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
Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Method...Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Methods We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital,Southern Medical University from June 1,2020,to February 1,2022.An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels,with the primary outcome being the 7-day mortality rate post-ICU admission.Cox proportional hazards and Restricted Mean Survival Time(RMST)analyses were utilized to explore survival outcomes.Results A total of 321 sepsis patients were included.IL-6(HR 1.69,95%CI:1.22,2.34)and IL-10(HR 1.81,95%CI:1.37,2.40)emerged as independent predictors of 7-day mortality.Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups:Cluster 1(n=166,low inflammatory response),Cluster 2(n=99,moderate inflammatory response with immune suppression),and Cluster 3(n=56,strong inflammatory and immune suppression).Compared to Cluster 1,Clusters 2 and 3 had higher 7-day mortality risks(14.4%vs 23.2%,HR=4.30,95%CI:1.51-12.26;14.4%vs 35.7%,HR=7.32,95%CI:2.57-20.79).Conclusion Septic patients in a protective immune response state(Cluster 1)exhibit better short-term prognoses,suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.展开更多
Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar format...Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.展开更多
In non-small cell lung cancer(NSCLC),poly(ADP-ribose)polymerase 1(PARP1)induces genomic instability and promotes tumor progression by impairing DNA repair pathways.Although PARP1-targeting proteolysis-targeting chimer...In non-small cell lung cancer(NSCLC),poly(ADP-ribose)polymerase 1(PARP1)induces genomic instability and promotes tumor progression by impairing DNA repair pathways.Although PARP1-targeting proteolysis-targeting chimeras(PROTACs)offer a promising strategy for selective protein degradation,their clinical application remains limited by poor water solubility and insufficient tumor selectivity.Here,we report a pHresponsive magnetic nanoparticle system co-delivering β-lapachone(β-lap)and a PARP1-targeted PROTAC(PRO)for synergistic and tumor-targeting therapy.Designed with a hydrophobic self-assembled core and a magnetic coating,the nanoparticle(NP_(β-lap+PRO))enables pHresponsive drug release and magnetic resonance imaging(MRI)monitoring.β-Lap is a bioactivated drug that relies on NAD(P)H:quinone oxidoreductase 1(NQO1),which is overexpressed in NSCLC cells.It has the potential to deliver tumor-selective DNA damage and induce cell death.The NP_(β-lap+PRO) exploits elevated NQO1 levels in NSCLC to initiate β-lap-driven oxidative stress and DNA damage,while simultaneously enhancing PROTAC-mediated PARP1 degradation within the acidic tumor microenvironment synergistically induces apoptosis.In A549 NSCLC tumor models,this system effectively induces PARP1 degradation,blocks DNA repair,and preserves NAD(P)H pools,thereby amplifying β-lapinduced reactive oxygen species production,leading to enhanced DNA double-strand breaks and apoptosis.This study presents a biomarker-driven nanotherapeutic strategy that integrates PROTAC technology with redox-targeted combination therapy,offering a promising approach for precision treatment of NSCLC.展开更多
Objective:To investigate effect of oleanolic acid(OA)on atherosclerosis and its related mechanisms.Methods:Human umbilical vein endothelial cells(HUVECs)were injured by oxidized low-density lipoprotein for 24 h and tr...Objective:To investigate effect of oleanolic acid(OA)on atherosclerosis and its related mechanisms.Methods:Human umbilical vein endothelial cells(HUVECs)were injured by oxidized low-density lipoprotein for 24 h and treated with OA,and the levels of cell proliferation,migration,adhesion,and apoptosis were evaluated by BrdU staining,scratch healing assay,monocyte-endothelial cell adhesion assay and flow cytometry.The mice were fed with a high-fat diet to induce an atherosclerosis model,and treated with OA by gastric gavage.The mice were divided into the control group,the model group,and the OA administration group.The blood lipid and plaque formation in mice were detected.In addition,oxidative stress and mitochondrial structure and function changes in cells and mice were evaluated by transmission electron microscopy,JC-1 fluorescent probe,and Western blotting assays.The expression levels of proteins in the AMPK/Drp1 pathway were examined through Western blot.Results:OA markedly increased cell viability and migration rate of HUVECs,and decreased the adhesion rate of THP-1 cells and the apoptosis rate.OA significantly reduced serum lipid levels,such as total cholesterol and triglyceride,in mice and inhibited plaque formation in the aorta.OA also significantly increased the content of superoxide dismutase and catalase,alleviated mitochondrial damage,such as mitochondrial swelling and mitochondrial cristae reduction,reduced the number of mitochondria,increased adenosine triphosphate content,and significantly reduced p-Drp1(Ser616)/Drp1,MFF and FIS1 levels,increased p-AMPK/AMPK levels,activated AMPK,and then regulated DRP1 activity.Conclusions:OA activates AMPK,which in turn regulates the activity of DRP1 to restore normal mitochondrial dynamics and reduce atherosclerosis.展开更多
