Journal of Advanced Research最新文献

{"title":"Trained immunity modulators: A new frontier in immunoregulation and disease intervention","authors":"Jiao Chen, Chenxi Wang, Shilin Chen, Hui Cai, Mengke Wang, Jingjie Chang, Xueting Cai, Jie Yang, Peng Cao","doi":"10.1016/j.jare.2025.09.029","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.029","url":null,"abstract":"<h3>Background</h3>Immunotherapy has emerged as one of the most revolutionary approaches in disease treatments. However, most current and emerging immunotherapeutic strategies primarily target the adaptive immune system. Recent studies have elucidated that innate immune myeloid cells can develop sustained phenotypic modifications upon exposure to specific immunomodulators, mediated through coordinated metabolic alterations and epigenetic reprogramming. These changes lead to either hyperresponsive or hyporesponsive innate immune cells when exposed to secondary stimuli, a phenomenon termed “trained immunity”. Over the past decade, trained immunity has garnered increasing attention for its potential to enhance host defense. While numerous studies have investigated trained immunity modulators, comprehensive reviews—especially those focusing on recently identified modulators—are still lacking.<h3>Aim of review</h3>This review aims to elucidate the molecular mechanisms underlying trained immunity and its dual roles in various pathological conditions. We provide a comprehensive summary of the classifications and mechanisms of trained immunity inducers and suppressors identified in the past decade, emphasizing their therapeutic potential in immune-related diseases. Additionally, we discuss the limitations of these trained immunity modulators and offer insights into future directions for developing novel therapies targeting trained immunity.<strong>Key scientific concepts of review:</strong> This review first provide an overview of the molecular mechanisms underlying trained immunity, highlighting both its beneficial and detrimental effects on various diseases. Then it focuses on summarizing the classification and mechanisms of trained immunity modulators, including vaccines, polysaccharides, nanobiologics, endogenous mediators and other non-canonical modulators. Finally, the limitations of current trained immunity modulators and insights into future directions for developing novel therapies targeting trained immunity are proposed.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"18 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints","authors":"Beibei Ran, Lingjun Xiao, Yan Liu, Chenglin Zhang, Lingkai Kong, Yuxin Zhang, Xiaosong Gu, Chunping Jiang, Junhua Wu","doi":"10.1016/j.jare.2025.09.025","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.025","url":null,"abstract":"<h3>Background</h3>Tumor-associated macrophages depend on their amino acid metabolism to determine their properties and immune function and play important roles in the tumor microenvironment (TME). Although in previous studies, targeting amino acid metabolism to transform the protumor function of tumor-associated macrophages (TAMs) into antitumor immune function has shown promising application as a tumor therapy, current clinical research is still limited. There is a lack of discussion on the mechanism and treatment strategy for determining tumor progression by controlling amino acid metabolism in TAMs, as does a summary of studies on promoting tumor progression by reshaping amino acid metabolism in TAMs.<h3>Aim of review</h3>This review aims to systematically review and summarize the crosstalk between amino acid metabolism in TAMs and the TME, analyze the determining role of its metabolic network in tumor occurrence and development, and summarize therapies on this basis to help determine the development status and emerging technologies in the field of amino acid metabolism in TAMs for tumor therapy.<h3>Key scientific concepts of review</h3>This review dissects how TAMs exploit amino acid dynamics via transporters, enzymes, and sensors to adopt protumoral phenotypes, depleting critical metabolites and crippling antitumor T-cell responses. We map the immunometabolic crosstalk through which TAMs reshape immunity, highlighting nutrient competition and metabolic byproducts as dual drivers of immune dysfunction. Emerging therapeutic strategies targeting these pathways (IFN-γ-JAK-STAT1 and IL-6/JAK2/STAT3) have been critically evaluated for their potential to reprogram TAMs and reverse immunosuppression. Key challenges, such as TAM heterogeneity, metabolic plasticity, and therapy resistance, are addressed, emphasizing the need for single-cell-resolution mapping of TAM metabolic states to identify context-dependent vulnerabilities. Finally, we advocate for combinatorial approaches that couple metabolic rewiring with immunotherapies, proposing that disrupting amino acid dependencies in TAMs could dismantle the immunosuppressive TME.