Background:The level of premature deaths(deaths among those aged 30-69 years)caused by cancer is an important indicator of evaluating the level of cancer prevention and control.However,the current burden and temporal ...Background:The level of premature deaths(deaths among those aged 30-69 years)caused by cancer is an important indicator of evaluating the level of cancer prevention and control.However,the current burden and temporal trends in cancer-related premature deaths,and their impact on life expectancy at the global,regional,and national levels are not clear.Methods:Cancer mortality data for 185 countries were obtained from the GLOBOCAN 2022 database.High-quality cancer mortality data and national population statistics for 47 countries were extracted from the United Nations and national cancer registry databases,covering the period 2003-2022.Countries were classified based on the human development index(HDI).The death probability,the year of life lost(YLL),and the potential gain in life expectancy(PGLE)attributable to premature deaths from site-specific and all-cancers combined were calculated.Results:Globally,the probability of premature cancer deaths was 6.49%(95%UI 6.49-6.50).The YLLs caused by cancer-related premature death were 163.86 million(95%UI 163.70-164.03),constituting 65.58%of the total cancer-related YLLs.The PGLEs were 1.16 years(95%UI 1.16-1.16).The premature death probability increased with higher HDI levels in men,but decreased in women.Cancer-related premature deaths as a proportion of total cancer deaths varied from 18.31%(95%UI 18.20-18.43)in Japan to 84.44%(95%UI 76.10-91.16)in São Toméand Príncipe.Lung cancer was the leading cause of cancer-related premature deaths in men,and breast cancer ranked first in women.By eradicating premature deaths attributable to lung,liver,colorectal,and stomach cancer in men,and to breast,cervical,and lung cancer in women,0.55 years(95%UI 0.55-0.55)and 0.49 years(95%UI 0.49-0.49)of PGLEs could be achieved,accounting for 48.67%and 42.24%of the total PGLEs,respectively.Cancer-related premature deaths decreased significantly in 38 countries during 2003-2022(P<0.05).The probability of premature cancer-related deaths decreased by more than 15.50%from 2015 to 2022 in 16 countries.Conclusions:Cancer-related premature deaths declined in many countries,with 16 of them having achieved the expected reduction by 2022.The current burden of cancer-related premature deaths is profound but varies around the world.Eliminating premature deaths from major cancer types could substantially increase life expectancy,underscoring the importance of prevention and treatment efforts for these cancers.展开更多
Objective:This integrative review aims to synthesize observational evidence on the prevalence,predictors,and psychosocial correlates of death anxiety in patients with hear t failure(HF).Methods:A comprehensive literat...Objective:This integrative review aims to synthesize observational evidence on the prevalence,predictors,and psychosocial correlates of death anxiety in patients with hear t failure(HF).Methods:A comprehensive literature search was conducted using 5 major databases:Scopus,Pub Med,Science Direct,Embase,and Pro Quest.Inclusion criteria were primary research studies published in English between January 2014 and March 2025 that quantitatively assessed death anxiety among patients with HF and explored its associations with demographic,clinical,or psychosocial variables.Results:A total of 12 eligible studies were identified and systematically reviewed,revealing that death anxiety is moderate to high among most samples.Key predictors of this anxiety included older age,feelings of loneliness,low socioeconomic status,and longer duration of HF.Additionally,several studies highlighted protective factors such as spiritual orientation,religious coping,and resilience.Interventions,including cognitive-behavioral therapy(CBT)and illness perception training,showed significant reductions in death anxiety.Conclusions:Death anxiety is a prevalent and impactful concern among Patients with HF,influenced by both individual and contextual factors.Routine assessment and integration of psychosocial and spiritual care—alongside evidence-based psychological interventions—are essential to address this critical aspect of HF management.展开更多
Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy ...Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin(DOX) prodrug nanoparticles(Cat B-NPs) for inducing tumor-specific immunogenic cell death(ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin Bactivatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide(FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles(163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, Cat B-NPs effectively induced cancer cellspecific ICD, while sparing normal cells and immune cells. When Cat B-NPs-treated B16F10cells were co-cultured with immune cells, Cat B-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells(DCs). In melanoma models,Cat B-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling highdose treatment that induced robust ICD. Importantly, combination therapy with Cat B-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, highdose Cat B-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.展开更多
Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell ...Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.展开更多
The development of highly efficient and multifunctional nanozymes holds promise for addressing the challenges posed by drugresistant bacteria.Here,copper single-atom-loaded MoS_(2) nanozymes(CuSAs/MoS_(2))were develop...The development of highly efficient and multifunctional nanozymes holds promise for addressing the challenges posed by drugresistant bacteria.Here,copper single-atom-loaded MoS_(2) nanozymes(CuSAs/MoS_(2))were developed to effectively combat drug-resistant bacteria by synergistically integrating the triple strategies of oxidative damage,cuproptosis-like death and disruption of cell wall synthesis.Density functional theory revealed that each Cu center coordinated with three sulfur ligands,enhancing the adsorption of H_(2)O_(2),which reduced the activation energy of the key step by 17%,thereby improving peroxidase-like(PODlike)activity.The generation of reactive oxygen species in combination with CuSAs/MoS_(2) glutathione peroxidase-like(GSH-Px-like)for glutathione scavenging resulted in an imbalance in redox homeostasis within bacteria.CuSAs/MoS_(2),which act as nanopioneers,drive oxidative stress to initiate the process of cuproptosis-like death,leading to abnormal aggregation of lipoylated proteins and inactivation of iron-sulfur cluster proteins.Moreover,CuSAs/MoS_(2) inhibited the biosynthesis of the peptidoglycan synthesis precursors D-glutamate and m-diaminopimelic acid and disrupted the peptidoglycan cross-linking process mediated by penicillin-binding proteins,effectively blocking the compensatory cell wall remodeling pathway ofβ-lactam-resistant bacteria.Overall,CuSAs/MoS_(2) with multiple functions can not only efficiently kill bacteria but also decelerate the development of bacterial resistance to combat drug-resistant bacterial infections.展开更多