Oral squamous cell carcinoma(OSCC)is typified by extensive stromal fibrosis and an immunosuppressive microenvironment,both of which impede effective responses to immune checkpoint blockade.In this study,we identify pr...Oral squamous cell carcinoma(OSCC)is typified by extensive stromal fibrosis and an immunosuppressive microenvironment,both of which impede effective responses to immune checkpoint blockade.In this study,we identify prolyl 3-hydroxylase family member 4(P3H4)as a critical mediator of extracellular matrix(ECM)remodeling,epithelial-mesenchymal transition(EMT),and the exclusion of cytotoxic CD8+T lymphocytes.Elevated P3H4 expression correlates with unfavorable clinical outcomes and resistance to immunotherapy.Genetic ablation of P3H4 significantly attenuates tumor progression and promotes CD8^(+)T cell infiltration.To pharmacologically target P3H4,we engineered a liposomal formulation of 1,4-dihydrophenanthroline-2,5-dicarboxylic acid(1,4-DPCA),a small-molecule prolyl hydroxylase inhibitor.This nanomedicine,designated Lipo-1,4-DPCA,effectively downregulates P3H4 expression,mitigates tumor-associated fibrosis,reprograms the immune microenvironment,and elicits robust anti-tumor responses in vivo.Collectively,our findings establish P3H4 as a promising therapeutic target and highlight Lipo-1,4-DPCA as a dualfunctional nanotherapeutic candidate capable of enhancing the efficacy of immunotherapy in OSCC.展开更多
Atomically ordered precious intermetallic nanoparticles have garnered significant attention for diverse applications due to their well-defined surface atomic arrangements and exceptional electronic and geometric prope...Atomically ordered precious intermetallic nanoparticles have garnered significant attention for diverse applications due to their well-defined surface atomic arrangements and exceptional electronic and geometric properties.However,synthesizing non-precious ordered intermetallics that exhibit high stability under operating conditions remains a formidable challenge,primarily owing to their strong oxyphilicity,highly negative reduction potentials,and low corrosion resistance.In this work,we report a facile yet versatile seed-mediated solid-phase approach for fabricating uniform Ni_(3)Ga_(1) intermetallic nanocubes(NCs)fully encapsulated within N-doped carbon layers(denoted as Ni_(3)Ga_(1)@NC-800).Extensive characterization confirms the formation of a unique core-shell architecture,with atomic-resolution structural analysis and X-ray absorption fine structure measurements unequivocally verifying the atomically ordered Ni_(3)Ga_(1) intermetallic phase.The Ni_(3)Ga_(1)@NC-800 catalyst demonstrates exceptional performance in the 1,4-hydrogenation of α,β-unsaturated carbonyl compounds,exhibiting both remarkable activity and exclusive selectivity while maintaining high stability over multiple reaction cycles without observable performance decay.Combined experimental and theoretical calculations reveal that the strong interatomic p-d orbital hybridization facilitates electron transfer from Ga to Ni atoms,resulting in electron localization on ordered Ni atoms.This electronic configuration positively influences H_(2)activation and optimizes substrate adsorption strength,thereby substantially improving catalytic efficiency.Furthermore,this synthetic strategy proves generalizable,successfully extending to the synthesis of other non-precious ordered Ni_(1)Sn_(1) and Ni_(2)In_(3) intermetallics confined within N-doped carbon matrices.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。
文摘Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Methods We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital,Southern Medical University from June 1,2020,to February 1,2022.An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels,with the primary outcome being the 7-day mortality rate post-ICU admission.Cox proportional hazards and Restricted Mean Survival Time(RMST)analyses were utilized to explore survival outcomes.Results A total of 321 sepsis patients were included.IL-6(HR 1.69,95%CI:1.22,2.34)and IL-10(HR 1.81,95%CI:1.37,2.40)emerged as independent predictors of 7-day mortality.Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups:Cluster 1(n=166,low inflammatory response),Cluster 2(n=99,moderate inflammatory response with immune suppression),and Cluster 3(n=56,strong inflammatory and immune suppression).Compared to Cluster 1,Clusters 2 and 3 had higher 7-day mortality risks(14.4%vs 23.2%,HR=4.30,95%CI:1.51-12.26;14.4%vs 35.7%,HR=7.32,95%CI:2.57-20.79).Conclusion Septic patients in a protective immune response state(Cluster 1)exhibit better short-term prognoses,suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.
