Life sciences最新文献

{"title":"The role of machine learning in predictive toxicology: A review of current trends and future perspectives","authors":"Olawale M. Ajisafe ,&nbsp;Yemi A. Adekunle ,&nbsp;Eghosasere Egbon ,&nbsp;Covenant Ebubechi Ogbonna ,&nbsp;David B. Olawade","doi":"10.1016/j.lfs.2025.123821","DOIUrl":"10.1016/j.lfs.2025.123821","url":null,"abstract":"<div><div>Adverse drug reactions (ADRs) are a major challenge in drug development, contributing to high attrition rates and significant financial losses. Due to species differences and limited scalability, traditional toxicity testing methods, such as in vitro assays and animal studies, often fail to predict human-specific toxicities accurately. The emergence of artificial intelligence (AI) and machine learning (ML) has introduced transformative approaches to predictive toxicology, leveraging large-scale datasets such as omics profiles, chemical properties, and electronic health records (EHRs). These AI-powered models provide early and accurate identification of toxicity risks, reducing reliance on animal testing and improving the efficiency of drug discovery. This review explores the role of AI models in predicting ADRs, emphasizing their ability to integrate diverse datasets and uncover complex toxicity mechanisms. Validation techniques, including cross-validation, external validation, and benchmarking against traditional methods, are discussed to ensure model robustness and generalizability. Furthermore, the ethical implications of AI, its alignment with the 3Rs principle (Replacement, Reduction, and Refinement), and its potential to address regulatory challenges are highlighted. By expediting the identification of safe drug candidates and minimizing late-stage failures, AI models significantly reduce costs and development timelines. However, challenges related to data quality, interpretability, and regulatory integration persist. Addressing these issues will enable AI to fully revolutionize predictive toxicology, ensuring safer and more effective drug development processes.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123821"},"PeriodicalIF":5.2,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144491203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative machine learning and structure-based drug repurposing for identifying potent inhibitors of human SYK activity against cancer","authors":"Muhammad Waleed Iqbal ,&nbsp;Xinxiao Sun ,&nbsp;Raghul Subin Sasidharan ,&nbsp;Syed Zeeshan Haider ,&nbsp;Khalid A. Al-Ghanim ,&nbsp;Muhammad Zohaib Nawaz ,&nbsp;Qipeng Yuan","doi":"10.1016/j.lfs.2025.123814","DOIUrl":"10.1016/j.lfs.2025.123814","url":null,"abstract":"<div><div>Overexpression of the spleen tyrosine kinase (SYK) has been found associated with different cancer types. Despite the investigation of inhibitors of SYK including fostamatinib, entospletinib, cerdulatinib, and TAK-659 for cancer therapy, their lack of specificity and potential off-target effects remain significant concerns. Addressing the need for targeted and non-toxic SYK inhibitors, this study integrates machine learning with structure-based drug design. Using bioactivity data, we employed machine learning algorithm, random forest, to screen an FDA-approved drug library. Molecular docking and dynamics simulations were then conducted to assess binding affinities and stability of identified compounds. Rifabutin, darunavir, and sildenafil were found as promising SYK inhibitors, showing strong interactions and stable conformations. Analysis of RMSD, RMSF, RoG, hydrogen bonding, PCA, and MMGBSA/MM-PBSA supported their efficacy as safer alternatives to current inhibitors. Our findings underscore the value of computational methods in drug discovery and advocate for further experimental validation of these compounds as SYK-targeted therapies. This study aims to advance the development of more effective and safer treatments for cancers associated with SYK overexpression.