Objective:To investigate the correlation between the occurrences of unexplained sudden death in Yunnan Province and the pathogen spectrum by using real-time fluorescent quantitative reverse transcription PCR,metagenom...Objective:To investigate the correlation between the occurrences of unexplained sudden death in Yunnan Province and the pathogen spectrum by using real-time fluorescent quantitative reverse transcription PCR,metagenomic next-generation sequencing(mNGS),and virus isolation techniques to test autopsy samples from cases of unexplained sudden death and fecal specimens from populations in affected areas.Methods:Real-time fluorescent quantitative reverse transcription PCR and Sanger sequencing were performed on 101 fecal samples collected from populations in affected areas.Virus isolation was conducted on fecal and gastric content samples from individuals who died suddenly.Additionally,metavirome sequencing and pathogen spectrum abundance detection were performed on 50 autopsy organ samples.Results:No specific fragments of enteroviruses were detected in 101 fecal samples from the population in the affected wards,and no viruses were isolated from fecal and gastric content samples of sudden death victims.Among the 50 autopsy organ samples,29 were successfully sequenced.High-throughput sequencing revealed low-abundance enterovirus reads in 11 samples(relative abundance≤0.91%in all cases);Enterovirus A114 was detected in 6 samples(with relative abundances of 0.211%,0.571%,0.910%,0.013%,0.002%,and 0.0000263%,respectively);Coxsackievirus A2 in 9 samples(with relative abundances of 0.111%,0.192%,0.051%,0.291%,0.007%,0.00019%,0.00342%,0.000551%,and 0.0000368%,respectively);and Coxsackievirus B3 in 9 samples(with relative abundances of 0.312%,0.486%,0.120%,0.765%,0.001%,0.001%,0.001%,0.0000999%,and 0.00000848%,respectively).Coexistence of 2-3 types of enteroviruses was observed in some samples.Genomic annotation results indicated that high-abundance bacteria were primarily Paeniclostridium sordellii and Escherichia coli,while viral species could not be successfully assembled due to their low abundance.Conclusion:Enterovirus infection may be one of the causes of some unexplained sudden deaths in Yunnan,and the possibility of varying degrees of enterovirus infection cannot be ruled out in some populations in the affected areas.The detection of bacteria may be attributed to the normal intestinal flora of the human body or contamination during the autopsy sampling process.展开更多
The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD...The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD inducer is severely hindered by complex biological barriers.How to design and build intelligent nanoplatform for adaptive and dynamic cancer therapy remains a big challenge.Herein,this article presents the design and preparation of CD44-targeting and ZIF-8 gated gold nanocage(Au@ZH) for programmed delivery of the 1,2-diaminocyclohexane-Pt(Ⅱ)(DACHPt) as ICD inducer.After actively targeting the CD44 on the surface of 4T1 tumor cell,this Pt-Au@ZH can be effectively endocytosed by the 4T1 cell and release the DACHPt in tumor acidic environment,resulting in ICD effect and superior antitumor efficacy both in vitro and in vivo in the presence of mild 808 nm laser irradiation.By integration of internal and external stimuli intelligently,this programmed nanoplatform is poised to become a cornerstone in the pursuit of effective and targeted cancer therapy in the foreseeable future.展开更多
Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 m...Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases.In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes,ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways(e.g.,apoptosis,necroptosis,pyroptosis,ferroptosis,and NETosis).This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death.In addition,we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases,aiming to provide a novel theoretical framework for human disease treatment.展开更多
Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenes...Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.展开更多
Background:That Central and Eastern Europe and Central Asia(CEECA)experienced a major mortality crisis in the 1990s is a well-established finding,with most analyses focusing on singular causes like alcohol-related dea...Background:That Central and Eastern Europe and Central Asia(CEECA)experienced a major mortality crisis in the 1990s is a well-established finding,with most analyses focusing on singular causes like alcohol-related deaths.However,the utility of the integrated“deaths of despair”framework,which views alcohol,drug,and suicide deaths as a unified socio-economic phenomenon,remains under-explored in this context.Crucially,the long-term evolution of the composition of despair within the region remains a largely unexplored area of inquiry.Therefore,this study aims to analyze the long-term trends,changing composition,and regional heterogeneity of deaths from despair in the CEECA region from 1980 to 2021.Methods:Using 2021 Global Burden of Disease(GBD)data(1980–2021),we analyzed deaths of despair mortality trends in 29 CEECA countries.We employed Joinpoint regression to identify significant trend changes and conducted stratified analyses by cause,gender,and age group.Results:The CEECA deaths of despair crisis began as an alcohol and suicide driven phenomenon concentrated in middle-aged men(50–74 years)during the 1990s,with mortality rates for alcohol use disorders and self-harm surging annually by 30.35%(p=0.002)and 13.44%(p=0.001),respectively,between 1991 and 1994.It has since evolved,marked by a contrasting and emerging threat in the 21st century:a rising proportion of drug-related deaths among the younger(15–49 years)male cohort,where the share of drug use disorders increased from 6.9%in 2000 to 11.8%in 2008.Conclusion:The deaths of despair crisis in the CEECA region is not a past event but an ongoing,evolving phenomenon.Its changing nature demands a shift in public health focus from solely historical drivers to new,generation-specific threats,particularly the rise of drug-related despair among youth.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in th...BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.展开更多
