Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,...Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.展开更多
目的探究核仁蛋白14(nucleolar protein 14,NOP14)过表达对卵巢癌SKOV3细胞增殖与迁移的影响及机制。方法检测卵巢癌细胞系(SKOV3、A2780、HO-8910、OVCAR)中NOP14的表达水平。SKOV3细胞中转染pcDNA-NOP14质粒以构建NOP14过表达细胞系...目的探究核仁蛋白14(nucleolar protein 14,NOP14)过表达对卵巢癌SKOV3细胞增殖与迁移的影响及机制。方法检测卵巢癌细胞系(SKOV3、A2780、HO-8910、OVCAR)中NOP14的表达水平。SKOV3细胞中转染pcDNA-NOP14质粒以构建NOP14过表达细胞系。细胞克隆形成实验和5-乙炔基-2′-脱氧尿苷(5-Ethynyl-2′-deoxyuridine,EdU)染色检测细胞增殖能力。无血清成球培养分析肿瘤干细胞特性。流式细胞术检测CD133阳性细胞比例。细胞形态学观察及上皮-间质转化(epithelial-mesenchymal transition,EMT)标志蛋白(E-cadherin、N-cadherin、Vimentin)检测评估EMT进程。蛋白质印迹和RT-qPCR检测核受体相互作用蛋白1(nuclear receptor interacting protein 1,NRIP1)及Wnt、β-catenin的表达水平。结果在卵巢癌细胞系中NOP14 mRNA和蛋白表达均显著低于正常卵巢上皮细胞。NOP14过表达后抑制SKOV3细胞增殖、干细胞特性及EMT转化(间质标志物N-cadherin、Vimentin下调,上皮标志物E-cadherin上调),以及NRIP1、Wnt和β-catenin的表达水平。结论NOP14可负向调控NRIP1和Wnt及β-catenin的表达,并抑制卵巢癌SKOV3细胞的增殖、干细胞特性及EMT进程。展开更多
This study investigated the impacts of spring runoff on the formation of halobenzoquinones(HBQs)and their correlation with common water quality parameters(WQPs)and aromatic amino acids(AAs)in source water.Source water...This study investigated the impacts of spring runoff on the formation of halobenzoquinones(HBQs)and their correlation with common water quality parameters(WQPs)and aromatic amino acids(AAs)in source water.Source water and treated water samples were collected at two drinking water treatment plants in 2021,2022,and 2023.HBQs and aromatic AAs were analyzed using solid phase extraction with high performance liquid chromatography–tandem mass spectrometry methods.The only HBQs detected in treated water were 2,6-dichloro-1,4-benzoquinone(DCBQ)and hydroxy–DCBQ(OH-DCBQ).The concentration of DCBQ was 3-4 times higher during spring runoff events than during non-spring-runoff periods,suggesting the impact of spring runoff on the formation of DCBQ.The DCBQ concentrations in finished water positively correlated with the color,dissolved organic carbon,total organic nitrogen,and specific ultraviolet absorbance WQPs of source water in 2021 and 2022.The temporal trend of the total aromatic AAs determined in source water was strongly and positively correlated to DCBQ in finished water.Finally,there was a significant positive correlation between the concentration of DCBQ determined immediately following the addition of chlorine and the presence of its transformation product,OH-DCBQ,in finished water.The results also showed that powdered activated carbon can remove some of the HBQ precursors in the sourcewater to reduce DCBQ formation.This study demonstrated that WQPs and aromatic AAs are useful indicators for the removal of precursors to reduce HBQ formation during drinking water treatment.展开更多
Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)...Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,wi...Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82172196(to KX),82372507(to KX)the Natural Science Foundation of Hunan Province,China,No.2023JJ40804(to QZ)the Key Laboratory of Emergency and Trauma(Hainan Medical University)of the Ministry of Education,China,No.KLET-202210(to QZ)。
文摘Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.