基金supported by the Health Commission of Hubei Province scientific research project(No.WJ2021M143)the Fundamental Research Funds for the Central Universities(No.413000714)+2 种基金the Research Fund of Anhui Institute of translational medicine(No.2023zhyx-C61)the Research Fund Project of Anhui Medical University(No.2022xkj148)Hubei Society of Pathology General Project(No.2025HBAP013).
文摘Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.
基金supported by the Key Laboratory of Advanced Interdisciplinary Studies,The First Affiliated Hospital of Guangzhou Medical University of China(No.2023A03J0355)OpenProject of State Key Laboratory of Respiratory Disease of China(No.SKIRD OP-202311)Guangdong Provincial Zhong Nanshan Medical Foundation of China(No.ZNS-XS-ZZ-202409-007).
文摘In non-small cell lung cancer(NSCLC),poly(ADP-ribose)polymerase 1(PARP1)induces genomic instability and promotes tumor progression by impairing DNA repair pathways.Although PARP1-targeting proteolysis-targeting chimeras(PROTACs)offer a promising strategy for selective protein degradation,their clinical application remains limited by poor water solubility and insufficient tumor selectivity.Here,we report a pHresponsive magnetic nanoparticle system co-delivering β-lapachone(β-lap)and a PARP1-targeted PROTAC(PRO)for synergistic and tumor-targeting therapy.Designed with a hydrophobic self-assembled core and a magnetic coating,the nanoparticle(NP_(β-lap+PRO))enables pHresponsive drug release and magnetic resonance imaging(MRI)monitoring.β-Lap is a bioactivated drug that relies on NAD(P)H:quinone oxidoreductase 1(NQO1),which is overexpressed in NSCLC cells.It has the potential to deliver tumor-selective DNA damage and induce cell death.The NP_(β-lap+PRO) exploits elevated NQO1 levels in NSCLC to initiate β-lap-driven oxidative stress and DNA damage,while simultaneously enhancing PROTAC-mediated PARP1 degradation within the acidic tumor microenvironment synergistically induces apoptosis.In A549 NSCLC tumor models,this system effectively induces PARP1 degradation,blocks DNA repair,and preserves NAD(P)H pools,thereby amplifying β-lapinduced reactive oxygen species production,leading to enhanced DNA double-strand breaks and apoptosis.This study presents a biomarker-driven nanotherapeutic strategy that integrates PROTAC technology with redox-targeted combination therapy,offering a promising approach for precision treatment of NSCLC.
文摘Objective:To investigate effect of oleanolic acid(OA)on atherosclerosis and its related mechanisms.Methods:Human umbilical vein endothelial cells(HUVECs)were injured by oxidized low-density lipoprotein for 24 h and treated with OA,and the levels of cell proliferation,migration,adhesion,and apoptosis were evaluated by BrdU staining,scratch healing assay,monocyte-endothelial cell adhesion assay and flow cytometry.The mice were fed with a high-fat diet to induce an atherosclerosis model,and treated with OA by gastric gavage.The mice were divided into the control group,the model group,and the OA administration group.The blood lipid and plaque formation in mice were detected.In addition,oxidative stress and mitochondrial structure and function changes in cells and mice were evaluated by transmission electron microscopy,JC-1 fluorescent probe,and Western blotting assays.The expression levels of proteins in the AMPK/Drp1 pathway were examined through Western blot.Results:OA markedly increased cell viability and migration rate of HUVECs,and decreased the adhesion rate of THP-1 cells and the apoptosis rate.OA significantly reduced serum lipid levels,such as total cholesterol and triglyceride,in mice and inhibited plaque formation in the aorta.OA also significantly increased the content of superoxide dismutase and catalase,alleviated mitochondrial damage,such as mitochondrial swelling and mitochondrial cristae reduction,reduced the number of mitochondria,increased adenosine triphosphate content,and significantly reduced p-Drp1(Ser616)/Drp1,MFF and FIS1 levels,increased p-AMPK/AMPK levels,activated AMPK,and then regulated DRP1 activity.Conclusions:OA activates AMPK,which in turn regulates the activity of DRP1 to restore normal mitochondrial dynamics and reduce atherosclerosis.