To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(II...To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(III)2-benzoylpyridine thiosemicarbazone complexes to obtain an Au(III)agent(5b)with excellent cytotoxicity to cancer.The results show that 5b effectively inhibits tumor growth and its metastasis in vivo.Interestingly,we revealed a new mechanism of 5b inhibiting tumor growth and metastasis:5b releases ICD-related damage-associated molecular patterns(DAMPs),such as calreticulin(CRT),ATP and high mobility group box 1(HMGB1)by inducing endoplasmic reticulum stress(ERS)and mitochondrial dysfunction,which then stimulated an antitumor CD8^(+)T cell response and Foxp^(3+)T cell depletion,thus establishing long-action antitumor immunity.展开更多
Heart failure(HF)has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology.Adeno-sine triphosphate(ATP)-induced cell death represents a nov...Heart failure(HF)has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology.Adeno-sine triphosphate(ATP)-induced cell death represents a novel form of regulated cell deaths,marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation,identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis.Growing evidence suggests that ATP-induced cell death(AICD)is predominantly governed by various biological pathways,including energy meta-bolism,redox homeostasis and intracellular calcium equilibrium.Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction,ischemia-reperfusion injury,and chemotherapy.Thus,it is essential to investigate the function of AICD in the pathogenesis of HF,as this may provide a foundation for the development of targeted therapies and novel treatment strategies.This review synthesizes current advancements in under-standing the link between AICD and HF,while further elucidating its invol-vement in cardiac remodeling and HF progression.展开更多
The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to...The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to intestinal inflammation,a hallmark of inflammatory bowel disease(IBD).While the role of the gut microbiome in IBD is increasingly recognized,the underlying mechanisms,particularly those involving endoplasmic reticulum(ER)stress,autophagy,and cell death,remain incompletely understood.ER stress,a cellular response to various stressors,can trigger inflammation and cell death.Autophagy,a cellular degradation process,can either alleviate or exacerbate ER stress-induced inflammation,depending on the specific context.The gut microbiome can influence both ER stress and autophagy pathways,further complicating the interplay between these processes.This review delves into the intricate relationship between ER stress,autophagy,and the gut microbiome in the context of intestinal inflammation.By exploring the molecular mechanisms underlying these interactions,we aim to provide a comprehensive theoretical framework for developing novel therapeutic strategies for IBD.A deeper understanding of the ER stress-autophagy axis,the gut microbial-ER stress axis,and the gut microbial-autophagy axis may pave the way for targeted interventions to restore intestinal health and mitigate the impact of IBD.展开更多
Ovarian cancer(OC),a common malignancy of the female reproductive system,has the highest mortality rate among gynecological cancers.A distinguishing feature of OC cells(OCCs)is their reduced autophagic flux compared w...Ovarian cancer(OC),a common malignancy of the female reproductive system,has the highest mortality rate among gynecological cancers.A distinguishing feature of OC cells(OCCs)is their reduced autophagic flux compared with normal cells.This phenomenon indicates that excessive autophagy activation or impaired autophagosome–lysosome fusion may lead to OCC death.This study investigated the anti-OC effects of dihydrotanshinone I(DHT),a tanshinone compound from Salvia miltiorrhiza.Proteomic analysis suggested that DHT suppressed OC growth via the autophagy–lysosome pathway,with sortilin 1(SORT1)identified as a critical target.In vitro,DHT promoted autophagosome formation mediated by microtubule-associated protein 1 light chain 3-II(LC3-II),while inhibiting autophagosome–lysosome fusion.The results of an orthotopic OC model corroborated these findings,showing that DHT induced autophagic cell death(ACD)and suppressed SORT1 expression in tumors.Further RNA interference experiments confirmed that SORT1 depletion caused autophagosomes to accumulate in OCCs.Notably,we found that SORT1 interacted with autophagy-related gene(ATG)-encoded proteins ATG5 and ATG16L1,and that depleting SORT1 increased the levels of these proteins.Co-immunoprecipitation,ubiquitination,and cellular thermal shift assay analyses revealed that DHT directly targeted and promoted ubiquitin-dependent degradation of SORT1.By degrading SORT1,ATG5 and ATG16L1 were released,which enhanced autophagosome formation and disrupted the autophagic flux.These findings identified DHT as a novel autophagosome inducer that induced ACD by targeting SORT1,making it a promising therapeutic candidate for OC.展开更多
Age-related macular degeneration(AMD)represents a predominant cause of blindness among older adults,with limited therapeutic options currently available.Oxidative stress,inflammation,and retinal pigment epithelium inj...Age-related macular degeneration(AMD)represents a predominant cause of blindness among older adults,with limited therapeutic options currently available.Oxidative stress,inflammation,and retinal pigment epithelium injury are recognized as key contributors to the pathogenesis of AMD.Regulated cell death plays a pivotal role in mediating cellular responses to stress,maintaining tissue homeostasis,and contributing to disease progression.Recent research has elucidated several regulated cell death pathwaysdsuch as apoptosis,ferroptosis,pyroptosis,necroptosis,and autophagydthat may contribute to the progression of AMD owing to cell death in the retinal pigment epithelium.These discoveries open new avenues for therapeutic interventions in patients with AMD.In this review,we provide a comprehensive summary and analysis of the latest advancements regarding the relationship between regulated cell death and AMD.Moreover,we examined the therapeutic potential of targeting regulated cell death pathways for the treatment and prevention of AMD,highlighting their roles as promising targets for future therapeutic strategies.展开更多
BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and com...BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a ...BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.展开更多
