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
Bisphenol A(BPA)is an industrial pollutant that can cause immune impairment.Selenium acts as an antioxidant,as selenium deficiency often accompanies oxidative stress,resulting in organ damage.This study is the first t...Bisphenol A(BPA)is an industrial pollutant that can cause immune impairment.Selenium acts as an antioxidant,as selenium deficiency often accompanies oxidative stress,resulting in organ damage.This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell(MDCC-MSB-1)via oxidative stress-induced endoplasmic reticulum(ER)stress.We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days.The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities(T-AOC,CAT,and GSH-Px),accumulation of peroxides(H2O2 and MDA),significant upregulation of ER stress-relatedmarkers(GRP78,IER 1,PERK,EIF-2α,ATF4,and CHOP),a significant increase in iron ion levels,significant upregulation of pyroptosis-related gene(NLRP3,ASC,Caspase1,GSDMD,IL-18 and IL-1β),significantly increase ferroptosis-related genes(TFRC,COX2)and downregulate GPX4,HO-1,FTH,NADPH.In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results,demonstrating that the addition of antioxidant(NAC),ER stress inhibitor(TUDCA)and pyroptosis inhibitor(Vx765)alleviated oxidative stress,endoplasmic reticulum stress,pyroptosis,and ferroptosis.Overall,this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.展开更多
Teucrifarides A-D(1-4),four previously unreported neo-clerodane-type diterpenoids,combined with sixteen known analogs(5-20),were purified from Teucrium quadrifarium.The absolute forma of compounds 1-4 were determined ...Teucrifarides A-D(1-4),four previously unreported neo-clerodane-type diterpenoids,combined with sixteen known analogs(5-20),were purified from Teucrium quadrifarium.The absolute forma of compounds 1-4 were determined via spectroscopic and ECD calculation methods,together with X-ray crystallography experiments.Among them,compound 1 possessed a 5,20-epoxy ring featuring a unique cage-like 12-oxatricyclo[5.3.2.0^(1,6)]undecane skeleton.Meanwhile,2 incorporated a 6,20-epoxy ring with a novel 12-oxatricyclo[6.2.2.0^(2,7)]undecane skeleton.Compounds 1 and 12 exhibited significant inhibitory effects against HT-22 cells ferroptosis induced by RSL3,with EC_(50)values of 11.8±1.0μM,and 4.52±1.24μM,respectively.Moreover,ROS accumulation in HT22 cells treated with compound 1 was also observed.展开更多
During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and e...During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.展开更多
Bisphenol compounds(BPs)have various industrial uses and can enter the environment through various sources.To evaluate the ecotoxicity of BPs and identify potential gene candidates involved in the plant toxicity,Arabi...Bisphenol compounds(BPs)have various industrial uses and can enter the environment through various sources.To evaluate the ecotoxicity of BPs and identify potential gene candidates involved in the plant toxicity,Arabidopsis thaliana was exposed to bisphenol A(BPA),BPB,BPE,BPF,and BPS at 1,3,10 mg/L for a duration of 14 days,and their growth status were monitored.At day 14,roots and leaves were collected for internal BPs exposure concentration detection,RNA-seq(only roots),and morphological observations.As shown in the results,exposure to BPs significantly disturbed root elongation,exhibiting a trend of stimulation at low concentration and inhibition at high concentration.Additionally,BPs exhibited pronounced generation of reactive oxygen species,while none of the pollutants caused significant changes in root morphology.Internal exposure concentration analysis indicated that BPs tended to accumulate in the roots,with BPS exhibiting the highest level of accumulation.The results of RNA-seq indicated that the shared 211 differently expressed genes(DEGs)of these 5 exposure groups were enriched in defense response,generation of precursormetabolites,response to organic substance,response to oxygen-containing,response to hormone,oxidation-reduction process and so on.Regarding unique DEGs in each group,BPS wasmainly associated with the redox pathway,BPB primarily influenced seed germination,and BPA,BPE and BPF were primarily involved in metabolic signaling pathways.Our results provide newinsights for BPs induced adverse effects on Arabidopsis thaliana and suggest that the ecological risks associated with BPA alternatives cannot be ignored.展开更多