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"79 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota: A key player for soluble dietary fiber in regulating inflammatory disease","authors":"Linkai Qu, Ruining Zhang, Ziyu Chu, Jiapei Cai, Yuhang He, Xinyu Zhang, Jiuxi Liu, Xufeng Xie, Yongguo Cao","doi":"10.1016/j.jare.2025.09.030","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.030","url":null,"abstract":"Soluble dietary fiber (SDF) plays a significant role in modulating immune responses, particularly in the context of inflammatory diseases. SDF enhances intestinal barrier integrity and regulates immune function by modulating the composition of the gut microbiota and increasing the production of beneficial microbial metabolites, such as short-chain fatty acids (SCFAs), 3-hydroxyoctadecaenoic acid, pentadecanoic acid, and bile acids. Current evidence suggests that SDF holds therapeutic potential in managing chronic inflammatory diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and metabolic dysfunction-associated steatohepatitis (MASH). Despite these promising findings, the mechanisms by which SDF exerts its effects, particularly in distal organs and neuroinflammatory conditions, remain poorly understood. This review explores the mechanistic pathways by which SDF modulates immune regulation and highlights the current challenges and future strategies for optimizing its clinical application in treating inflammatory diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"84 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145072052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics elucidation of recombinant collagen‐mediated modulation of mesenchymal stem cell functions","authors":"Taishan Liu, Juanli Dang, Chenhui Zhu, Xiaoxuan Ma, Linlin Qu, Huan Lei, Daidi Fan","doi":"10.1016/j.jare.2025.09.032","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.032","url":null,"abstract":"<h3>Introduction</h3>Regenerative medicine leverages the potential of mesenchymal stem cells (MSCs) and biomaterials to overcome the limitations of traditional organ transplantation. Collagen, a key extracellular matrix component, is widely used, yet its molecular interactions with MSCs remain insufficiently understood.<h3>Objectives</h3>This study investigates how recombinant collagens modulate MSC behavior and paracrine functions to inform the development of bioactive scaffolds for tissue regeneration.<h3>Methods</h3>Recombinant type I and III collagens were biosynthesized using Pichia pastoris. Multi-omics analyses, including transcriptomics and proteomics, were conducted to evaluate the effects of these collagens on MSC gene expression, secretory profiles, and functional impacts on fibroblasts, endothelial cells, and macrophages.<h3>Results</h3>Recombinant collagens regulated key MSC pathways related to angiogenesis, wound healing, adhesion, cytoskeletal organization, and osteogenesis. Proteomic data further revealed enhanced secretion of cytokines and growth factors that influenced the behavior of surrounding stromal and immune cells.<h3>Conclusion</h3>Recombinant collagen, as a bioactive material, can remodel the functions of mesenchymal stem cells. Specifically, recombinant type I collagen primarily activates the FAK/RHOA/ROCK signaling pathway, while recombinant type III collagen activates the PI3K/Akt signaling pathway; in contrast, bovine-derived type I collagen mainly regulates glycolysis. These findings further support the potential of recombinant collagen in constructing regenerative medicine scaffolds with intelligent regulatory functions.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative proteomic characterization of human lung adenocarcinoma with KRAS G12 mutations reveals molecular pathogenesis","authors":"Xinyu Shi, Liling Hu, Yongshi Huang, Mei-Fang Zhang, Xingfeng Ying, Xiaoyi Yuan, Nengqiao Wen, Jiangli Lu, Hanchen Zou, Xiaohui Tan, Qing-Yu He, Fang Wang, Hong Yang, Chris Zhiyi Zhang","doi":"10.1016/j.jare.2025.09.014","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.014","url":null,"abstract":"<h3>Introduction</h3>Integrated proteogenomic studies of lung adenocarcinoma (LUAD) have provided unique insights with potential clinical effects. Comprehensive proteomic analyses are needed to better understand the molecular landscape of LUAD with <em>KRAS</em> G12 mutations.<h3>Objectives</h3>This study aims to characterize the proteogenomic profile of LUAD with KRAS G12 mutation variants.<h3>Methods</h3>We performed next-generation sequencing (NGS) on 9,479 solid tumors, including 3,523 lung cancers. Proteomic profiling was conducted on 96 LUAD patients with KRAS G12 mutations or wild-type status using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LUAD tumor immune microenvironment (TIME) was characterized by multiplex immunohistochemistry (mIHC), and protein–protein interactions (PPIs) in KRAS G12-mutant lung cancer cells were mapped using biotin-based proximity labeling.