Background:Colorectal cancer(CRC)holds the third position in global cancer prevalence mortality.Although chemotherapy is a conventional treatment,recent investigations have shed light on the therapeutic potential of t...Background:Colorectal cancer(CRC)holds the third position in global cancer prevalence mortality.Although chemotherapy is a conventional treatment,recent investigations have shed light on the therapeutic potential of the cGAS cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway in CRC management.Despite the primary role of the death domain-associated protein(Daxx)in cellular apoptosis,its influence on the regulation of cGAS-STING activation remains elusive.Methods:The Daxx degradation and speck formation were conducted using immunofluorescence and Western blotting.The Daxx knock-down and over-expression in CRC cells were performed to detect in vivo and in vitro migration,proliferation,cGAS-STING activation,and immune responses.Results:Our study reveals that treatment with irinotecan(CPT-11)and oxaliplatin(OXA)significantly accelerated the Daxx degradation and diminished the formation of Daxx specks within the nucleus of CRC cells.Genetic elimination of Daxx enhanced the irinotecan and oxaliplatin-induced suppression of proliferation and migration in CRC cells,and overexpression of Daxx resulted in similar results.Mechanistically,Daxx overexpression reduced DNA damage repair by restraining homologous recombination(HR)over non-homologous end-joining(NHEJ),which suppressed TBK1 and IRF3 phosphorylation downstream of the cGAS-STING signal.In a murine model of CT-26 tumors,Daxx knockdown amplified the OXA-mediated tumor growth inhibition by promoting STING activation and immune responses.Conclusions:Our findings show that the degradation of nuclear Daxx potentiates the cGAS-STING pathway,thereby bolstering the efficacy of chemotherapy.展开更多
BACKGROUND We previously demonstrated that the antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)is a promising new marker of programmed death-ligand 1(PD-L1)expression that correlates with both brea...BACKGROUND We previously demonstrated that the antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)is a promising new marker of programmed death-ligand 1(PD-L1)expression that correlates with both breast cancer(BC)clinicopathological characteristics and tumor sensitivity to chemotherapy.However,the concordance of PDCD1 LG1 expression scoring with immunohistochemical(IHC)tests approved for clinical use and with the polymerase chain reaction(PCR)method has not been previously studied.AIM To evaluate the concordance of methods for assessing PD-L1 expression,IHC tests with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and PCR.METHODS This prospective single-center observational cohort study included 148 patients with BC.PD-L1 expression in immune cells was assessed by the IHC method with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and by PCR.The concordance of PD-L1 scores between tests was assessed with positive percentage agreement(PPA)and negative percentage agreement(NPA).The strength of the agreement between the methods was calculated via the Cohen kappa index.P<0.05 was considered statistically significant.RESULTS Regardless of the method used to assess marker expression,PD-L1 expression was significantly more often detected in patients with negative estrogen receptor status,human epidermal growth factor receptor-2-positive(HER2+)status,luminal B HER+BC,nonluminal HER+BC and triple-negative BC.PPA and NPA were 38.3%and 70.4%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(SP142);26.3%and 63.3%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(PCR);and 36.5%and 74.4%,respectively,for PD-L1(SP142)and PD-L1(PCR).Cohen's kappa index for PD-L1(PDCD1 LG1)and PD-L1(SP142)was 0.385(95%CI:0.304–0.466),that for PD-L1(PDCD1 LG1)and PD-L1(PCR)was 0.207(95%CI:0.127–0.287),and that for PD-L1(SP142)and PD-L1(PCR)was 0.389(95%CI:0.309–0.469).CONCLUSION Thus,all three markers of PD-L1 expression are associated with the characteristics of aggressive BC,demonstrating moderate concordance between the tests.展开更多
基金supported by the Capital’s Funds for Health Improvement and Research(CFH2024-2G-40214)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-011,2021-I2M-1-061).
文摘Background:The level of premature deaths(deaths among those aged 30-69 years)caused by cancer is an important indicator of evaluating the level of cancer prevention and control.However,the current burden and temporal trends in cancer-related premature deaths,and their impact on life expectancy at the global,regional,and national levels are not clear.Methods:Cancer mortality data for 185 countries were obtained from the GLOBOCAN 2022 database.High-quality cancer mortality data and national population statistics for 47 countries were extracted from the United Nations and national cancer registry databases,covering the period 2003-2022.Countries were classified based on the human development index(HDI).The death probability,the year of life lost(YLL),and the potential gain in life expectancy(PGLE)attributable to premature deaths from site-specific and all-cancers combined were calculated.Results:Globally,the probability of premature cancer deaths was 6.49%(95%UI 6.49-6.50).The YLLs caused by cancer-related premature death were 163.86 million(95%UI 163.70-164.03),constituting 65.58%of the total cancer-related YLLs.The PGLEs were 1.16 years(95%UI 1.16-1.16).The premature death probability increased with higher HDI levels in men,but decreased in women.Cancer-related premature deaths as a proportion of total cancer deaths varied from 18.31%(95%UI 18.20-18.43)in Japan to 84.44%(95%UI 76.10-91.16)in São Toméand Príncipe.Lung cancer was the leading cause of cancer-related premature deaths in men,and breast cancer ranked first in women.By eradicating premature deaths attributable to lung,liver,colorectal,and stomach cancer in men,and to breast,cervical,and lung cancer in women,0.55 years(95%UI 0.55-0.55)and 0.49 years(95%UI 0.49-0.49)of PGLEs could be achieved,accounting for 48.67%and 42.24%of the total PGLEs,respectively.Cancer-related premature deaths decreased significantly in 38 countries during 2003-2022(P<0.05).The probability of premature cancer-related deaths decreased by more than 15.50%from 2015 to 2022 in 16 countries.Conclusions:Cancer-related premature deaths declined in many countries,with 16 of them having achieved the expected reduction by 2022.The current burden of cancer-related premature deaths is profound but varies around the world.Eliminating premature deaths from major cancer types could substantially increase life expectancy,underscoring the importance of prevention and treatment efforts for these cancers.