Utilizing small molecules as markers for specific cells or organs within biosystems is a crucial approach for studying and regulating physiological processes. However, current tagging strategies, due to the presence o...Utilizing small molecules as markers for specific cells or organs within biosystems is a crucial approach for studying and regulating physiological processes. However, current tagging strategies, due to the presence of exposed highly reactive groups, suffer from drawbacks such as low tagging efficiency or insufficient spatial specificity, thereby diminishing their expected effectiveness. Consequently, there is a pressing need to develop a strategy capable of in situ labeling of active groups in response to cellular or in vivo stimuli, ensuring both high tagging efficiency and spatial specificity. In this work, we devised a strategy for releasing aldehyde groups activated by hypochlorous acid(HOCl). Compounds synthesized through this strategy can release the fiuorophore methylene blue(MB) and aldehyde-based compounds upon HOCl activation. Given high reactivity of the released aldehyde group, it can effectively interact with macromolecules in biological systems, facilitating tagging and enabling prolonged imaging. To validate this concept, we further incorporated a naphthalimide structure with stable light emission to create SW-110. SW-110 can specifically respond to in vitro and endogenous HOCl, when release MB, it also releases naphthalimide fiuorophore with highly reactive aldehyde group for tagging within cells. This strategy provides a simple but efficient strategy for proximity tagging in situ.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
Background:Picropodophllotoxin(PPT),a principal component of Podophyllum hexandrum root,demonstrates various beneficial biological activities in multiple cancer types,including antitumor and antiproliferative properti...Background:Picropodophllotoxin(PPT),a principal component of Podophyllum hexandrum root,demonstrates various beneficial biological activities in multiple cancer types,including antitumor and antiproliferative properties.Despite its known effects,the specific mechanisms by which PPT induces apoptosis in oral squamous cell carcinoma(OSCC)cells lack full clarification.Aims:This study aimed to evaluate the role of PPT in inducing apoptosis in OSCC cells by targeting signal transducer and activator of transcription 3(STAT3)and to investigate the underlying molecular pathways.Methods:Human OSCC cell lines(HN22 and HSC4)were treated with PPT.Cell viability,colony formation,and apoptotic morphological changes were evaluated.Reactive oxygen species(ROS)generation and mitochondrial function were assessed using tetramethyl rhodamine methyl ester,MitoSOX,and 2′,7′-dichlorodihydrofluorescein diacetate(DCFH-DA)assays following PPT treatment.The expression of apoptosis markers,including cleaved Poly(ADP-Ribose)Polymerase(c-PARP)and other target proteins,was measured using western blotting.ROS involvement was further confirmed using the ROS scavenger N-acetylcysteine(NAC).Results:Treatment with PPT resulted in a substantial reduction in cell viability,a decrease in colony formation capacity,and evident morphological changes in OSCC cells.These effects were dose-and time-dependent,as evidenced by increased expression of c-PARP.PPT-induced apoptosis was mediated by excessive ROS generation,which was almost completely blocked by NAC pretreatment.Conclusions:These findings suggest that PPT may serve as a promising therapeutic agent for treating human oral cancer by inhibiting the STAT3 pathway and inducing ROS-mediated apoptosis.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
To explore the mechanism of sperm dysfunction caused by dibutyl phthalate(DBP),the effects of DBP on intracellular[Ca^(2+)]and[pH],reactive oxygen species(ROS),lipid peroxidation(LPO),mitochondrial permeability transi...To explore the mechanism of sperm dysfunction caused by dibutyl phthalate(DBP),the effects of DBP on intracellular[Ca^(2+)]and[pH],reactive oxygen species(ROS),lipid peroxidation(LPO),mitochondrial permeability transition pore(mPTP)opening,mitochondrial membrane potential(MMP),adenosine triphosphate(ATP)levels,phosphorylation of protein kinase A(PKA)substrate proteins and phosphotyrosine(p-Tyr)proteins,sperm motility,spontaneous acrosome reaction,and tail bending were examined in mouse spermatozoa.At 100μg/mL,DBP significantly increased tail bending and[Ca^(2+)]i.Interestingly,DBP showed biphasic effects on[pH]i.DBP at 10–100μg/mL significantly decreased sperm motility.Similarly,Ca^(2+)ionophore A23187 decreased[pH]_(i)sperm motility,suggesting that DBP-induced excessive[Ca^(2+)]_(i)decreased sperm motility.DBP significantly increased ROS and LPO.DBP at 100μg/mL significantly decreased mPTP closing,MMP,and ATP levels in spermatozoa,as did H2O2,indicative of ROS-mediatedmitochondrial dysfunction caused by DBP.DBP as well as H2O2 increased p-Tyr sperm proteins and phosphorylated PKA substrate sperm proteins.DBP at 1–10μg/mL significantly increased the spontaneous acrosome reaction,suggesting that DBP can activate sperm capacitation.Altogether,DBP showed a biphasic effect on intracellular signaling in spermatozoa.At concentrations relevant to seminal ortho-phthalate levels,DBP activates[pH]i,protein tyrosine kinases and PKA via physiological levels of ROS generation,potentiating sperm capacitation.DBP at high doses excessively raises[Ca^(2+)]_(i)and ROS and disrupts[pH]i,impairing the mitochondrial function,tail structural integrity,and sperm motility.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 Natural Science Foundation of China Regional Joint Innovation Fund (No.U22A20524)the Heilongjiang Province Natural Science Foundation Key projects (No.ZD2023C002).
