Life sciences最新文献

{"title":"ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications","authors":"Mengdi Zhang ,&nbsp;Shengbo Zhou ,&nbsp;Bing Han ,&nbsp;Yining Ge","doi":"10.1016/j.lfs.2026.124216","DOIUrl":"10.1016/j.lfs.2026.124216","url":null,"abstract":"<div><h3>Aims</h3><div>To elucidate the oncogenic role and mechanistic basis of ERCC6L in cutaneous melanoma, focusing on its impact on tumor metabolism and progression.</div></div><div><h3>Materials and methods</h3><div>Multi-omics bioinformatics analysis of public datasets (GEO, TCGA) defined the clinical relevance of ERCC6L. <em>In vitro</em> functional assays (CCK-8, colony formation, Transwell, flow cytometry) were performed in melanoma cell lines following genetic manipulation. Mechanistic studies employed gene set enrichment analysis, chromatin immunoprecipitation-quantitative PCR, dual-luciferase reporter assays, western blotting, and metabolic flux analysis. The functional significance of the ERCC6L-PLK1 axis was validated in an NSG mouse subcutaneous xenograft model.</div></div><div><h3>Key findings</h3><div>ERCC6L is significantly upregulated in melanoma tissues, and its high expression is an independent prognostic factor for poor survival. Genetic ablation of ERCC6L potently inhibited melanoma cell proliferation, migration, invasion, and tumor growth, while promoting apoptosis. Mechanistically, <em>ERCC6L</em> transcriptionally activates <em>PLK1</em> by directly binding to its promoter. This ERCC6L-PLK1 axis drives aerobic glycolysis (the Warburg effect), upregulating key glycolytic enzymes (GLUT1, LDHA, PKM2, HK2) and enhancing lactate production and ATP generation. Crucially, PLK1 inhibition or glycolysis blockade effectively reversed the tumor-promoting phenotypes induced by ERCC6L.</div></div><div><h3>Significance</h3><div>Our study identifies <em>ERCC6L</em> as a novel upstream transcriptional regulator of <em>PLK1</em> that fuels melanoma progression by reprogramming glucose metabolism. The ERCC6L-PLK1-glycolysis axis represents a promising prognostic biomarker and a potential therapeutic target for cutaneous melanoma.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124216"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018876","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":"Reversible ubiquitination regulates HSF1 phase separation in response to proteotoxic stress","authors":"Yue Zhu ,&nbsp;Jianhua Wang ,&nbsp;Shuhong Tang ,&nbsp;Zhiqiang Li ,&nbsp;Ruilin Wang ,&nbsp;Peng Wang ,&nbsp;Jiayu Li ,&nbsp;Shaoxuan Cheng ,&nbsp;Han Liu ,&nbsp;Yingqiu Zhang ,&nbsp;Zhaoxia Dai ,&nbsp;Qitao Yan ,&nbsp;Shuyan Liu","doi":"10.1016/j.lfs.2026.124224","DOIUrl":"10.1016/j.lfs.2026.124224","url":null,"abstract":"<div><h3>Aims</h3><div>Heat shock factor 1 (HSF1) undergoes phase separation to form nuclear condensates in response to proteotoxic stress, which governs cell fate. Protein ubiquitination is a widely existed post-translational modification and closely participated in liquid-liquid phase separation. However, the exact roles of ubiquitination in HSF1 condensation remain obscure. Here, we aimed to investigate the regulation of HSF1 phase separation by ubiquitination in cells under proteotoxic conditions.</div></div><div><h3>Materials and methods</h3><div>Endogenous and exogenous HSF1 condensate formation was detected by immunofluorescence assays. HSF1 phase separation properties were analyzed by fluorescence recovery after photobleaching (FRAP) analysis. Western blotting, immunofluorescence, immunoprecipitation and co-transfection assays were performed to identify E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) regulating HSF1 phase separation. The influence of ubiquitination sites on HSF1 phase separation was investigated by site-directed mutagenesis.