Life sciences最新文献

{"title":"Gastric dilation following vertical sleeve gastrectomy reflects adaptive stem cell-driven regeneration without association with weight regain or increased cancer risk","authors":"Oluwatosin Asunloye ,&nbsp;Ruchita Shelat ,&nbsp;McKenzie McCarthy ,&nbsp;Britney Le ,&nbsp;Rima Patel ,&nbsp;Amit Elad ,&nbsp;Haya Benhayon ,&nbsp;Rachel Ben-Haroush Schyr ,&nbsp;Danny Ben-Zvi ,&nbsp;Ki-Suk Kim","doi":"10.1016/j.lfs.2025.123899","DOIUrl":"10.1016/j.lfs.2025.123899","url":null,"abstract":"<div><h3>Aims</h3><div>Bariatric surgery is the most effective intervention for sustained weight loss and the improvement of obesity-related comorbidities. Among these procedures, vertical sleeve gastrectomy (VSG) is the most commonly performed worldwide. Yet, post-VSG gastric dilation has been hypothesized to contribute to failure in weight loss or even weight regain by increasing the secretion of ghrelin, an orexigenic hormone primarily produced in the stomach. However, the relationship between gastric dilation, its underlying mechanism, and its clinical implications remain unclear.</div></div><div><h3>Materials and methods</h3><div>To investigate this, we utilized both a mouse model of VSG and corpus epithelial samples from patients who had undergone VSG.</div></div><div><h3>Key findings</h3><div>Using a diet-induced obese mouse model, we found that VSG leads to significant gastric remodeling, yet neither stomach expansion nor increased ghrelin secretion correlated with weight regain. Single-cell RNA sequencing of corpus epithelial cells from VSG patients further revealed an associated with epithelial regeneration, marked by gastric stem cell expansion and upregulation of repair-associated genes. RNA sequencing also showed enhanced stem cell activity alongside upregulation of tumor suppressor genes and long non-coding RNAs, suggesting a potential protective mechanism against gastric cancer despite rapid cellular proliferation.</div></div><div><h3>Significance</h3><div>These findings challenge the assumption that gastric dilation is a predictor of poor surgical outcomes and instead suggest that it is an adaptive response to VSG, offering new insights into post-VSG gastric remodeling.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123899"},"PeriodicalIF":5.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859349","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":"Reduced expression of PDZK1 mediates fibroblast activation and cardiac fibrosis via EGFR phosphorylation in diabetic cardiomyopathy","authors":"Yanan Cheng ,&nbsp;Yan Wang ,&nbsp;Ruili Yin ,&nbsp;Yongsong Xu ,&nbsp;Yuechao Xu ,&nbsp;Jianan Lang ,&nbsp;Lingling Wei ,&nbsp;Yuanyuan Zhang ,&nbsp;Jing Ke ,&nbsp;Dong Zhao ,&nbsp;Longyan Yang","doi":"10.1016/j.lfs.2025.123916","DOIUrl":"10.1016/j.lfs.2025.123916","url":null,"abstract":"<div><h3>Aims</h3><div>To clarify the molecular mechanisms underlying PDZK1-mediated regulation of cardiac fibroblast (CF) activation and cardiac fibrosis in diabetic cardiomyopathy (DCM).</div></div><div><h3>Materials and methods</h3><div>DCM models were constructed using db/db mice fed a high-fat diet (HFD) and C57BL/6 mice induced by multiple low-dose streptozotocin (STZ) combined with HFD. PDZK1 expression in myocardial tissues was detected via molecular assays; cardiac function was evaluated using echocardiography, and cardiac fibrosis was assessed by histopathological staining. The effects of PDZK1 knockout and overexpression on cardiac dysfunction and fibrosis were systematically evaluated, and the molecular interaction between PDZK1 and epidermal growth factor receptor (EGFR) was explored through co-immunoprecipitation and phosphorylation analysis.</div></div><div><h3>Key findings</h3><div>PDZK1 expression was significantly downregulated in myocardial tissues of DCM mice compared with controls. PDZK1 knockout further aggravated STZ/HFD-induced cardiac dysfunction and excessive cardiac fibrosis, whereas PDZK1 overexpression markedly ameliorated these pathological changes in diabetic mice. Mechanistically, PDZK1 specifically interacted with the carboxyl terminus of EGFR via its PDZ1 and PDZ3 domains, thereby inhibiting EGFR phosphorylation at critical tyrosine residues and subsequent activation of downstream Akt signaling, which in turn suppressed CF activation and extracellular matrix deposition. This novel PDZK1-EGFR interaction in the context of DCM is reported for the first time.