文摘目的探究核仁蛋白14(nucleolar protein 14,NOP14)过表达对卵巢癌SKOV3细胞增殖与迁移的影响及机制。方法检测卵巢癌细胞系(SKOV3、A2780、HO-8910、OVCAR)中NOP14的表达水平。SKOV3细胞中转染pcDNA-NOP14质粒以构建NOP14过表达细胞系。细胞克隆形成实验和5-乙炔基-2′-脱氧尿苷(5-Ethynyl-2′-deoxyuridine,EdU)染色检测细胞增殖能力。无血清成球培养分析肿瘤干细胞特性。流式细胞术检测CD133阳性细胞比例。细胞形态学观察及上皮-间质转化(epithelial-mesenchymal transition,EMT)标志蛋白(E-cadherin、N-cadherin、Vimentin)检测评估EMT进程。蛋白质印迹和RT-qPCR检测核受体相互作用蛋白1(nuclear receptor interacting protein 1,NRIP1)及Wnt、β-catenin的表达水平。结果在卵巢癌细胞系中NOP14 mRNA和蛋白表达均显著低于正常卵巢上皮细胞。NOP14过表达后抑制SKOV3细胞增殖、干细胞特性及EMT转化(间质标志物N-cadherin、Vimentin下调,上皮标志物E-cadherin上调),以及NRIP1、Wnt和β-catenin的表达水平。结论NOP14可负向调控NRIP1和Wnt及β-catenin的表达,并抑制卵巢癌SKOV3细胞的增殖、干细胞特性及EMT进程。
基金supported by grants from the Natural Sciences and Engineering Research Council of Canada(NSERC)Alberta Innovates,and the Canada Research Chairs Program.The authors acknowledge the support of the NSERC Postgraduate Doctoral Scholarship(NJPW),the Alberta Innovates Graduate Student Scholarship(KC),and the 75th Anniversary Graduate Student Award and the Graduate Student Recruitment Scholarship of the Faculty of Medicine and Dentistry at the University of Alberta(KNMC).
文摘This study investigated the impacts of spring runoff on the formation of halobenzoquinones(HBQs)and their correlation with common water quality parameters(WQPs)and aromatic amino acids(AAs)in source water.Source water and treated water samples were collected at two drinking water treatment plants in 2021,2022,and 2023.HBQs and aromatic AAs were analyzed using solid phase extraction with high performance liquid chromatography–tandem mass spectrometry methods.The only HBQs detected in treated water were 2,6-dichloro-1,4-benzoquinone(DCBQ)and hydroxy–DCBQ(OH-DCBQ).The concentration of DCBQ was 3-4 times higher during spring runoff events than during non-spring-runoff periods,suggesting the impact of spring runoff on the formation of DCBQ.The DCBQ concentrations in finished water positively correlated with the color,dissolved organic carbon,total organic nitrogen,and specific ultraviolet absorbance WQPs of source water in 2021 and 2022.The temporal trend of the total aromatic AAs determined in source water was strongly and positively correlated to DCBQ in finished water.Finally,there was a significant positive correlation between the concentration of DCBQ determined immediately following the addition of chlorine and the presence of its transformation product,OH-DCBQ,in finished water.The results also showed that powdered activated carbon can remove some of the HBQ precursors in the sourcewater to reduce DCBQ formation.This study demonstrated that WQPs and aromatic AAs are useful indicators for the removal of precursors to reduce HBQ formation during drinking water treatment.
基金supported by Guangdong Province Basic and Applied Basic Research Fund Project(2023A1515220104)Open Fund of Key Laboratory of Hepatoaplenic Surgery,Ministry of Education(Award Number:GPKF202407).
文摘Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.
基金funded by Shanghai Yangpu District Science and Technology Commission(Grant No.YPQ202303(Xuejing Lin))Shanghai Yangpu Hospital Foundation(Grant No.Se1202420(Wenchao Wang)and Ye1202423(Juan Huang)).
文摘Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.
