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
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
This study investigates the neuroprotective potential of extracellular vesicles(EVs)delivering quercetin-3-O-b-D-glucuronic acid(QG-EVs)in cerebral ischemia-reperfusion injury(CIRI).Targeted brain delivery of QG-EVs w...This study investigates the neuroprotective potential of extracellular vesicles(EVs)delivering quercetin-3-O-b-D-glucuronic acid(QG-EVs)in cerebral ischemia-reperfusion injury(CIRI).Targeted brain delivery of QG-EVs was confirmed,with neuron cells identified as pivotal in modulating CIRI through single-cell RNA sequencing(scRNA-seq).Activating transcription factor 4(Atf4)was highlighted as a critical regulatory factor,and in vitro studies revealed that silencing Atf4 diminished the neuroprotective effects of QG-EVs,increasing oxidative stress levels and neuronal apoptosis.In a CIRI mouse model,the knockdown of Atf4 attenuated the protective outcomes provided by QG-EVs,further affirming the role of Atf4 in mediating neuroprotection.Behavioral assessments and protein analysis showed that QG-EVs significantly reduced neuronal damage and pro-apoptotic markers,while improving neurological function via Atf4 upregulation.The outcomes hint at the potential of QG-EVs as a beneficial therapeutic modality to mitigate neuronal damage in CIRI by enhancing Atf4 expression,highlighting its potential for improving ischemic stroke outcomes.展开更多
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 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.
基金supported by Liaoning Xingliao Talent Program,China(Grant No.:YXMJ-JC-05).
文摘This study investigates the neuroprotective potential of extracellular vesicles(EVs)delivering quercetin-3-O-b-D-glucuronic acid(QG-EVs)in cerebral ischemia-reperfusion injury(CIRI).Targeted brain delivery of QG-EVs was confirmed,with neuron cells identified as pivotal in modulating CIRI through single-cell RNA sequencing(scRNA-seq).Activating transcription factor 4(Atf4)was highlighted as a critical regulatory factor,and in vitro studies revealed that silencing Atf4 diminished the neuroprotective effects of QG-EVs,increasing oxidative stress levels and neuronal apoptosis.In a CIRI mouse model,the knockdown of Atf4 attenuated the protective outcomes provided by QG-EVs,further affirming the role of Atf4 in mediating neuroprotection.Behavioral assessments and protein analysis showed that QG-EVs significantly reduced neuronal damage and pro-apoptotic markers,while improving neurological function via Atf4 upregulation.The outcomes hint at the potential of QG-EVs as a beneficial therapeutic modality to mitigate neuronal damage in CIRI by enhancing Atf4 expression,highlighting its potential for improving ischemic stroke outcomes.