</div></div><div><h3>Significance</h3><div>These findings identify PDZK1 as a key regulator of cardiac fibrosis in DCM through modulation of the PDZK1-EGFR-Akt pathway, highlighting its potential as a promising anti-fibrotic therapeutic target for DCM treatment.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123916"},"PeriodicalIF":5.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859352","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":"MRP4 deficiency drives lipid metabolism dysregulation and adipose tissue inflammation through cAMP-CREB-CRTC2 activation","authors":"Ankit P. Laddha ,&nbsp;Hangyu Wu ,&nbsp;Jaeeun Lee ,&nbsp;Ji-Young Lee ,&nbsp;Neha Mishra ,&nbsp;José E. Manautou","doi":"10.1016/j.lfs.2025.123895","DOIUrl":"10.1016/j.lfs.2025.123895","url":null,"abstract":"<div><div>Multidrug resistance-associated protein 4 (MRP4/ABCC4), a plasma membrane transporter, plays a critical role in the efflux of endogenous metabolites and xenobiotics. Recent studies have also implicated MRP4 in adipogenesis and fatty acid metabolism. Our previous work using MRP4 knockout (MRP4^-/-) mice demonstrated a strong association between MRP4 deficiency and the development of obesity and diabetes. However, the underlying mechanisms through which MRP4 regulates adipose tissue function remain unclear.</div></div><div><h3>Aim</h3><div>To investigate the role of MRP4 in adipose tissue dysfunction and metabolic regulation under high-fat, high-sucrose (HFHS) diet conditions.</div></div><div><h3>Materials and methods</h3><div>MRP4 knockout (MRP4^-/-) and wild-type (WT) mice were fed either a regular chow or HFHS diet for 24 weeks. Body weight, plasma glucose, cholesterol, insulin secretion, glucose tolerance, and insulin sensitivity were assessed. Body composition, physical activity, and energy expenditure were measured. Epididymal adipose tissue (EA) was analyzed for gene expression (adipogenic, lipogenic, fibrotic, and inflammatory markers), histology, cAMP levels, and protein expression of phosphorylated CREB (P-CREB) and CRTC2.</div></div><div><h3>Key findings</h3><div>MRP4^-/- mice showed greater body weight gain than WT controls, even on a chow diet. Under HFHS conditions, they exhibited exacerbated metabolic dysfunction, including elevated glucose and cholesterol levels, increased adiposity, adipocyte hypertrophy, and altered leptin levels. These mice also showed impaired insulin secretion, reduced glucose tolerance, and decreased insulin sensitivity. Body composition analysis revealed higher fat mass, lower lean mass, and increased water retention. MRP4^-/- mice displayed reduced physical activity, altered energy expenditure, and upregulation of adipogenic, fibrotic, and inflammatory genes in EA. Histological analysis confirmed inflammation and fibrosis. Elevated cAMP levels, along with increased P-CREB and CRTC2 expression, indicated activation of the cAMP-CREB-CRTC2 signaling pathway.</div></div><div><h3>Significance</h3><div>MRP4 deficiency promotes adipose tissue inflammation, fibrosis, and metabolic dysfunction through activation of the cAMP-CREB-CRTC2 signaling axis. These findings reveal a novel regulatory role for MRP4 in maintaining adipose tissue homeostasis and protecting against diet-induced metabolic disease.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123895"},"PeriodicalIF":5.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859350","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":"PPARγ agonist alleviates sepsis-related liver injury by modulating M1/M2 macrophage polarization via the PPARγ/IκBα/NF-κB pathway","authors":"Fan Yang ,&nbsp;Wenjing Yang ,&nbsp;Mingyuan Chen ,&nbsp;Wenqian Ye ,&nbsp;Ying Zhang ,&nbsp;Huizhi Wei ,&nbsp;Xuan Zhang","doi":"10.1016/j.lfs.2025.123881","DOIUrl":"10.1016/j.lfs.2025.123881","url":null,"abstract":"<div><div>Sepsis-related liver injury (SRLI) results from sepsis and can lead to abnormal liver function, biochemical changes, or liver failure, with limited treatment options. This study analyzed two GEO datasets (GSE139602 and GSE57065) to identify genes associated with SRLI using weighted gene co-expression network analysis (WGCNA), focusing on