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123814"},"PeriodicalIF":5.2,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144365689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dapagliflozin attenuates diabetic cardiomyopathy via NRF2 protein upregulation-driven glutathione synthesis to inhibit myocardial ferroptosis","authors":"Xuepin Chen ,&nbsp;Tianying Wang ,&nbsp;Yan Gao ,&nbsp;Guoan Wang ,&nbsp;Likun Zhuang ,&nbsp;Xi Liu ,&nbsp;Li Gong ,&nbsp;Mengran Wang ,&nbsp;Hongyan Dai ,&nbsp;Jun Guan","doi":"10.1016/j.lfs.2025.123819","DOIUrl":"10.1016/j.lfs.2025.123819","url":null,"abstract":"<div><h3>Aims</h3><div>Ferroptosis has emerged as a critical pathological mechanism contributing to the development and progression of type 2 diabetic cardiomyopathy (DCM). Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i) with established cardiovascular benefits, however, DAPA's efficacy in modulating ferroptosis during type 2 DCM remains to be elucidated.</div></div><div><h3>Methods and fundings</h3><div>In vivo, using a spontaneously diabetic Goto-Kakizaki (GK) rat model, we conducted proteomic profiling revealing distinct myocardial ferroptosis signatures associated with dysregulated glutathione metabolism across normal control, GK and GK + DAPA groups. Subsequent validation demonstrated characteristic ferroptosis markers in diabetic myocardium, including elevated Fe²⁺ level, increased Fe³⁺ deposition, heightened malondialdehyde (MDA)-mediated lipid peroxidation, and ultrastructural mitochondrial aberrations. DAPA administration (5 mg/kg/d) significantly restored glutathione homeostasis, mitigated myocardial ferroptosis and remodeling and enhanced cardiac function. This effect correlated with upregulated expression of ferroptosis regulators: NRF2, SLC7A11, GPX4 and FTH-1 proteins. Cardiomyocyte-specific AAV9-mediated <em>Nrf2</em> overexpression and pharmacological interventions (erastin/ferrostatin-1) identified NRF2 as the key mediator of DAPA's anti-ferroptotic action. Notably, DAPA rescued erastin-induced ferroptosis in DCM. In vitro, validation using high glucose-stimulated H9C2 cardiomyocytes replicated the ferroptotic phenotype, showing iron overload, MDA and lipid ROS elevation, and mitochondrial depletion. Genetic <em>Nrf2</em> silencing, genetic <em>Gpx4</em> silencing or erastin treatment exacerbated these effects, while both DAPA (10μM) and ferrostatin-1 (10 μM) demonstrated comparable ferroptosis inhibition.</div></div><div><h3>Significance</h3><div>DAPA attenuates type 2 DCM via NRF2 protein upregulation-driven glutathione synthesis to inhibit myocardial ferroptosis, identifying upregulation of NRF2 as a promising therapeutic target for ferroptosis intervention in type 2 DCM.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123819"},"PeriodicalIF":5.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144471083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD4+TH17 cells play a critical role in conferring resistance to Trypanosoma cruzi infection while also demonstrating potential in mitigating the development of severe cardiac complications","authors":"Mariana Costa Duarte ,&nbsp;Gildo Pedro Ribeiro ,&nbsp;Ana Maria Ravena Severino Carvalho ,&nbsp;Rafaela Donadoni de Souza ,&nbsp;Matheus Ribeiro Ávila ,&nbsp;Lucas Fróis Fernandes de Oliveira ,&nbsp;Thiago Miranda de Souza ,&nbsp;Sanny Cristina de Castro Faria ,&nbsp;Daniella Castanheira Bartholomeu ,&nbsp;Níbia Mariana Eleutério ,&nbsp;Matheus Fernandes Costa-Silva ,&nbsp;Fernanda Alvarenga Cardoso Medeiros ,&nbsp;Manoel Otávio da Costa Rocha ,&nbsp;Henrique Silveira Costa ,&nbsp;Daniel Menezes-Souza","doi":"10.1016/j.lfs.2025.123815","DOIUrl":"10.1016/j.lfs.2025.123815","url":null,"abstract":"<div><div>Chagas disease (CD), caused by <em>Trypanosoma cruzi</em>, persists as a global health challenge characterized by a complex immunopathogenesis. CD4⁺ T_H17 cells, producers of the pro-inflammatory cytokine IL-17A, have been implicated in various inflammatory and cardiac diseases, but their role in CD remains debated. This study investigated the role of T_H17 IL-17A⁺ cells in Chagasic patients, focusing on their contribution to the immune response and cardiac protection. Our results demonstrated a distinct and potentially protective role for T_H17 IL-17A⁺ cells in CD, particularly in the absence of dilated cardiomyopathy. In patients without systolic dysfunction, we observed an accentuated T_H17 response, with elevated IL-17A expression, associated with favourable echocardiographic parameters, such as left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVDd). Furthermore, we observed an inverse correlation between IL-17A expression and intracellular parasite burden, suggesting a role for IL-17A in infection control. This study highlights the complex immunomodulatory role of T_H17 cells in chronic Chagas cardiomyopathy (CCC). IL-17A may be a therapeutic target for preserving cardiac function and controlling parasite persistence in Chagasic patients, especially prior to the development of severe cardiac dysfunction.