<h3>Results</h3>Genomic analysis revealed heterogeneous KRAS-informed mutational profiles across pan-cancer and lung cancer, with allele-specific resolution for KRAS G12 mutations. Proteomic profiling of KRAS G12-mutant LUAD delineated distinct molecular features and tumor progression hallmarks. Unsupervised clustering identified three molecular subtypes, with the immune modulation subtype (S2) characterized by KRAS G12C enrichment, aggressive clinical features, and the greatest potential benefit from immunotherapy. The immune landscape of LUAD showed increased immune cell infiltration in KRAS G12C-mutant tumors. Additionally, proximal proteomics mapped a landscape of gain-of-interactions driven by KRAS G12 mutations, with ion transporter SLC4A7 emerged as a potential effector in immune modulation in the G12C variant.<h3>Conclusions</h3>This comprehensive proteogenomic study provides insights into the molecular features of LUAD harboring <em>KRAS</em> G12 mutations, which may inform patient stratification and potential therapeutic approaches, pending further clinical validation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"3 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The global burden of non-communicable diseases attributable to behavioral risk factors and its trends from 1990 to 2021","authors":"Xiaohan Geng, Fengzhi Liang, Peigang Wang","doi":"10.1016/j.jare.2025.09.022","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.022","url":null,"abstract":"<h3>Background</h3>Non-communicable diseases (NCDs) are one of the major challenges to global public health. High alcohol use, dietary risks, and low physical activity are three risk factors that can increase the burden of NCDs. Yet, a comprehensive study on the impacts of these three factors is currently lacking.<h3>Methods</h3>The estimated annual percentage changes (EAPCs) were used to quantify trends in disease burden. Additionally, correlation analysis was performed to explore the relationship between disease burden and the socio-demographic index (SDI). Frontier analysis was utilized to examine the potential development space of 204 countries and regions, and predictive analysis was employed to study the trend of burden over the next 15 years.<h3>Results</h3>From 1990 to 2021, the burden of NCDs caused by high alcohol use among males decreased significantly, with the disease burden most significant in the 40–90 age group. The disease burden caused by dietary risks in the 60–89 age group was evident. The burden of NCDs caused by low physical activity among females decreased significantly. In the next 15 years, the age-standardized mortality rate (ASMR) of NCDs will show a downward trend.<h3>Conclusions</h3>The burden of NCDs has decreased but remains heavy. Countries should formulate and implement corresponding public health policies in light of their actual situations to reduce the disease burden.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"111 3S 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CPK3-mediated cytosolic–nuclear translocation of bHLH107 recruits HY5 to regulate the Cu2+-triggered upregulation of ACS8","authors":"Yue Yu, Haoran Xia, Haifeng Liu, Xiangsong Chen, Wenchao Huang, Zhaohui Chu","doi":"10.1016/j.jare.2025.09.023","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.023","url":null,"abstract":"<h3>Introduction</h3>Copper serves as a key component of plant micronutrients and copper-based antimicrobial compounds (CBACs), and it has been used to protect plants against diseases for more than 130 years. We previously revealed that low concentrations of Cu²⁺ elicit plant immune responses by activating the expression of the ethylene synthesis rate-limiting enzyme <em>1-aminocyclopropanecarboxylic acid (ACC) synthesis 8</em> (<em>ACS8</em>), which depends on the copper response element (CuRE) in the promoter. However, the transcription regulatory mechanism of Cu²⁺-triggered immunity upstream of <em>ACS8</em> remains unclear.<h3>Objectives</h3>Here, we aimed to identify the CuRE-binding transcription factor (CuTF) and elucidate it roles in activating the Cu²⁺-induced expression of <em>ACS8</em>.<h3>Methods</h3>To identify the CuTF and its interactors, we performed DNA-pull-down and mass spectrometry and protein phosphorylation proteomics assays. Cu²⁺-induced plant immune responses were conducted assays measuring the <em>ACS8</em> expression, bacterial populations and RNA-seq. Additionally, protein-DNA and protein–protein interactions were performed using yeast one hybridization, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR), pull-down, luciferase complementation assay, and coimmunopreciptitation assay.