</div></div><div><h3>Key findings</h3><div>Proteasome inhibitor PS341 induced HSF1 to form nuclear phase-separated condensates in a time-dependent manner. E3 ubiquitin ligase STUB1 promoted the phase separation of HSF1 by enhancing HSF1 ubiquitination, while DUBs USP13 and ATXN3 negatively regulated HSF1 condensation. Mutations of all nine ubiquitination sites within HSF1 dramatically inhibited condensate formation, with single-site mutations also showing significantly attenuated phase separation.</div></div><div><h3>Significance</h3><div>Ubiquitination at multiple lysine residues jointly drives HSF1 phase separation in cells exposed to proteotoxic stress, which is coordinately regulated by E3 ubiquitin ligase STUB1 and DUBs including USP13 and ATXN3.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124224"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044314","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":"Light exposure-induced circadian rhythm disruption impairs male reproductive health through oxidative stress and apoptosis","authors":"Guodong Liu ,&nbsp;Yuyang Zhang ,&nbsp;Hui Gao ,&nbsp;Xu Wu ,&nbsp;Feng Li ,&nbsp;Wei Zhang ,&nbsp;Hui Jiang ,&nbsp;Xiansheng Zhang","doi":"10.1016/j.lfs.2026.124222","DOIUrl":"10.1016/j.lfs.2026.124222","url":null,"abstract":"<div><h3>Aims</h3><div>Artificial light exposure at night and irregular light schedules are increasingly prevalent environmental stressors in modern society and have been implicated in male reproductive disorders. This study aimed to determine how distinct patterns of circadian rhythm disruption differentially affect male reproductive function and to elucidate the underlying mechanisms.</div></div><div><h3>Materials and methods</h3><div>Three groups of male rats were subjected to standard 12-h light/12-h dark cycles (LD), fixed inverted light-dark cycles (DL), and a dynamic alternating light-dark-dark-light cycle (LDDL) designed to induce circadian rhythm instability. Reproductive outcomes including body weight, testicular index, serum testosterone levels, and sperm parameters were assessed. Testicular oxidative status was evaluated by measuring NOX4/5, HO-1, SOD, and MDA levels, while apoptosis was examined using Bax/Bcl-2 ratio, cleaved caspase-3 expression, and TUNEL staining.</div></div><div><h3>Key findings</h3><div>Male rats exposed to the LDDL cycle exhibited significant reproductive dysfunction, manifested as markedly reduced testicular index, decreased serum testosterone concentration, and impaired sperm motility. Mechanistically, LDDL conditions enhanced testicular oxidative stress, manifested by NOX4/5 upregulation and HO-1/SOD suppression. This redox imbalance was accompanied by germ cell apoptosis activation, evidenced by elevated Bax/Bcl-2 ratios, increased cleaved caspase-3 expression, and a higher proportion of TUNEL-positive cells. Notably, reproductive damage was more pronounced under dynamic circadian rhythm disruption than under fixed light-dark reversal conditions.</div></div><div><h3>Significance</h3><div>By linking dynamically light-induced circadian disruption to testicular oxidative stress and apoptotic signaling pathways, it elucidates potential mechanisms by which modern lighting environments impair male fertility and provides strategies for circadian rhythm intervention and environmental mitigation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124222"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081266","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":"STAT1/SLC31A1 signaling promotes diabetic retinopathy progression by mediating cuproptosis-induced M1 polarization in microglial cells","authors":"Jiayang Huang ,&nbsp;Qiang Hu ,&nbsp;Xue Zhang ,&nbsp;Hongsong Peng ,&nbsp;Shan Luo ,&nbsp;Zhangxin Huang ,&nbsp;Jitian Guan ,&nbsp;Ali Hafezi-Moghadam ,&nbsp;Bo Jiang ,&nbsp;Dawei Sun","doi":"10.1016/j.lfs.2026.124241","DOIUrl":"10.1016/j.lfs.2026.124241","url":null,"abstract":"<div><div>One of the main causes of vision impairment in diabetics is diabetic retinopathy (DR). However, the molecular mechanisms controlling its progression