文摘Objective:This integrative review aims to synthesize observational evidence on the prevalence,predictors,and psychosocial correlates of death anxiety in patients with hear t failure(HF).Methods:A comprehensive literature search was conducted using 5 major databases:Scopus,Pub Med,Science Direct,Embase,and Pro Quest.Inclusion criteria were primary research studies published in English between January 2014 and March 2025 that quantitatively assessed death anxiety among patients with HF and explored its associations with demographic,clinical,or psychosocial variables.Results:A total of 12 eligible studies were identified and systematically reviewed,revealing that death anxiety is moderate to high among most samples.Key predictors of this anxiety included older age,feelings of loneliness,low socioeconomic status,and longer duration of HF.Additionally,several studies highlighted protective factors such as spiritual orientation,religious coping,and resilience.Interventions,including cognitive-behavioral therapy(CBT)and illness perception training,showed significant reductions in death anxiety.Conclusions:Death anxiety is a prevalent and impactful concern among Patients with HF,influenced by both individual and contextual factors.Routine assessment and integration of psychosocial and spiritual care—alongside evidence-based psychological interventions—are essential to address this critical aspect of HF management.
基金supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)(RS-2024-00351185, RS-2025-02219039)by the Korea Health Industry Development Institute (KHIDI)grant funded by the Korea government (MOHW)(RS-2023-KH135133)by Korea Drug Development Fund (KDDF)funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2025-02223093)。
文摘Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin(DOX) prodrug nanoparticles(Cat B-NPs) for inducing tumor-specific immunogenic cell death(ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin Bactivatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide(FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles(163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, Cat B-NPs effectively induced cancer cellspecific ICD, while sparing normal cells and immune cells. When Cat B-NPs-treated B16F10cells were co-cultured with immune cells, Cat B-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells(DCs). In melanoma models,Cat B-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling highdose treatment that induced robust ICD. Importantly, combination therapy with Cat B-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, highdose Cat B-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.
基金The National Natural Science Foundation of China(Nos.82473864,82400095)the Natural Science Foundation of Jiangsu Province(No.BK20231009)+2 种基金the National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01015)“Double First-Class”Initiative Program in China Pharmaceutical Universitythe National Innovation and Entrepreneurship Training Program for Undergraduate(Nos.202310316007Z,2023103161133,2023103161333).
文摘Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.
基金supported by the National Natural Science Foundation of China(82372552)the Excellent Youth of Natural Science Research Projects in Anhui Province Universities(2023AH030060)+1 种基金Anhui Provincial Natural Science Foundation(2408085Y016)Anhui Province Excellent Research and Innovation Team Project(2024AH010013)。
文摘The development of highly efficient and multifunctional nanozymes holds promise for addressing the challenges posed by drugresistant bacteria.Here,copper single-atom-loaded MoS_(2) nanozymes(CuSAs/MoS_(2))were developed to effectively combat drug-resistant bacteria by synergistically integrating the triple strategies of oxidative damage,cuproptosis-like death and disruption of cell wall synthesis.Density functional theory revealed that each Cu center coordinated with three sulfur ligands,enhancing the adsorption of H_(2)O_(2),which reduced the activation energy of the key step by 17%,thereby improving peroxidase-like(PODlike)activity.The generation of reactive oxygen species in combination with CuSAs/MoS_(2) glutathione peroxidase-like(GSH-Px-like)for glutathione scavenging resulted in an imbalance in redox homeostasis within bacteria.CuSAs/MoS_(2),which act as nanopioneers,drive oxidative stress to initiate the process of cuproptosis-like death,leading to abnormal aggregation of lipoylated proteins and inactivation of iron-sulfur cluster proteins.Moreover,CuSAs/MoS_(2) inhibited the biosynthesis of the peptidoglycan synthesis precursors D-glutamate and m-diaminopimelic acid and disrupted the peptidoglycan cross-linking process mediated by penicillin-binding proteins,effectively blocking the compensatory cell wall remodeling pathway ofβ-lactam-resistant bacteria.Overall,CuSAs/MoS_(2) with multiple functions can not only efficiently kill bacteria but also decelerate the development of bacterial resistance to combat drug-resistant bacterial infections.
