Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an imp...Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.展开更多
Surface-adhering biofilms contribute significantly to irreversible biofouling and corrosion,presenting a multi-trillion-dollar annual problem in public health and industry.Strategies employing antibacterial elements a...Surface-adhering biofilms contribute significantly to irreversible biofouling and corrosion,presenting a multi-trillion-dollar annual problem in public health and industry.Strategies employing antibacterial elements are emerging to fabricate multifunctional coatings that effectively combat such microbially produced damage.However,rapid,reliable,and robust surface engineering remains challenging due to stability limitations and intricate anti-biofilm additive dynamics.Herein,a silver-capsule-conjugated polyurethane coating with high stability and antimicrobial efficacy in a cooperative manner is developed through controlled supramolecular self-assembly.Polyvinylpyrrolidone(PVP)-mediated molecule entanglement breaks through the incompatibility between polymeric components and nanomaterials,strengthening the dispersion and fixation of encapsulated silver nanoparticles.The facilitation and control of the nanoscale interfacial binding significantly suppresses the aggregation of inorganic nanoparticles and consequent microcracks development,giving rise to mechanical robustness and thermal stability of the hybrid coating under extreme conditions.A synergistic combination of exposed residues,electrostatic,and coordination interactions could readily integrate the resultant coating on virtually arbitrary material sur-faces.This composite coating exhibits broad-spectrum and high bactericidal efficiencies of 99.99% against Staphylococcus aureus and Escherichia coli,as well as excellent biofilm formation suppression.Moreover,our coating has robust resistance to microbial-influenced corrosion(MIC)and can even endure 720 h of salt spray.This study deciphers a general code for creating stable and durable nanohybrid coatings to mitigate microbially related risks.展开更多
Male sterile lines serve as a pivotal tool in plant breeding,offering an effective strategy for developing hybrid cultivars.In cucumber(Cucumis sativus L.),the creation of male sterile lines,most of which exhibit abno...Male sterile lines serve as a pivotal tool in plant breeding,offering an effective strategy for developing hybrid cultivars.In cucumber(Cucumis sativus L.),the creation of male sterile lines,most of which exhibit abnormal pollen development,is essential for harnessing heterosis.Accumulating evidence suggests that male sterility in plants is linked to the overaccumulation of Reactive Oxygen Species(ROS),which causes oxidative damage to biomolecules and cellular structures,ultimately leading to aberrant anther development(Li et al.,2004).展开更多
Prostate cancer(PCa)is a leading cause of cancer-related mortality among men.Radiotherapy is the cornerstone of PCa treatment.However,a major limitation of radiotherapy is the development of resistance,which compromis...Prostate cancer(PCa)is a leading cause of cancer-related mortality among men.Radiotherapy is the cornerstone of PCa treatment.However,a major limitation of radiotherapy is the development of resistance,which compromises treatment efficacy.Reactive oxygen species(ROS),which are generated by radiation,have a dual role in PCa by inducing DNA damage and apoptosis,while also promoting tumor progression and radioresistance.Elevated ROS levels enhance metabolic reprogramming,activate oncogenic pathways,and influence the tumor microenvironment by modulating immune responses and promoting the epithelial-mesenchymal transition(EMT).Key molecular mechanisms,including the Nrf2/Keap1 signaling axis,Bcl-2 mutations,and Speckle-type POZ protein alterations,contribute to radioresistance by enhancing antioxidant defenses and DNA repair capacity.Additionally,the interplay between hypoxia,androgen receptor variants(AR-Vs),and ferroptosis regulators further influence radiotherapy outcomes.Understanding these resistance mechanisms is crucial for developing targeted strategies to enhance radiosensitivity and improve therapeutic outcomes in PCa patients.展开更多
基金supported by the National Natural Science Foundation of China(82270386,82070252,and 8207025)the Zhejiang Provincial Medical and Health Science and Technology Plan(2023RC020)the Zhejiang Provincial Natural Science Foundation(LR21H020001).
文摘Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.