peroxisome proliferator-activated receptor gamma (PPARγ). The therapeutic effects of pioglitazone, a PPARγ agonist, were investigated in SRLI through modulation of macrophage polarization in vivo and in vitro. A rat SRLI model was established using cecal ligation and puncture (CLP), and the study included control, CLP, CLP + pioglitazone (Pio), and CLP + GW9662 (PPARγ inhibitor) groups. Biochemical indices, pathological changes, flow cytometry, and transcriptomics were used to assess pioglitazone's effects. Additionally, RAW264.7 cells were employed to explore the underlying mechanisms in vitro. PPARγ was identified as a key gene linked to SRLI. In vivo, pioglitazone treatment promoted Kupffer cell polarization towards the M2 phenotype, reducing inflammatory cytokines and alleviating liver damage and systemic inflammation. Transcriptomic analysis revealed 1234 genes were no longer significantly upregulated in the CLP + Pio group compared to the CLP group. KEGG pathway enrichment analysis highlighted IκBα and NF-κB signaling via GSEA. In vitro, pioglitazone further facilitated M2 macrophage polarization. Molecular docking and western blotting confirmed that pioglitazone inhibits the PPARγ/IκBα/NF-κB pathway both in vitro and in vivo. Activation of PPARγ alleviates SRLI in rats by modulating M1/M2 macrophage polarization through the PPARγ/IκBα/NF-κB pathway.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123881"},"PeriodicalIF":5.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859351","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":"Upregulation of PRSS27 driven by super-enhancers attenuates oxidative stress and apoptosis via activating PI3K/AKT pathway in lung adenocarcinoma","authors":"Ziming Wang ,&nbsp;Haofeng Yin ,&nbsp;Qing Wu ,&nbsp;Shuimei Luo ,&nbsp;Xiaowei Du ,&nbsp;Xianhe Xie","doi":"10.1016/j.lfs.2025.123903","DOIUrl":"10.1016/j.lfs.2025.123903","url":null,"abstract":"<div><div>Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. This study aims to elucidate the mechanisms by which super-enhancers (SEs) drive persistent oncogenic expression of protease serine 27 (PRSS27)—a previously uncharacterised gene in LUAD. Integrated multi-omics analyses, including histone H3 lysine 27 acetylation (H3K27ac) Cleavage Under Targets and Tagmentation sequencing (CUT&amp;Tag-seq), RNA sequencing (RNA-seq), and public datasets, identified PRSS27 as a LUAD-specific SE-regulated gene, with high expression correlating with poor prognosis. Functional assays demonstrated that inhibition of SEs (JQ-1 and i-BET151) suppressed LUAD cell viability, proliferation, and colony formation while promoting apoptosis. PRSS27 overexpression enhanced LUAD tumour growth in vitro and in vivo, decreased oxidative stress and apoptosis, and activated the PI3K/AKT signalling pathway. Mechanistically, CRISPR interference (CRISPRi), luciferase reporter assays, and chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) confirmed that the SE region at chr16:2689953-2714630 transcriptionally activated PRSS27. Notably, rescue assays showed that PRSS27 overexpression effectively mitigated inhibitor-induced oxidative stress and apoptosis of SEs. Collectively, these findings identify SE-driven activation of PRSS27 as a novel oncogene that promotes LUAD progression by modulating PI3K/AKT signalling pathway, highlighting its potential as a therapeutic target.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123903"},"PeriodicalIF":5.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859353","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 dioxygenase TET2 regulates pathological cardiac hypertrophy","authors":"Wenxuan Hong ,&nbsp;Yuwen Zhu ,&nbsp;Mengwen Qi ,&nbsp;Xiaoyan Wang ,&nbsp;Mingming Fang","doi":"10.1016/j.lfs.2025.123915","DOIUrl":"10.1016/j.lfs.2025.123915","url":null,"abstract":"<div><h3>Aims</h3><div>Heart failure (HF) is one of the most devastating consequences of cardiovascular diseases. Regardless of etiology, heart failure is often preceded by cardiac hypertrophy. In the present study we investigated the effect of cardiomyocyte-specific deletion of ten-and-eleven translocation 2 (TET2) on cardiac hypertrophy.</div></div><div><h3>Methods and materials</h3><div>Cardiac hypertrophy was induced <em>in vitro</em> by exposing cardiomyocytes to angiotensin II (Ang II), isoproterenol (ISO), or phenyleprine (PE) and <em>in vivo</em> by subjecting the mice to transverse aortic constriction (TAC).