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123815"},"PeriodicalIF":5.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144365619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improvement of the stability of ginsenoside Rg5 and its pharmacological efficacy in nonalcoholic steatohepatitis","authors":"Jiahui Ma ,&nbsp;Xue Bai ,&nbsp;Zhiguang Duan ,&nbsp;Rongzhan Fu ,&nbsp;Wen Zeng ,&nbsp;Yang Li ,&nbsp;Zhenghui Guan ,&nbsp;Chenhui Zhu","doi":"10.1016/j.lfs.2025.123818","DOIUrl":"10.1016/j.lfs.2025.123818","url":null,"abstract":"<div><h3>Aims</h3><div>Ginsenoside Rg5 (Rg5) has been certified to have superior activity in relieving the symptoms of non-alcoholic steatohepatitis (NASH). Nevertheless, the potential application of Rg5 is limited owing to its instability during storage. This study aims to enhance the stability of Rg5 through structural modification and evaluate its efficacy in treating NASH.</div></div><div><h3>Materials and methods</h3><div>The modification involved the hydrogenation of the double bonds at C-20 (22) and C-24 (25) to form 2H-ginsenoside Rg5 (2H<img>Rg5). We used spectroscopic techniques including H-NMR, C-NMR, and high-resolution mass spectrometry to characterize the structure of 2H<img>Rg5. In addition, we used High-performance liquid chromatography (HPLC) to study the stability changes through stability experiments at 25 or 60°C for 25 days. We created NASH models in vitro and in vivo and used transcriptomics, molecular docking, and molecular dynamics simulations to examine the impact of 2H<img>Rg5 on NASH lipid accumulation, fibrosis, and liver inflammation.</div></div><div><h3>Key findings</h3><div>After 25 days at 60°C, 2H<img>Rg5 retained 82.7% of the active content compared to 9.4% for Rg5<em>,</em> with superior reduction in lipid accumulation, inflammation, and fibrosis in NASH mice. 2H<img>Rg5 inhibits the STING-TBK1-IRF3 pathway and reduces type I interferon release and inflammation. Moreover, the high binding efficiency and remarkable system stability between 2H<img>Rg5 and STING further support our findings.</div></div><div><h3>Significance</h3><div>2H<img>Rg5 provides improved storage stability and efficacy, making it a promising therapeutic candidate for NASH.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123818"},"PeriodicalIF":5.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological role of cytochrome P450 family 1 subfamily A member 1 (CYP1A1) in ketogenic diet-induced modulation of lung cancer","authors":"Jaehyeon Kang ,&nbsp;Dong Soo Seo ,&nbsp;Yusra Ahmad ,&nbsp;Sungjun Park ,&nbsp;Jeongwoo Yoo ,&nbsp;Junhyeok Lee ,&nbsp;Seungwoo Baek ,&nbsp;Sungmin Joo ,&nbsp;Huiyoung Kwon ,&nbsp;Ho Jung Bae ,&nbsp;Heedoo Lee ,&nbsp;Taeg Kyu Kwon ,&nbsp;Younghoon Jang","doi":"10.1016/j.lfs.2025.123811","DOIUrl":"10.1016/j.lfs.2025.123811","url":null,"abstract":"<div><div>Cancer is a metabolic disease influenced by diet, diet-related nutrients, the tumor microenvironment, and metabolic signaling, all of which can significantly affect cancer progression. Although ketogenic diet (KD) has gained attention for its potential therapeutic effects in cancer, the relationship between KD, cancer biology, and metabolic signaling remains underexplored. In this study, we aimed to investigate the effect of KD on lung cancer biology using an in vivo model developed with AAV and CRISPR-Cas9 knock-in mice fed either a KD or high-carbohydrate diet (HCD). RNA-seq analysis revealed that KD markedly upregulated expression of Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) in lung cancer tissues compared to HCD. Protein analysis confirmed increased CYP1A1 levels under KD independently of aryl hydrocarbon receptor (AhR) protein levels. Similarly, in A549 and H460 human