文摘Bisphenol A(BPA)is an industrial pollutant that can cause immune impairment.Selenium acts as an antioxidant,as selenium deficiency often accompanies oxidative stress,resulting in organ damage.This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell(MDCC-MSB-1)via oxidative stress-induced endoplasmic reticulum(ER)stress.We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days.The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities(T-AOC,CAT,and GSH-Px),accumulation of peroxides(H2O2 and MDA),significant upregulation of ER stress-relatedmarkers(GRP78,IER 1,PERK,EIF-2α,ATF4,and CHOP),a significant increase in iron ion levels,significant upregulation of pyroptosis-related gene(NLRP3,ASC,Caspase1,GSDMD,IL-18 and IL-1β),significantly increase ferroptosis-related genes(TFRC,COX2)and downregulate GPX4,HO-1,FTH,NADPH.In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results,demonstrating that the addition of antioxidant(NAC),ER stress inhibitor(TUDCA)and pyroptosis inhibitor(Vx765)alleviated oxidative stress,endoplasmic reticulum stress,pyroptosis,and ferroptosis.Overall,this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.
基金supported by the National Natural Science Foundation of China(32100322,32460112,32060100)and the Science and Technology Department of Guizhou Province(QKHZC[2022]019).
文摘Teucrifarides A-D(1-4),four previously unreported neo-clerodane-type diterpenoids,combined with sixteen known analogs(5-20),were purified from Teucrium quadrifarium.The absolute forma of compounds 1-4 were determined via spectroscopic and ECD calculation methods,together with X-ray crystallography experiments.Among them,compound 1 possessed a 5,20-epoxy ring featuring a unique cage-like 12-oxatricyclo[5.3.2.0^(1,6)]undecane skeleton.Meanwhile,2 incorporated a 6,20-epoxy ring with a novel 12-oxatricyclo[6.2.2.0^(2,7)]undecane skeleton.Compounds 1 and 12 exhibited significant inhibitory effects against HT-22 cells ferroptosis induced by RSL3,with EC_(50)values of 11.8±1.0μM,and 4.52±1.24μM,respectively.Moreover,ROS accumulation in HT22 cells treated with compound 1 was also observed.
基金supported by grants fromthe Shenzhen Medical Research Fund(Grant No.A2302040).
文摘During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.
基金supported by the National Science Foundation of China (No.22106098)the Youth Science and Technology Research Foundation of Shanxi Province (No.20210302124298)+2 种基金the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (Nos.2020L0174,and 2020L0025)the Startup Foundation for Doctors of Shanxi Province (No.SD1917)the Startup Foundation for Doctors of Shanxi Medical University (No.XD1917).
文摘Bisphenol compounds(BPs)have various industrial uses and can enter the environment through various sources.To evaluate the ecotoxicity of BPs and identify potential gene candidates involved in the plant toxicity,Arabidopsis thaliana was exposed to bisphenol A(BPA),BPB,BPE,BPF,and BPS at 1,3,10 mg/L for a duration of 14 days,and their growth status were monitored.At day 14,roots and leaves were collected for internal BPs exposure concentration detection,RNA-seq(only roots),and morphological observations.As shown in the results,exposure to BPs significantly disturbed root elongation,exhibiting a trend of stimulation at low concentration and inhibition at high concentration.Additionally,BPs exhibited pronounced generation of reactive oxygen species,while none of the pollutants caused significant changes in root morphology.Internal exposure concentration analysis indicated that BPs tended to accumulate in the roots,with BPS exhibiting the highest level of accumulation.The results of RNA-seq indicated that the shared 211 differently expressed genes(DEGs)of these 5 exposure groups were enriched in defense response,generation of precursormetabolites,response to organic substance,response to oxygen-containing,response to hormone,oxidation-reduction process and so on.Regarding unique DEGs in each group,BPS wasmainly associated with the redox pathway,BPB primarily influenced seed germination,and BPA,BPE and BPF were primarily involved in metabolic signaling pathways.Our results provide newinsights for BPs induced adverse effects on Arabidopsis thaliana and suggest that the ecological risks associated with BPA alternatives cannot be ignored.