<h3>Results</h3>We identified a CuTF of basic helix-loop-helix 107 (bHLH107) which is required for Cu²⁺-triggered activation of <em>ACS8</em> expression and resistance to <em>Pseudomonas syringae</em> pv. <em>tomato</em> (<em>Pst</em>) DC3000. Calcium-dependent protein kinase 3 (CPK3) interacts with and phosphorylates bHLH107 at Ser62 and Ser72 to mediate bHLH107 translocation from the cytoplasm into the nucleus, leading to an increase in the transactivation activity of bHLH107. Moreover, our findings revealed that bHLH107 interacts with Arabidopsis ELONGATED HYPOCOTYL5 (HY5) in nucleus. HY5 directly binds to the ACGT-containing elements (ACE-box) and acts as a coactivator to promote bHLH107 binding to the CuRE <em>cis</em>-element and to increase transcription of <em>ACS8</em> upon Cu²⁺ treatment.<h3>Conclusion</h3>Overall, we revealed a CPK3-bHLH107-HY5 module that regulates the network of Cu²⁺-triggered plant immunity upstream of <em>ACS8</em> that is involved in the cytosolic-nuclear translocation of bHLH107.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"48 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The eternal struggle between titans: Fecal microbiota transplant (FMT) versus metformin in type 2 diabetes (T2D) gut dysmotility","authors":"Lucia La Sala, Valentina Carlini, Maria Belen Macas-Granizo, Emilio Trabucchi, Antonio E. Pontiroli, Cesare Berra, Angelo Naselli, Marco D’Anzeo, Andrea Porta, Jimmy Martin Delgado, Elena Vianello, Elena Dozio, Massimiliano Corsi Romanelli, Lorenzo Drago","doi":"10.1016/j.jare.2025.09.021","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.021","url":null,"abstract":"<h3>Background</h3>The prevalence of dysbiosis in type 2 diabetes (T2D) is increasing globally as a consequence of an imbalance in the distribution of gut microbial populations. Dysmotility of the gastrointestinal tract has emerged as a contributor to pathophysiology of T2D, where impaired motility may exacerbate dysbiosis and metabolic dysfunction.Current management of T2D, such as Metformin (Metf), demonstrate efficacy in improving metabolic parameters but are linked to gastrointestinal side effects, the mechanisms of which remain poorly understood.Novel promising therapeutic agents, based on the modulation of the gut microbiota has emerged for the treatment of metabolic disorders, particularly for T2D, in which Fecal microbiota transplant (FMT) assumes the major weight as strategy to improves insulin sensitivity and glucose tolerance, and potentially ameliorating gut motility. Although FMT represents a potential therapeutic alternative, its comparative effectiveness and safety profile relative to Metf in this specific setting remain to be established.<h3>Aim of the review</h3>This review aims to evaluate and compare these two potent modulators of microbial landscape, Metf and FMT, in addressing insulin resistance (IR) and gastrointestinal dysmotility in T2D. The study seeks to systematically delineate the mechanisms underlying their effects and assess their therapeutic potential, safety, and clinical efficacy.<h3>Key scientific concepts of the review</h3>The physiological roles of the gut microbiota and their metabolites are explored, highlighting their contribution to the onset and progression of metabolic disorders, particularly T2D. We examined the mechanisms through which Metf and FMT influence gut microbiota, insulin sensitivity, and glucose tolerance. Novel therapeutic approaches, including the combined use of Metf and FMT, are discussed in terms of molecular mechanisms, clinical outcomes, and safety profiles. Finally, the potential integration of these strategies into T2D management and their impact on gastrointestinal dysfunction are considered as areas for further research.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"34 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction drives ZBP1-mediated PANoptosis to increase the susceptibility of heart failure with preserved ejection fraction-associated atrial fibrillation","authors":"Jinfeng Duan, Zijun Cao, Zijun Zhou, Xinyi Huang, Jikai Zhao, Yuting Huang, Tao Huang, Shan Meng, Xin Chen, Tao Hong, Tong Su, Bo Xing, Liming Yu, Huishan Wang","doi":"10.1016/j.jare.2025.09.016","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.016","url":null,"abstract":"<h3>Introduction</h3>Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by atrial fibrillation (AF), but underlying molecular mechanisms remain poorly defined. Mitochondrial dysfunction drives ZBP1-mediated PANoptosis is crucial in understanding the progression of HFpEF-associated AF and exploring novel therapeutic avenues.<h3>Objectives</h3>This study investigates the Z-DNA binding protein 1 (ZBP1) as a critical mediator linking mitochondrial dysfunction with PANoptosis by sensing mitochondrial Z-DNA (mtZ-DNA) in HFpEF-associated AF.