remains incompletely known. In this research, we identified the STAT1/SLC31A1 signaling pathway as a key regulator of cuproptosis-induced M1 polarization in microglial cells, thereby contributing to the pathogenesis of DR. STAT1 expression was markedly elevated under settings of high glucose (HG), both in in vitro experiments and in streptozotocin (STZ)-induced diabetic mouse models. Mechanistically, STAT1 transcriptionally upregulated the copper transporter SLC31A1, leading to copper accumulation and enhanced cuproptosis, as indicated by decreased levels of L-DLAT, FDX1, and NDUFS8. This cellular stress promoted M1 polarization and increased the expression of pro-inflammatory cytokines. Inhibition of either STAT1 or SLC31A1 significantly attenuated HG-induced cuproptosis and microglial activation. In vivo, STAT1 inhibition reduced retinal inflammation and structural damage, supporting its pathological role in DR progression. These findings confirm that the STAT1/SLC31A1/cuproptosis axis is a critical driver of microglial polarization and retinal injury and imply that SLC31A1 may act as DR's potential therapeutic target.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124241"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081265","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":"Lactate promotes cuproptosis in acute kidney injury by activating H3K18 lactylation-dependent upregulation of HSPA6 expression","authors":"Mingxing Sui ,&nbsp;Jiazhao Fu ,&nbsp;Yuhong Li ,&nbsp;Junhao Yu ,&nbsp;Hanlan Lu ,&nbsp;Li Zeng ,&nbsp;Yanhua Li ,&nbsp;Wenyu Zhao","doi":"10.1016/j.lfs.2026.124244","DOIUrl":"10.1016/j.lfs.2026.124244","url":null,"abstract":"<div><h3>Aims</h3><div>The present study aims to investigate the role and mechanism of lactate-induced histone lactylation in regulating cuproptosis during renal IRI.</div></div><div><h3>Materials and methods</h3><div>We employed both in vivo (mouse IRI) and in vitro (HK-2 cell oxygen-glucose deprivation/reperfusion, OGD/R) models. Multi-omics analyses (proteomics, CUT&amp;Tag, RNA-seq) were integrated with molecular techniques (Western blot, transmission electron microscopy, biochemical assays, ChIP-qPCR, RT-qPCR) to examine histone lactylation and cuproptosis.</div></div><div><h3>Key findings</h3><div>Renal IRI led to significant lactate accumulation and a global increase in histone lactylation, with the H3K18 site being most prominently modified. Proteomics indicated significant enrichment of cuproptosis-related pathways, alongside copper dysmetabolism, mitochondrial damage, and elevated oxidative stress. Inhibition of lactate dehydrogenase (LDHA) reduced H3K18la levels and alleviated cuproptosis. Integrated multi-omics analysis identified HSPA6 (heat shock protein family A member 6) as a direct downstream target of H3K18la, linked to MAPK (mitogen-activated protein kinase) signaling. Lactate stimulation or inhibition reciprocally regulated HSPA6 expression via H3K18la, confirmed by ChIP-qPCR. Knockdown of HSPA6 effectively suppressed OGD/R-induced cuproptosis.</div></div><div><h3>Significance</h3><div>The present study unveils a previously unidentified epigenetic pathway in AKI, whereby lactate-driven H3K18 lactylation transcriptionally activates HSPA6, consequently promoting cuproptosis and exacerbating renal damage. The “lactate-H3K18la-HSPA6” axis has been identified as a promising new target for therapeutic intervention in AKI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124244"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081264","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":"Endothelial NLRP3 inflammasome activation drives immunothrombosis in Streptococcus pyogenes infection","authors":"Yi-Hsin Lai ,&nbsp;Ya-Hui Liu ,&nbsp;Jyun-You Chen ,&nbsp;Chung-Ta Lee ,&nbsp;Shu-Ying Wang ,&nbsp;Chuan Chiang-Ni ,&nbsp;Yueh-Hsia Luo ,&nbsp;Chia-Yu Chi ,&nbsp;Takeshi Noda ,&nbsp;Shiou-Ling Lu ,&nbsp;Yau-Sheng Tsai ,&nbsp;Jiunn-Jong