lung cancer cells treated with β-hydroxybutyrate and low-glucose conditions mimicking KD, CYP1A1 expression was also elevated. Interestingly, we observed that CYP1A1 expression is dependent on AhR activity and nuclear translocation in A549 cells in vitro. Transcriptome analysis of CYP1A1 knockdown A549 cells indicated that CYP1A1 is crucial for regulating cell cycle genes, including cyclin D. These findings highlight the biological significance of CYP1A1 in KD-induced changes in lung cancer, suggesting its role in cell proliferation and tumor development. This study also provides insights into the metabolic signaling underlying the effects of KD on cancer, offering potential directions for future therapeutic strategies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123811"},"PeriodicalIF":5.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α depletion regulates autophagy to improve arteriosclerosis obliterans of the lower extremities via the TSP-1/CD47 axis","authors":"Haichao Wu ,&nbsp;Xianfei Zhou ,&nbsp;Yang Zhang ,&nbsp;Long Zhou ,&nbsp;Qiang Wang ,&nbsp;Tao Wang ,&nbsp;Siyuan Liang","doi":"10.1016/j.lfs.2025.123817","DOIUrl":"10.1016/j.lfs.2025.123817","url":null,"abstract":"<div><h3>Aims</h3><div>Hypoxia-inducible factor 1α (HIF-1α) is overexpressed in vascular smooth muscle cells (VSMCs) and Arteriosclerosis obliterans (ASO) of the lower extremities, one of the peripheral arterial diseases (PAD), but its role in ASO autophagy remains unclear. This study aims to explore the effects of HIF-1α and autophagy on ASO.</div></div><div><h3>Materials and methods</h3><div>Hypoxic VSMCs and VSMC-macrophage co-culture models were treated with lificiguat (YC-1) or small Interfering RNA (siRNA) to deplete HIF-1α. Observing cell proliferation, apoptosis, migration, and invasion was used cell counting kit-8, flow cytometry, 5-Ethynyl-2′-deoxyuridine staining, wound-healing and Transwell assays. Observing autophagy was used Transmission electron microscopy and western blot (WB). ASO rats treated with YC-1, autophagy activator rapamycin (RAPA), or autophagy inhibitor 3-Methyladenine (3-MA) were underwent Oil red O, Hematoxylin and Eosin staining, immunohistochemistry, enzyme-linked immunosorbent assay and WB.</div></div><div><h3>Key findings</h3><div>HIF-1α depletion decreased cell viability, proliferation, and autophagic flux. Silencing HIF-1α inhibited migration and invasion, the thrombospodin-1 (TSP-1)/cluster of differentiation (CD) 47 pathway, Beclin-1 and microtubule-associated proteins 1 A/1B light chain 3-II levels and increased apoptosis and sequestosome 1. RAPA or overexpressing TSP-1/CD47 antagonized these effects. Silencing HIF-1α also promoted mTOR phosphorylation, macrophage-induced apoptosis, suppressing the TSP-1/CD47 pathway and overexpressing TSP-1/CD47 reversed these effects. In ASO rat femoral arteries, HIF-1α depletion attenuated lipid deposition and autophagy-related protein expression, while increasing the TSP-1/CD47 pathway activity, apoptosis-related protein levels, serum inflammation markers, and cell adhesion molecule concentration.</div></div><div><h3>Significance</h3><div>HIF-1α/TSP-1/CD47 axis is critical for VSMC activation and ASO progression. This research highlighted HIF-1α and autophagy as potential therapeutic targets for ASO.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123817"},"PeriodicalIF":5.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLIPR2 regulates EndoMT and cardiac fibrosis after AMI via PDGFRL/AKT/mTOR signaling pathway","authors":"Sijun Yuan ,&nbsp;Shujun Yang ,&nbsp;Yajie Guo ,&nbsp;Zijie Huang,&nbsp;Wan Li,&nbsp;Cuicui Meng,&nbsp;Yibei Xie,&nbsp;Shuangmei Li,&nbsp;Xuxiang Chen,&nbsp;Huibao Long,&nbsp;Haidong Wu,&nbsp;Tong Wang","doi":"10.1016/j.lfs.2025.123816","DOIUrl":"10.1016/j.lfs.2025.123816","url":null,"abstract":"<div><h3>Background</h3><div>The endothelium-mesenchymal transition (EndoMT) is a pivotal mechanism in cardiac fibrosis following acute myocardial infarction (AMI), as endothelial cells are a primary source of interstitial stromal cells contributing to organ fibrosis. Glioma pathogenesis-related protein 2(GLIPR2) has been reported to be associated with EndoMT, but whether it can regulate cardiac fibrosis is unknown. This study aimed to explore the contribution of GLIPR2 to post-AMI fibrosis and its underlying mechanism.