基金supported by the National Key Research and Development Program of China(Grant No.2022YFB3808800,Dake Xu)the National Natural Science Foundation of China(Grant Nos.U2006219(Dake Xu),52301081(Xiangyu Li))+4 种基金the National Postdoctoral Program for Innovative Talents(Grant No.BX20220059,Xiangyu Li)the China Postdoctoral Science Foundation(Grant No.2022M720677,Xiangyu Li)the Liaoning Provincial Natural Science Foundation of China(Grant No.2023-BS-052,Xiangyu Li)the Fundamental Research Funds for the Central Universities(Grant No.N2302015,Xiangyu Li)the State Key Laboratory of Marine Coatings Funded Project(Grant No.2024020800027,Xiangyu Li).
文摘Surface-adhering biofilms contribute significantly to irreversible biofouling and corrosion,presenting a multi-trillion-dollar annual problem in public health and industry.Strategies employing antibacterial elements are emerging to fabricate multifunctional coatings that effectively combat such microbially produced damage.However,rapid,reliable,and robust surface engineering remains challenging due to stability limitations and intricate anti-biofilm additive dynamics.Herein,a silver-capsule-conjugated polyurethane coating with high stability and antimicrobial efficacy in a cooperative manner is developed through controlled supramolecular self-assembly.Polyvinylpyrrolidone(PVP)-mediated molecule entanglement breaks through the incompatibility between polymeric components and nanomaterials,strengthening the dispersion and fixation of encapsulated silver nanoparticles.The facilitation and control of the nanoscale interfacial binding significantly suppresses the aggregation of inorganic nanoparticles and consequent microcracks development,giving rise to mechanical robustness and thermal stability of the hybrid coating under extreme conditions.A synergistic combination of exposed residues,electrostatic,and coordination interactions could readily integrate the resultant coating on virtually arbitrary material sur-faces.This composite coating exhibits broad-spectrum and high bactericidal efficiencies of 99.99% against Staphylococcus aureus and Escherichia coli,as well as excellent biofilm formation suppression.Moreover,our coating has robust resistance to microbial-influenced corrosion(MIC)and can even endure 720 h of salt spray.This study deciphers a general code for creating stable and durable nanohybrid coatings to mitigate microbially related risks.
基金supported by the Project of National Key Research and Development Program‘Strategic Science and Technology Innovation Cooperation’Key Special Project(Grant No.2023YFE0206900)the 2115 Talent Development Program of China Agricultural University,the 111 project(B17043)the Project of Yazhouwan Scientific,Technological Administration of Sanya.
文摘Male sterile lines serve as a pivotal tool in plant breeding,offering an effective strategy for developing hybrid cultivars.In cucumber(Cucumis sativus L.),the creation of male sterile lines,most of which exhibit abnormal pollen development,is essential for harnessing heterosis.Accumulating evidence suggests that male sterility in plants is linked to the overaccumulation of Reactive Oxygen Species(ROS),which causes oxidative damage to biomolecules and cellular structures,ultimately leading to aberrant anther development(Li et al.,2004).
基金supported by grants from Ningbo Yongjiang Talent programme-Project for Innovative Talents(Grant No.20240340)Jinhua Science and Technology Bureau(Grant No.2022-4-258)2022 Shandong Medical Association Clinical Research Special Fund for Dynamic Monitoring of Lymphocyte Subpopulations by Flow Cytometry(Grant No.YXH2022ZX03227)。
文摘Prostate cancer(PCa)is a leading cause of cancer-related mortality among men.Radiotherapy is the cornerstone of PCa treatment.However,a major limitation of radiotherapy is the development of resistance,which compromises treatment efficacy.Reactive oxygen species(ROS),which are generated by radiation,have a dual role in PCa by inducing DNA damage and apoptosis,while also promoting tumor progression and radioresistance.Elevated ROS levels enhance metabolic reprogramming,activate oncogenic pathways,and influence the tumor microenvironment by modulating immune responses and promoting the epithelial-mesenchymal transition(EMT).Key molecular mechanisms,including the Nrf2/Keap1 signaling axis,Bcl-2 mutations,and Speckle-type POZ protein alterations,contribute to radioresistance by enhancing antioxidant defenses and DNA repair capacity.Additionally,the interplay between hypoxia,androgen receptor variants(AR-Vs),and ferroptosis regulators further influence radiotherapy outcomes.Understanding these resistance mechanisms is crucial for developing targeted strategies to enhance radiosensitivity and improve therapeutic outcomes in PCa patients.