Wu ,&nbsp;Pei-Jane Tsai","doi":"10.1016/j.lfs.2026.124239","DOIUrl":"10.1016/j.lfs.2026.124239","url":null,"abstract":"<div><div><em>Streptococcus pyogenes</em> (Strep A), a formidable human pathogen, is notorious for causing life-threatening diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome, often complicated by thrombosis and coagulation abnormalities. While macrophage inflammasome activation has been widely studied in Strep A pathogenesis, the contribution of vascular endothelial cells-key regulators of immunity and coagulation-remains largely unexplored. This study aimed to determine whether endothelial NLRP3 inflammasome activation drives immunothrombosis during invasive Strep A infection and to define the roles of streptolysin O (SLO) and streptolysin S (SLS) in this mechanism. Using a murine intramuscular infection model in wild-type and NOD-like receptor family pyrin domain-containing 3 (NLRP3)-deficient mice together with infection of human microvascular endothelial cells with wild-type or toxin-deficient Strep A strains, we found that Strep A robustly activated the endothelial NLRP3 inflammasome, leading to caspase-1 activation, IL-1β secretion, endothelial pyroptosis, and a cascade of immunothrombotic events. Genetic ablation of NLRP3 or pharmacological inhibition of caspase-1 significantly attenuated inflammasome activation, immunothrombosis, and tissue injury. Both SLO and SLS were essential for these pathogenic effects. These findings illuminate a hitherto unrecognized endothelial inflammasome-mediated axis in Strep A infection and pave the way for innovative therapeutic strategies targeting endothelial immune responses to combat invasive streptococcal diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124239"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092783","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":"Targeting the lysine methyltransferase Suv39h1 in cardiac fibroblasts attenuates post-infarct myocardial fibrosis","authors":"Shuai Liu ,&nbsp;Xiaoping Wu ,&nbsp;Yujia Xue ,&nbsp;Mengwen Qi ,&nbsp;Tianfa Li ,&nbsp;Yuanyuan Zhang ,&nbsp;Mingming Fang","doi":"10.1016/j.lfs.2026.124221","DOIUrl":"10.1016/j.lfs.2026.124221","url":null,"abstract":"<div><h3>Aims</h3><div>Adverse ventricular remodeling following myocardial infarction contributes to heart failure. Following cardiac injury, quiescent fibroblasts trans-differentiate into myofibroblasts and produce extracellular matrix proteins to initiate ventricular remodeling. We investigated the role of Suv39h1, a lysine methyltransferase, in this process.</div></div><div><h3>Methods</h3><div>Myocardial infarction was induced by permanent ligation of the left anterior descending (LAD) coronary artery.</div></div><div><h3>Results</h3><div>Suv39h1 expression was up-regulated in cardiac fibroblasts isolated from mice subjected to the LAD procedure compared to the sham procedure mirroring the induction of Periostin, a myofibroblast marker. Reporter assay and chromatin immunoprecipitation (ChIP) assay showed that C/EBPβ was recruited to the Suv39h1 promoter to mediate Suv39h1 trans-activation by pro-fibrogenic stimuli in fibroblasts. Genetic deletion of Suv39h1 from either quiescent fibroblasts or activated fibroblasts (myofibroblasts) in mice attenuated cardiac fibrosis and rescued the decline of heart function following myocardial infarction. Importantly, administration of a small-molecule Suv39h1 inhibitor F5446 ameliorated cardiac fibrosis and partially normalized heart function in mice following myocardial infarction. RNA-seq identified several potential Suv39h1 targets that might contribute to fibroblast-myofibroblast transition.