基金Project for Cultivating Technological Innovation Talents in Yunnan Province(Project No.:202405AD350026)Special Project for Medical and Health Talents under the“Xingdian Talent Support Program”in Yunnan Province(Project No.:XDYC-YLWS-2024-0065)Young Talent Cultivation and Funding Program of the Yunnan Institute of Endemic Disease Control and Prevention(Project No.:YIEDC-G202104)。
文摘Objective:To investigate the correlation between the occurrences of unexplained sudden death in Yunnan Province and the pathogen spectrum by using real-time fluorescent quantitative reverse transcription PCR,metagenomic next-generation sequencing(mNGS),and virus isolation techniques to test autopsy samples from cases of unexplained sudden death and fecal specimens from populations in affected areas.Methods:Real-time fluorescent quantitative reverse transcription PCR and Sanger sequencing were performed on 101 fecal samples collected from populations in affected areas.Virus isolation was conducted on fecal and gastric content samples from individuals who died suddenly.Additionally,metavirome sequencing and pathogen spectrum abundance detection were performed on 50 autopsy organ samples.Results:No specific fragments of enteroviruses were detected in 101 fecal samples from the population in the affected wards,and no viruses were isolated from fecal and gastric content samples of sudden death victims.Among the 50 autopsy organ samples,29 were successfully sequenced.High-throughput sequencing revealed low-abundance enterovirus reads in 11 samples(relative abundance≤0.91%in all cases);Enterovirus A114 was detected in 6 samples(with relative abundances of 0.211%,0.571%,0.910%,0.013%,0.002%,and 0.0000263%,respectively);Coxsackievirus A2 in 9 samples(with relative abundances of 0.111%,0.192%,0.051%,0.291%,0.007%,0.00019%,0.00342%,0.000551%,and 0.0000368%,respectively);and Coxsackievirus B3 in 9 samples(with relative abundances of 0.312%,0.486%,0.120%,0.765%,0.001%,0.001%,0.001%,0.0000999%,and 0.00000848%,respectively).Coexistence of 2-3 types of enteroviruses was observed in some samples.Genomic annotation results indicated that high-abundance bacteria were primarily Paeniclostridium sordellii and Escherichia coli,while viral species could not be successfully assembled due to their low abundance.Conclusion:Enterovirus infection may be one of the causes of some unexplained sudden deaths in Yunnan,and the possibility of varying degrees of enterovirus infection cannot be ruled out in some populations in the affected areas.The detection of bacteria may be attributed to the normal intestinal flora of the human body or contamination during the autopsy sampling process.
基金financially supported by the Natural Science Foundation of Jiangsu Province (No.BK20200709)the Natural Science Foundation of China (Nos.62288102,32201127 and 82270113)+2 种基金the Natural Science Foundation of Guangdong Province (No.2023A1515011386)the Natural Science Foundation of the Jiangsu Higher Education Institutes (No.20KJB430031)the startup fund from Nanjing Tech University,and Disciplinary Fund of School of Pharmaceutical Sciences (2024)。
文摘The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD inducer is severely hindered by complex biological barriers.How to design and build intelligent nanoplatform for adaptive and dynamic cancer therapy remains a big challenge.Herein,this article presents the design and preparation of CD44-targeting and ZIF-8 gated gold nanocage(Au@ZH) for programmed delivery of the 1,2-diaminocyclohexane-Pt(Ⅱ)(DACHPt) as ICD inducer.After actively targeting the CD44 on the surface of 4T1 tumor cell,this Pt-Au@ZH can be effectively endocytosed by the 4T1 cell and release the DACHPt in tumor acidic environment,resulting in ICD effect and superior antitumor efficacy both in vitro and in vivo in the presence of mild 808 nm laser irradiation.By integration of internal and external stimuli intelligently,this programmed nanoplatform is poised to become a cornerstone in the pursuit of effective and targeted cancer therapy in the foreseeable future.
基金supported by the State Key Program of the National Natural Science Foundation of China(82030059)the National Science and Technology Major Project(2023ZD0505501)+2 种基金the National Natural Science Foundation of China(81701952 and 82172127)the National Key Research and Development Program of China(2020YFC1512700)the Key Research and Development Program of Shandong Province(2021SFGC0503 and 2022ZLGX03).
文摘Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases.In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes,ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways(e.g.,apoptosis,necroptosis,pyroptosis,ferroptosis,and NETosis).This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death.In addition,we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases,aiming to provide a novel theoretical framework for human disease treatment.
基金supported by the National Natural Science Foundation of China(Grant nos.62576136 to Yan Huang82372507,82572869 to Kun Xiongthe National Natural Science Foundation of Hunan Province(Grant no.2026JJ30177).
文摘Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.
基金supported by grants from the National Research Foundation of Korea(NRF)under the Ministry of Science and Information and Communication Technology(grant number:RS-2023-00249082)Korea University(grant number:K2225791).
文摘Background:That Central and Eastern Europe and Central Asia(CEECA)experienced a major mortality crisis in the 1990s is a well-established finding,with most analyses focusing on singular causes like alcohol-related deaths.However,the utility of the integrated“deaths of despair”framework,which views alcohol,drug,and suicide deaths as a unified socio-economic phenomenon,remains under-explored in this context.Crucially,the long-term evolution of the composition of despair within the region remains a largely unexplored area of inquiry.Therefore,this study aims to analyze the long-term trends,changing composition,and regional heterogeneity of deaths from despair in the CEECA region from 1980 to 2021.Methods:Using 2021 Global Burden of Disease(GBD)data(1980–2021),we analyzed deaths of despair mortality trends in 29 CEECA countries.We employed Joinpoint regression to identify significant trend changes and conducted stratified analyses by cause,gender,and age group.Results:The CEECA deaths of despair crisis began as an alcohol and suicide driven phenomenon concentrated in middle-aged men(50–74 years)during the 1990s,with mortality rates for alcohol use disorders and self-harm surging annually by 30.35%(p=0.002)and 13.44%(p=0.001),respectively,between 1991 and 1994.It has since evolved,marked by a contrasting and emerging threat in the 21st century:a rising proportion of drug-related deaths among the younger(15–49 years)male cohort,where the share of drug use disorders increased from 6.9%in 2000 to 11.8%in 2008.Conclusion:The deaths of despair crisis in the CEECA region is not a past event but an ongoing,evolving phenomenon.Its changing nature demands a shift in public health focus from solely historical drivers to new,generation-specific threats,particularly the rise of drug-related despair among youth.