基金supported by grants from the National Natural Science Foundation of China(Nos.82501207,81700993,52403312,and 82571151)Postdoctoral Fellowship Program of CPSF(No.GZC20251219)+1 种基金the Beijing Nova Program(No.20250484855)the Beijing Natural Science Foundation(No.L252168).
文摘Oral squamous cell carcinoma(OSCC)is typified by extensive stromal fibrosis and an immunosuppressive microenvironment,both of which impede effective responses to immune checkpoint blockade.In this study,we identify prolyl 3-hydroxylase family member 4(P3H4)as a critical mediator of extracellular matrix(ECM)remodeling,epithelial-mesenchymal transition(EMT),and the exclusion of cytotoxic CD8+T lymphocytes.Elevated P3H4 expression correlates with unfavorable clinical outcomes and resistance to immunotherapy.Genetic ablation of P3H4 significantly attenuates tumor progression and promotes CD8^(+)T cell infiltration.To pharmacologically target P3H4,we engineered a liposomal formulation of 1,4-dihydrophenanthroline-2,5-dicarboxylic acid(1,4-DPCA),a small-molecule prolyl hydroxylase inhibitor.This nanomedicine,designated Lipo-1,4-DPCA,effectively downregulates P3H4 expression,mitigates tumor-associated fibrosis,reprograms the immune microenvironment,and elicits robust anti-tumor responses in vivo.Collectively,our findings establish P3H4 as a promising therapeutic target and highlight Lipo-1,4-DPCA as a dualfunctional nanotherapeutic candidate capable of enhancing the efficacy of immunotherapy in OSCC.
基金financially supported by the program of the National Natural Science Foundation of Shandong Province(No.ZR2023ZD23)the Shandong Province Key Research and Development Plan(No.2023CXGC010607).
文摘Atomically ordered precious intermetallic nanoparticles have garnered significant attention for diverse applications due to their well-defined surface atomic arrangements and exceptional electronic and geometric properties.However,synthesizing non-precious ordered intermetallics that exhibit high stability under operating conditions remains a formidable challenge,primarily owing to their strong oxyphilicity,highly negative reduction potentials,and low corrosion resistance.In this work,we report a facile yet versatile seed-mediated solid-phase approach for fabricating uniform Ni_(3)Ga_(1) intermetallic nanocubes(NCs)fully encapsulated within N-doped carbon layers(denoted as Ni_(3)Ga_(1)@NC-800).Extensive characterization confirms the formation of a unique core-shell architecture,with atomic-resolution structural analysis and X-ray absorption fine structure measurements unequivocally verifying the atomically ordered Ni_(3)Ga_(1) intermetallic phase.The Ni_(3)Ga_(1)@NC-800 catalyst demonstrates exceptional performance in the 1,4-hydrogenation of α,β-unsaturated carbonyl compounds,exhibiting both remarkable activity and exclusive selectivity while maintaining high stability over multiple reaction cycles without observable performance decay.Combined experimental and theoretical calculations reveal that the strong interatomic p-d orbital hybridization facilitates electron transfer from Ga to Ni atoms,resulting in electron localization on ordered Ni atoms.This electronic configuration positively influences H_(2)activation and optimizes substrate adsorption strength,thereby substantially improving catalytic efficiency.Furthermore,this synthetic strategy proves generalizable,successfully extending to the synthesis of other non-precious ordered Ni_(1)Sn_(1) and Ni_(2)In_(3) intermetallics confined within N-doped carbon matrices.
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.