</div></div><div><h3>Significance</h3><div>In conclusion, our data demonstrate that Suv39h1 might play an important role regulating ventricular remodeling in ischemic cardiomyopathy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124221"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044322","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":"Estrogen receptors α/β exhibit distinct intermolecular interactions to mediate gene regulatory events","authors":"Ayushi Chhabra,&nbsp;Sheeba Rizvi,&nbsp;Sudhir Kumar,&nbsp;Anjali Tripathi,&nbsp;Rakesh K. Tyagi","doi":"10.1016/j.lfs.2026.124249","DOIUrl":"10.1016/j.lfs.2026.124249","url":null,"abstract":"<div><h3>Aim</h3><div>Estrogen receptors (ERα and ERβ) are intracellular transcription factors that regulate gene expression when bound by estrogens. Although their roles in cellular functions and the onset of disease are relatively well-documented, their interactions with mitotic chromatin in the context of ‘mitotic bookmarking’ remain largely unexplored. The current study revealed distinct mechanisms underlying mitotic chromatin retention of ERα and ERβ, emphasizing structural and functional determinants of ER-chromatin association. We further assessed how diverse modulatory ligands impact ER-chromatin interactions during mitosis with potential implications in endocrine therapy.</div></div><div><h3>Materials and methods</h3><div>The study was conducted primarily using live-cell imaging, chromatin immunoprecipitation assays, and site-directed mutagenesis.</div></div><div><h3>Key findings</h3><div>We discovered that ERα associates with chromatin in a ligand-dependent manner through a critical RK amino acid stretch in its nuclear localization signal. On the contrary, ERβ binds mitotic chromatin constitutively without ligand involvement. Moreover, ERβ influenced ERα's chromatin association via heterodimeric interactions. Diverse modulatory ligands differentially altered ER dynamics; agonists increased ERα's chromatin binding, whereas antagonists did not. However, only SERMs modulated ERβ's constitutive association with mitotic chromatin. ChIP results indicated that 17β-estradiol-bound ERα and unliganded ERβ associate with their target gene promoters during mitosis, suggesting a role in mitotic bookmarking.</div></div><div><h3>Significance</h3><div>The study advances our understanding of ER-mediated epigenetic regulation and offers a framework for evaluating ER-associated disease states and improving endocrine therapeutic strategies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124249"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100346","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":"Amniotic fluid stem cell-derived extracellular vesicles enhance functional recovery of neurogenic bladder and neurovascular plasticity after cerebral ischemia in rats","authors":"Ching-Chung Liang ,&nbsp;Steven W. Shaw ,&nbsp;Hsien-Ming Wu ,&nbsp;Yi-Haou Lin ,&nbsp;Tzu-Hsiang Hsieh ,&nbsp;Yung-Hsin Huang ,&nbsp;Tsong-Hai Lee","doi":"10.1016/j.lfs.2026.124225","DOIUrl":"10.1016/j.lfs.2026.124225","url":null,"abstract":"<div><h3>Background</h3><div>Post-stroke neurogenic bladder dysfunction impairs patients' quality of life, yet current treatments offer limited effectiveness. This study investigated the therapeutic effects and underlying mechanisms of human amniotic fluid stem cell-derived extracellular vesicle (hAFSC-EV) on bladder dysfunction and neurovascular plasticity after cerebral ischemia.</div></div><div><h3>Methods</h3><div>Thirty-six female rats underwent bilateral ovariectomy and were assigned to sham-operated or 90-min middle cerebral artery occlusion (MCAO) groups, with or without a single injection of hAFSC-EVs. Magnetic resonance imaging (MRI), cystometry, blood-brain barrier (BBB) permeability, and markers of neurogenesis and angiogenesis in ischemic brain were assessed. Bladder levels of brain-derived neurotrophic factor (BDNF), β3-adrenoceptor, adenylate cyclase, and M2- and M3-muscarinic receptors were evaluated at 7 and 28 days post-MCAO or sham-operation.