基金Supported by the Natural Science Foundation of Gansu Province,No.21JR7RA373 and No.24JRRA295.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
基金supported by the Natural Science Foundation of Guangxi(No.2022GXNSFGA035003)the National Natural Science Foundation of China(No.22077021).
文摘To treat cancer and inhibit its metastasis to the greatest extent,we proposed to develop an Au(III)agent to induce immunogenic cell death(ICD)and establish long-term immunity.To this end,we optimized a series of Au(III)2-benzoylpyridine thiosemicarbazone complexes to obtain an Au(III)agent(5b)with excellent cytotoxicity to cancer.The results show that 5b effectively inhibits tumor growth and its metastasis in vivo.Interestingly,we revealed a new mechanism of 5b inhibiting tumor growth and metastasis:5b releases ICD-related damage-associated molecular patterns(DAMPs),such as calreticulin(CRT),ATP and high mobility group box 1(HMGB1)by inducing endoplasmic reticulum stress(ERS)and mitochondrial dysfunction,which then stimulated an antitumor CD8^(+)T cell response and Foxp^(3+)T cell depletion,thus establishing long-action antitumor immunity.
基金Supported by Science and Technology Department of Yunnan Province-Kunming Medical University,Kunming Medical Joint Special Project-Surface Project,No.202401AY070001-164Yunnan Provincial Clinical Research Center Cardiovascular Diseases-New Technology Research for Development Project for Diagnosis and Treatment Cardiovascular Diseases,No.202102AA310002the Key Technology Research and Device Development Project for Innovative Diagnosis and Treatment of Structural Heart Disease in the Southwest Plateau Region,No.202302AA310045.
文摘Heart failure(HF)has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology.Adeno-sine triphosphate(ATP)-induced cell death represents a novel form of regulated cell deaths,marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation,identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis.Growing evidence suggests that ATP-induced cell death(AICD)is predominantly governed by various biological pathways,including energy meta-bolism,redox homeostasis and intracellular calcium equilibrium.Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction,ischemia-reperfusion injury,and chemotherapy.Thus,it is essential to investigate the function of AICD in the pathogenesis of HF,as this may provide a foundation for the development of targeted therapies and novel treatment strategies.This review synthesizes current advancements in under-standing the link between AICD and HF,while further elucidating its invol-vement in cardiac remodeling and HF progression.
基金supported by the fund for the Project of the National Key Research and Development Program of China(2024YFD1300203)Project support was provided by the Fund opened from Key Laboratory of Fujian Universities Preventive Veterinary Medicine and Biotechnology,Longyan University(grant No.2021KF01)the Cyanine Project of Yangzhou University(2020)。
文摘The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to intestinal inflammation,a hallmark of inflammatory bowel disease(IBD).While the role of the gut microbiome in IBD is increasingly recognized,the underlying mechanisms,particularly those involving endoplasmic reticulum(ER)stress,autophagy,and cell death,remain incompletely understood.ER stress,a cellular response to various stressors,can trigger inflammation and cell death.Autophagy,a cellular degradation process,can either alleviate or exacerbate ER stress-induced inflammation,depending on the specific context.The gut microbiome can influence both ER stress and autophagy pathways,further complicating the interplay between these processes.This review delves into the intricate relationship between ER stress,autophagy,and the gut microbiome in the context of intestinal inflammation.By exploring the molecular mechanisms underlying these interactions,we aim to provide a comprehensive theoretical framework for developing novel therapeutic strategies for IBD.A deeper understanding of the ER stress-autophagy axis,the gut microbial-ER stress axis,and the gut microbial-autophagy axis may pave the way for targeted interventions to restore intestinal health and mitigate the impact of IBD.
基金supported by the National Key Research and Development Program of China(2023YFC3503900)the National Natural Science Foundation of China(82305001)+3 种基金the Zhejiang Provincial Natural Science Foundation of China(LQ24H280011)the Science Research Fund of Administration of Traditional Chinese Medicine of Zhejiang Province(2023ZR014)the National Young Qihuang Scholars Training Programthe Research Project of Zhejiang Chinese Medical University(2022RCZXZK18,2023JKZKTS17)。
文摘Ovarian cancer(OC),a common malignancy of the female reproductive system,has the highest mortality rate among gynecological cancers.A distinguishing feature of OC cells(OCCs)is their reduced autophagic flux compared with normal cells.This phenomenon indicates that excessive autophagy activation or impaired autophagosome–lysosome fusion may lead to OCC death.This study investigated the anti-OC effects of dihydrotanshinone I(DHT),a tanshinone compound from Salvia miltiorrhiza.Proteomic analysis suggested that DHT suppressed OC growth via the autophagy–lysosome pathway,with sortilin 1(SORT1)identified as a critical target.In vitro,DHT promoted autophagosome formation mediated by microtubule-associated protein 1 light chain 3-II(LC3-II),while inhibiting autophagosome–lysosome fusion.The results of an orthotopic OC model corroborated these findings,showing that DHT induced autophagic cell death(ACD)and suppressed SORT1 expression in tumors.Further RNA interference experiments confirmed that SORT1 depletion caused autophagosomes to accumulate in OCCs.Notably,we found that SORT1 interacted with autophagy-related gene(ATG)-encoded proteins ATG5 and ATG16L1,and that depleting SORT1 increased the levels of these proteins.Co-immunoprecipitation,ubiquitination,and cellular thermal shift assay analyses revealed that DHT directly targeted and promoted ubiquitin-dependent degradation of SORT1.By degrading SORT1,ATG5 and ATG16L1 were released,which enhanced autophagosome formation and disrupted the autophagic flux.These findings identified DHT as a novel autophagosome inducer that induced ACD by targeting SORT1,making it a promising therapeutic candidate for OC.
