCrAl,U_(3)Si_(2)−SiC,and U_(3)Si_(2)−FeCrAl,based on a PWR fuel management code,the Bamboo-C deterministic code.In the steady state,the burnup calculations,reactivity coefficients,power and temperature distributions,and control rod reactivity worth were studied.The transients of the control rod ejection accident for the two control rods with the maximum and minimum reactivity worth were analyzed.The results showed that 5%B-10 enrichment in the wet annular burnable absorbers assembly can effectively reduce the initial reactivity and end-of-life reactivity penalty.The BeO+UO2−SiC core exhibited superior neutronic characteristics in terms of burnup and negative temperature reactivity compared with the other three cases owing to the strong moderation ability of BeO+UO_(2)and low neutron absorption of SiC.However,the U_(3)Si_(2)core had a marginally better power-flattening effect than BeO+UO_(2),and the differential worth of each control rod group was similar between different ATFs.During the transient of a control rod ejection,the changes in the fuel temperature,coolant temperature,and coolant density were similar.The maximum difference was less than 10℃ for the fuel temperature and 2℃ for the coolant temperature.展开更多
Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tu...Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors,has yet to be investigated in combination with radiotherapy.This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.Methods:Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo.Reactive oxygen species(ROS),lipid peroxidation assays,and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death.Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.Results:The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo.Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4,the expression of which was elevated in response to radiation as an adaptive mechanism.Consequently,nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.Conclusion:These findings support the use of nintedanib in combination with radiotherapy as an effective,low-toxicity treatment strategy,highlighting the antitumor potential of ATF4-targeted agents.展开更多
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.
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 National Natural Science Foundation of China (No. 12205150)Natural Science Foundation of Jiangsu Province (No. BK20210304)+1 种基金China Postdoctoral Science Foundation (Nos. 2020M681594 and 2019TQ0148)Jiangsu Province Postdoctoral Science Foundation (Nos. 2020Z231)
文摘Small modular reactors have received widespread attention owing to their inherent safety,low investment,and flexibility.Small pressurized water reactors(SPWRs)have become important candidates for SMRs owing to their high technological maturity.Since the Fukushima accident,research on accident-tolerant fuels(ATFs),which are more resistant to serious accidents than conventional fuels,has gradually increased.This study analyzes the neutronics and thermal hydraulics of an SPWR(ACPR50S)for different ATFs,BeO+UO_(2)−SiC,BeO+UO_(2)−FeCrAl,U_(3)Si_(2)−SiC,and U_(3)Si_(2)−FeCrAl,based on a PWR fuel management code,the Bamboo-C deterministic code.In the steady state,the burnup calculations,reactivity coefficients,power and temperature distributions,and control rod reactivity worth were studied.The transients of the control rod ejection accident for the two control rods with the maximum and minimum reactivity worth were analyzed.The results showed that 5%B-10 enrichment in the wet annular burnable absorbers assembly can effectively reduce the initial reactivity and end-of-life reactivity penalty.The BeO+UO2−SiC core exhibited superior neutronic characteristics in terms of burnup and negative temperature reactivity compared with the other three cases owing to the strong moderation ability of BeO+UO_(2)and low neutron absorption of SiC.However,the U_(3)Si_(2)core had a marginally better power-flattening effect than BeO+UO_(2),and the differential worth of each control rod group was similar between different ATFs.During the transient of a control rod ejection,the changes in the fuel temperature,coolant temperature,and coolant density were similar.The maximum difference was less than 10℃ for the fuel temperature and 2℃ for the coolant temperature.
基金supported by State Key Program of National Natural Science Foundation of China(Grant No.82130092)the General Program of National Natural Science Foundation of China(Grant No.82373522)the National Natural Science Foundation of China(Grant No.82404196).
文摘Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors,has yet to be investigated in combination with radiotherapy.This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.Methods:Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo.Reactive oxygen species(ROS),lipid peroxidation assays,and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death.Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.Results:The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo.Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4,the expression of which was elevated in response to radiation as an adaptive mechanism.Consequently,nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.Conclusion:These findings support the use of nintedanib in combination with radiotherapy as an effective,low-toxicity treatment strategy,highlighting the antitumor potential of ATF4-targeted agents.