</div></div><div><h3>Results</h3><div>Compared with untreated rats, hAFSC-EV treatment significantly reduced cerebral infarct volume and BBB leakage, and enhanced microvessel and vascular density, along with angiogenesis. Neural markers such as BDNF, nestin, and doublecortin were significantly upregulated at 7 and/or 28 days post-MCAO. hAFSC-EV treatment ameliorated MCAO-induced bladder dysfunction by reducing peak voided volume, intercontraction interval, and bladder capacity, along with improving residual urine volume. hAFSC-EV treatment significantly increased bladder expression of BDNF and M3-muscarinic receptors, and recovers the expressions of M2, β3-adrenoceptor, and adenylate cyclase to near control levels at 7 and 28 days post-MCAO.</div></div><div><h3>Conclusion</h3><div>hAFSC-EV treatment improves neurogenic bladder dysfunction and cerebral ischemia post-MCAO, potentially through reducing infarct volume and BBB disruption, enhancing neurogenesis and angiogenesis in the ischemic brain, and modulating the expression of bladder BDNF, β3-adrenoceptor, adenylate cyclase and muscarinic receptors.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124225"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146026265","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":"Aerobic exercise stabilizes atherosclerotic plaques by suppressing miR-15a-5p-mediated repression of Semaphorin-3A in vascular smooth muscle cells","authors":"Guomin Hu ,&nbsp;Weijia Chen ,&nbsp;Xiangyuan Zhou ,&nbsp;Yueshen Wang ,&nbsp;Na Feng ,&nbsp;Wei Gao ,&nbsp;Haiyi Yu","doi":"10.1016/j.lfs.2026.124226","DOIUrl":"10.1016/j.lfs.2026.124226","url":null,"abstract":"<div><h3>Aims</h3><div>Aerobic exercise reduces cardiovascular events in atherosclerosis, but the causal roles of microRNAs (miRNAs) in mediating exercise-induced vascular smooth muscle cell (VSMC) phenotypic switching and plaque stabilization remains unclear. This study investigated whether aerobic exercise stabilizes atherosclerotic plaques by reprogramming VSMC miRNA expression, focusing on the miR-15a-5p/Semaphorin-3A (Sema3A) axis.</div></div><div><h3>Materials and methods</h3><div>High-fat diet-fed <em>ApoE</em>^{<em>−/−</em>} mice were assigned to sedentary or 12-week moderate-intensity treadmill exercise. Aortic miRNA profiles were analyzed by small RNA sequencing and integrated with exercise-responsive circulating miRNAs. Plaque burden and vulnerability were evaluated by histology and immunohistochemistry. Molecular mechanisms were validated in vitro and in vivo using luciferase reporter assays, qPCR, Western blotting, and VSMC-specific AAV9-mediated miR-15a-5p overexpression. miR-15a-5p and Sema3A expression were examined in human carotid atherosclerotic plaques.</div></div><div><h3>Key findings</h3><div>Exercise reduced plaque vulnerability, increased collagen content, reduced lipid content, and attenuated macrophage infiltration. Integrative miRNA profiling revealed that miR-15a-5p was markedly upregulated in atherosclerotic aortas but significantly suppressed by exercise locally and in circulation. In human carotid plaques, miR-15a-5p levels positively correlated with the plaque vulnerability index. Mechanistically, miR-15a-5p directly targeted the 3′-UTR of Sema3A, repressing its expression. VSMC-specific miR-15a-5p overexpression in vivo downregulated contractile markers, accelerated phenotypic switching, and destabilized plaques, such traits resembled those in cells from sedentary mice.</div></div><div><h3>Significance</h3><div>Aerobic exercise stabilizes plaques by downregulating miR-15a-5p, relieving Sema3A repression and preserving the contractile VSMC phenotype. The miR-15a-5p/Sema3A signaling axis mediates exercise-induced atheroprotection. Notably, elevated miR-15a-5p levels in human carotid plaques correlate positively with plaque vulnerability, supporting its potential as an atherosclerotic therapeutic target.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124226"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146026266","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}