基金financially supported by the National Natural Science Foundation of China (Nos. 22177019, 22377010, 22371038)State Key Laboratory for Modification of Chemical Fibers and Polymer Materials (No. KF2206)。
文摘Utilizing small molecules as markers for specific cells or organs within biosystems is a crucial approach for studying and regulating physiological processes. However, current tagging strategies, due to the presence of exposed highly reactive groups, suffer from drawbacks such as low tagging efficiency or insufficient spatial specificity, thereby diminishing their expected effectiveness. Consequently, there is a pressing need to develop a strategy capable of in situ labeling of active groups in response to cellular or in vivo stimuli, ensuring both high tagging efficiency and spatial specificity. In this work, we devised a strategy for releasing aldehyde groups activated by hypochlorous acid(HOCl). Compounds synthesized through this strategy can release the fiuorophore methylene blue(MB) and aldehyde-based compounds upon HOCl activation. Given high reactivity of the released aldehyde group, it can effectively interact with macromolecules in biological systems, facilitating tagging and enabling prolonged imaging. To validate this concept, we further incorporated a naphthalimide structure with stable light emission to create SW-110. SW-110 can specifically respond to in vitro and endogenous HOCl, when release MB, it also releases naphthalimide fiuorophore with highly reactive aldehyde group for tagging within cells. This strategy provides a simple but efficient strategy for proximity tagging in situ.
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 Korea Institute of Toxicology(KIT)Research Program[No.2710008763(KK-2401-01)]the Korea Environmental Industry&Technology Institute(KEITI)through the Core Technology Development Project for Environmental Diseases Prevention and Management[No.2480000072(RS-2021-KE001705)]。
文摘Background:Picropodophllotoxin(PPT),a principal component of Podophyllum hexandrum root,demonstrates various beneficial biological activities in multiple cancer types,including antitumor and antiproliferative properties.Despite its known effects,the specific mechanisms by which PPT induces apoptosis in oral squamous cell carcinoma(OSCC)cells lack full clarification.Aims:This study aimed to evaluate the role of PPT in inducing apoptosis in OSCC cells by targeting signal transducer and activator of transcription 3(STAT3)and to investigate the underlying molecular pathways.Methods:Human OSCC cell lines(HN22 and HSC4)were treated with PPT.Cell viability,colony formation,and apoptotic morphological changes were evaluated.Reactive oxygen species(ROS)generation and mitochondrial function were assessed using tetramethyl rhodamine methyl ester,MitoSOX,and 2′,7′-dichlorodihydrofluorescein diacetate(DCFH-DA)assays following PPT treatment.The expression of apoptosis markers,including cleaved Poly(ADP-Ribose)Polymerase(c-PARP)and other target proteins,was measured using western blotting.ROS involvement was further confirmed using the ROS scavenger N-acetylcysteine(NAC).Results:Treatment with PPT resulted in a substantial reduction in cell viability,a decrease in colony formation capacity,and evident morphological changes in OSCC cells.These effects were dose-and time-dependent,as evidenced by increased expression of c-PARP.PPT-induced apoptosis was mediated by excessive ROS generation,which was almost completely blocked by NAC pretreatment.Conclusions:These findings suggest that PPT may serve as a promising therapeutic agent for treating human oral cancer by inhibiting the STAT3 pathway and inducing ROS-mediated apoptosis.
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.
基金supported by the National Research Foundation of Republic of Korea(NRF)grant funded by the Republic of Korea government(MSIT)(No.2022R1A2C1007831).
文摘To explore the mechanism of sperm dysfunction caused by dibutyl phthalate(DBP),the effects of DBP on intracellular[Ca^(2+)]and[pH],reactive oxygen species(ROS),lipid peroxidation(LPO),mitochondrial permeability transition pore(mPTP)opening,mitochondrial membrane potential(MMP),adenosine triphosphate(ATP)levels,phosphorylation of protein kinase A(PKA)substrate proteins and phosphotyrosine(p-Tyr)proteins,sperm motility,spontaneous acrosome reaction,and tail bending were examined in mouse spermatozoa.At 100μg/mL,DBP significantly increased tail bending and[Ca^(2+)]i.Interestingly,DBP showed biphasic effects on[pH]i.DBP at 10–100μg/mL significantly decreased sperm motility.Similarly,Ca^(2+)ionophore A23187 decreased[pH]_(i)sperm motility,suggesting that DBP-induced excessive[Ca^(2+)]_(i)decreased sperm motility.DBP significantly increased ROS and LPO.DBP at 100μg/mL significantly decreased mPTP closing,MMP,and ATP levels in spermatozoa,as did H2O2,indicative of ROS-mediatedmitochondrial dysfunction caused by DBP.DBP as well as H2O2 increased p-Tyr sperm proteins and phosphorylated PKA substrate sperm proteins.DBP at 1–10μg/mL significantly increased the spontaneous acrosome reaction,suggesting that DBP can activate sperm capacitation.Altogether,DBP showed a biphasic effect on intracellular signaling in spermatozoa.At concentrations relevant to seminal ortho-phthalate levels,DBP activates[pH]i,protein tyrosine kinases and PKA via physiological levels of ROS generation,potentiating sperm capacitation.DBP at high doses excessively raises[Ca^(2+)]_(i)and ROS and disrupts[pH]i,impairing the mitochondrial function,tail structural integrity,and sperm motility.