</div></div><div><h3>Methods</h3><div>Serum protein levels of GLIPR2 were measured in patients with AMI. LAD ligation surgery was used to establish AMI animal models in C57BL/6 J mice. Adeno-associated virus (AAV)-targeted knockdown of GLIPR2 was employed to investigate the effects of GLIPR2 on cardiac fibrosis, cardiac pumping function, and EndoMT after AMI in mice. In human cardiac microvascular endothelial cells (HCMECs), GLIPR2 overexpression and knockdown via lentivirus (LV) were utilized to examine angiogenesis, migration, proliferation, and EndoMT under hypoxic conditions.</div></div><div><h3>Results</h3><div>In the serum of AMI patients, GLIPR2 expression was significantly increased. In mice with AMI, GLIPR2 knockdown reversed EndoMT, attenuated heart fibrosis, and partially restored ventricular pumping function. In a hypoxic cell model, GLIPR2 overexpression enhanced cell proliferation, migration, neovascularization, and EndoMT, whereas GLIPR2 knockdown inhibited these processes. Furthermore, transcriptome sequencing and recovery studies identified the platelet-derived growth factor receptor-like protein (PDGFRL)/AKT/mTOR pathway as a critical regulator of GLIPR2-mediated EndoMT.</div></div><div><h3>Conclusions</h3><div>GLIPR2 promotes cardiac fibrosis repair by regulating EndoMT through the PDGFRL/AKT/mTOR signaling pathway. Its inhibition represents a potential therapeutic strategy to mitigate cardiac fibrosis and improve ventricular function following AMI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123816"},"PeriodicalIF":5.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “TRAF2 mediates Wnt-induced β-catenin nuclear translocation by associating with nuclear pore complex” [Life Sci. 377 (2025) 123722]","authors":"Min Yang ,&nbsp;Ying Xuan ,&nbsp;Piliang Hao ,&nbsp;Yushu Li ,&nbsp;Chengqian Zhang ,&nbsp;Weiwei Zhao ,&nbsp;Yiyuan Zhang ,&nbsp;Xue Zhang ,&nbsp;Xianglian Zhou ,&nbsp;Hongyan Zhu ,&nbsp;Huihui Li ,&nbsp;Yan Yang ,&nbsp;Jiaqi Wang ,&nbsp;Rong Yan ,&nbsp;Yi Qu ,&nbsp;Xisong Ke","doi":"10.1016/j.lfs.2025.123806","DOIUrl":"10.1016/j.lfs.2025.123806","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123806"},"PeriodicalIF":5.2,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role and mechanism of the NLRP3-IL-1β/IL-18 signaling axis in the progression of sepsis under an aging phenotype","authors":"Chuchu Xu ,&nbsp;Renjun Zhu ,&nbsp;Qingfeng Dai ,&nbsp;Guangen Xu ,&nbsp;Guolin Zhang","doi":"10.1016/j.lfs.2025.123812","DOIUrl":"10.1016/j.lfs.2025.123812","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the impact of age on sepsis outcomes and explore potential therapeutic targets using the mouse model.</div></div><div><h3>Materials and methods</h3><div>Sepsis was induced via cecal ligation and puncture (CLP) in naturally aged mice (18 months) and young mice (3 months). Sepsis severity, mortality rates, bacterial loads, and cytokine levels (IL-18 and IL-1β) were compared between the two groups. NLRP3 expression was analyzed in various organs. Additionally, NLRP3 inhibitor MCC950 and specific antibodies against IL-18 and IL-1β were administered to assess their therapeutic effects. Note: This study was partially based on human samples.</div></div><div><h3>Key findings</h3><div>Aged mice demonstrated more severe sepsis symptoms and increased mortality compared to young mice. Elevated levels of IL-18 and IL-1β were observed in aged septic mice, indicative of augmented NLRP3 inflammasome activation. Human data corroborated these findings, showing higher serum levels of IL-18 and IL-1β in older sepsis patients. Treatment with NLRP3 inhibition (MCC950) and antibodies against IL-18 and IL-1β alleviated sepsis symptoms in aged mice, suggesting these pathways as potential therapeutic targets.</div></div><div><h3>Significance</h3><div>The study highlights the critical role of the NLRP3-IL-18/IL-1β axis in age-related disparities in sepsis outcomes and suggests potential therapeutic targets for improving outcomes in aged sepsis patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"378 ","pages":"Article 123812"},"PeriodicalIF":5.2,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}