基金supported by the Natural Science Foundation of Sichuan Province(Grant No.:2023NSFSC1783)the National Natural Science Foundation of China(Grant No.:82274372).
文摘Age-related macular degeneration(AMD)represents a predominant cause of blindness among older adults,with limited therapeutic options currently available.Oxidative stress,inflammation,and retinal pigment epithelium injury are recognized as key contributors to the pathogenesis of AMD.Regulated cell death plays a pivotal role in mediating cellular responses to stress,maintaining tissue homeostasis,and contributing to disease progression.Recent research has elucidated several regulated cell death pathwaysdsuch as apoptosis,ferroptosis,pyroptosis,necroptosis,and autophagydthat may contribute to the progression of AMD owing to cell death in the retinal pigment epithelium.These discoveries open new avenues for therapeutic interventions in patients with AMD.In this review,we provide a comprehensive summary and analysis of the latest advancements regarding the relationship between regulated cell death and AMD.Moreover,we examined the therapeutic potential of targeting regulated cell death pathways for the treatment and prevention of AMD,highlighting their roles as promising targets for future therapeutic strategies.
基金Science and Technology Program of Guangzhou,No.202102010077International Science Foundation of Guangzhou Fuda Cancer Hospital,No.Y2020-ZD-03.
文摘BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
基金supported by the National Natural Science Foundation of China(82202956)。
文摘Background:Colorectal cancer(CRC)holds the third position in global cancer prevalence mortality.Although chemotherapy is a conventional treatment,recent investigations have shed light on the therapeutic potential of the cGAS cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway in CRC management.Despite the primary role of the death domain-associated protein(Daxx)in cellular apoptosis,its influence on the regulation of cGAS-STING activation remains elusive.Methods:The Daxx degradation and speck formation were conducted using immunofluorescence and Western blotting.The Daxx knock-down and over-expression in CRC cells were performed to detect in vivo and in vitro migration,proliferation,cGAS-STING activation,and immune responses.Results:Our study reveals that treatment with irinotecan(CPT-11)and oxaliplatin(OXA)significantly accelerated the Daxx degradation and diminished the formation of Daxx specks within the nucleus of CRC cells.Genetic elimination of Daxx enhanced the irinotecan and oxaliplatin-induced suppression of proliferation and migration in CRC cells,and overexpression of Daxx resulted in similar results.Mechanistically,Daxx overexpression reduced DNA damage repair by restraining homologous recombination(HR)over non-homologous end-joining(NHEJ),which suppressed TBK1 and IRF3 phosphorylation downstream of the cGAS-STING signal.In a murine model of CT-26 tumors,Daxx knockdown amplified the OXA-mediated tumor growth inhibition by promoting STING activation and immune responses.Conclusions:Our findings show that the degradation of nuclear Daxx potentiates the cGAS-STING pathway,thereby bolstering the efficacy of chemotherapy.
基金Supported by Russian Science Foundation,No.23-25-00183.
文摘BACKGROUND We previously demonstrated that the antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)is a promising new marker of programmed death-ligand 1(PD-L1)expression that correlates with both breast cancer(BC)clinicopathological characteristics and tumor sensitivity to chemotherapy.However,the concordance of PDCD1 LG1 expression scoring with immunohistochemical(IHC)tests approved for clinical use and with the polymerase chain reaction(PCR)method has not been previously studied.AIM To evaluate the concordance of methods for assessing PD-L1 expression,IHC tests with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and PCR.METHODS This prospective single-center observational cohort study included 148 patients with BC.PD-L1 expression in immune cells was assessed by the IHC method with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and by PCR.The concordance of PD-L1 scores between tests was assessed with positive percentage agreement(PPA)and negative percentage agreement(NPA).The strength of the agreement between the methods was calculated via the Cohen kappa index.P<0.05 was considered statistically significant.RESULTS Regardless of the method used to assess marker expression,PD-L1 expression was significantly more often detected in patients with negative estrogen receptor status,human epidermal growth factor receptor-2-positive(HER2+)status,luminal B HER+BC,nonluminal HER+BC and triple-negative BC.PPA and NPA were 38.3%and 70.4%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(SP142);26.3%and 63.3%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(PCR);and 36.5%and 74.4%,respectively,for PD-L1(SP142)and PD-L1(PCR).Cohen's kappa index for PD-L1(PDCD1 LG1)and PD-L1(SP142)was 0.385(95%CI:0.304–0.466),that for PD-L1(PDCD1 LG1)and PD-L1(PCR)was 0.207(95%CI:0.127–0.287),and that for PD-L1(SP142)and PD-L1(PCR)was 0.389(95%CI:0.309–0.469).CONCLUSION Thus,all three markers of PD-L1 expression are associated with the characteristics of aggressive BC,demonstrating moderate concordance between the tests.