<h3>Methods</h3>Variety of <em>in vivo</em> and <em>in vitro</em> experimental approaches were employed, majorly including HFpEF mouse model establishment, Histological staining, RNA sequencing, Western blotting, co-immunoprecipitation, Transmission electron microscopy (TEM) and confocal imaging.<h3>Results</h3>In a “Two-hit” HFpEF mouse model, we observed increased AF susceptibility with prolonged modeling. Additionally, bioinformatics analysis and <em>in vivo</em> and <em>in vitro</em> studies highlighted progressive ZBP1-mediated PANoptosis accompanied by mitochondrial dysfunction in HFpEF atria. Inflammation and cardiomyocyte loss caused by PANoptosis contributed to atrial remodeling and AF. Also, NAD⁺ depletion in HFpEF cardiomyocytes downregulated mitochondrial topoisomerases (TOP3A and TOP1MT) and mitochondrial DNA (mtDNA) stress, promoting mtZ-DNA formation. ZBP1 sensed and stabilized Z-DNA via its Zα1 domain and recruited Receptor-Interacting Protein Kinases (RIPKs) and Caspase8 to assemble the PANoptosome and initiate PANoptosis. Silencing Zbp1 alleviated atrial remodeling and reduced AF vulnerability. Moreover, NAD⁺ supplementation suppressed Z-DNA formation and ZBP1 activation by improving mitochondrial dysfunction. These findings identify ZBP1 as a molecular bridge between mitochondrial dysfunction and PANoptosis, highlighting its central role in HFpEF-associated AF pathogenesis. Targeting this axis may provide a promising therapeutic strategy combatting AF in HFpEF.<h3>Conclusions</h3>These findings identify ZBP1 as a molecular bridge between mitochondrial dysfunction and PANoptosis by sensing mitochondrial Z-DNA, highlighting its central role in HFpEF-associated AF pathogenesis. Targeting this axis may provide a promising therapeutic strategy combatting AF in HFpEF.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"35 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissemination of antimicrobial resistance in Klebsiella spp. from urban aquatic environments: a multi-country genomic perspective","authors":"Zelin Yan, Yan Li, Xiaoyang Ju, Hanyu Wang, Jing Zhang, Yanyan Zhang, Yuchen Wu, Chunzhen Wang, Dev Raj Joshi, Tista Prasai Joshi, Yu Zhang, Ruichao Li, Rong Zhang","doi":"10.1016/j.jare.2025.09.020","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.020","url":null,"abstract":"<h3>Introduction</h3>Antibiotic resistance, particularly carbapenem-resistant <em>Klebsiella pneumoniae</em> (CRKP), poses significant clinical and environmental threats, especially in urban aquatic ecosystems and hospital wastewaters.<h3>Objectives</h3>This study aims to analyze the epidemiological and genomic features of CRKP isolates in urban aquatic environments and evaluate their public health and environmental impacts.<h3>Methods and Results</h3>Water samples were collected from 113 rivers and 3 hospitals in China, Sri Lanka, and Nepal to isolate carbapenem-resistant <em>Klebsiella</em> spp. isolates. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatics analyses were performed to characterize resistance phenotypes, antibiotic resistance genes (ARGs), and evolutionary trends. Big data analysis further elucidated the genomic characteristics of CRKP in global water sources, and <em>Galleria mellonella</em> larvae were used to assess virulence. Statistical analysis validated the findings. A total of 192 carbapenem-resistant <em>Klebsiella</em> spp. isolates were identified from urban aquatic ecosystems in China (n = 60) and Nepal (n = 132), with CRKP (n = 161) being the predominant species. All CRKP isolates exhibited a multidrug-resistant phenotype, yet significant differences in resistance profiles and associated ARGs were observed between isolates from the two countries. Nine carbapenem resistance genes (CRGs) were detected, with <em>bla</em>_NDM-1 being the most prevalent (57.8 %). Correlation analysis revealed a strong association between these CRGs and multiple Inc-type plasmids. Global genomic analysis of CRKP from water sources across eight countries identified ten distinct CRGs across 45 serotypes, with KL64 being the most predominant. Notably, carbapenem-resistant hypervirulent <em>Klebsiella pneumoniae</em> was detected in water samples from Nepal.<h3>Conclusion</h3>Our findings highlight significant regional disparities in CRKP prevalence and ARG dissemination across urban aquatic environments, with Nepal showing the highest prevalence, particularly in untreated rivers. China exhibited lower prevalence but distinct resistance gene profiles, while no CRKP was detected in Sri Lanka, underscoring the impact of environmental management and healthcare infrastructure on ARG spread.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"17 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}