</div></div><div><h3>Key findings</h3><div>TET2 expression was elevated in cardiac tissues in animal models of cardiac hypertrophy, in cardiomyocytes exposed to pro-hypertrophic stimuli, and in HF patients. TET2 knockdown dampened the hypertrophic response in cultured cardiomyocytes treated with different pro-hypertrophic stimuli. Constitutive deletion of TET2 from cardiomyocytes in mice attenuated pathological hypertrophy and improved heart function in the trans-aortic constriction (TAC) model. In addition, induced deletion of TET2 after the onset of pathological hypertrophy similarly averted the pathogenic progression and rescued the decline of heart function.</div></div><div><h3>Significance</h3><div>TET2 may play an essential role mediating the hypertrophic response in cardiomyocytes. Screening for small-molecule compounds that selectively target TET2 can be considered as a reasonable approach for the intervention of heart failure.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123915"},"PeriodicalIF":5.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841670","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":"Telomere-targeted medicine: Bridging molecular mechanisms and clinical applications in age-related diseases","authors":"Sarfaraz K. Niazi","doi":"10.1016/j.lfs.2025.123904","DOIUrl":"10.1016/j.lfs.2025.123904","url":null,"abstract":"<div><div>Telomeres, the nucleoprotein structures at the ends of chromosomes, have emerged as critical regulators of cellular aging and key contributors to the pathogenesis of age-related diseases. This comprehensive review examines the evolution of telomere biology from fundamental research to therapeutic applications, analyzing molecular mechanisms of telomere dysfunction across diverse disease categories, including autoimmune disorders, cardiovascular diseases, neurodegeneration, respiratory diseases, metabolic disorders, chronic kidney disease, cancer, and premature aging syndromes. We explore current therapeutic strategies ranging from telomerase modulation to senolytic approaches, highlighting emerging technologies in drug discovery, including CRISPR-based interventions, nanomedicine, mRNA-based therapies, partial cellular reprogramming, and artificial intelligence applications. The convergence of mechanistic understanding with innovative therapeutic approaches positions telomere biology as a promising frontier for addressing multiple age-related conditions simultaneously, potentially shifting medicine from reactive disease treatment toward proactive aging-focused prevention. However, significant challenges remain, including safety considerations, biomarker development, and establishing regulatory frameworks for aging-targeted therapeutics. The success of telomere-targeted interventions could herald a paradigm shift toward geroscience-based medicine, extending lifespan and health span by targeting fundamental biological aging processes.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123904"},"PeriodicalIF":5.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828808","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":"Unraveling the protective mechanisms of Angiotensin-(1–7) in Intestinal Ischemia-Reperfusion injury: Interplay between Nrf-2/HO-1 and NF-κB/NLRP3 pathways","authors":"Heba A. Abdel-Hamid ,&nbsp;Doaa Mohamed Elroby Ali ,&nbsp;Shimaaabdel Baset Abdel hakim ,&nbsp;Manar Fouli Gaber Ibrahim","doi":"10.1016/j.lfs.2025.123898","DOIUrl":"10.1016/j.lfs.2025.123898","url":null,"abstract":"<div><h3>Aim</h3><div>Intestinal ischemic reperfusion (I-I/R) injury is a serious clinical case with high death rate. This research assessed the influence of Angiotensin 1-7 (Ang-(1–7)) alone on the induced I-I/R injury or combined with each of nuclear factor erythroid 2 related factor 2 (Nrf-2) inhibitor (ML-385) or Mas receptor antagonist (A779). The primary objective of our study was to assess the role of Mas receptor and Nrf-2 pathway in mediating the probable protective effect of Ang-(1–7) against intestinal I/R injury.</div></div><div><h3>Material and methods</h3><div>Albino rats from Wistar strain were separated into; Sham group, I-I/R group, I-I/R+ Ang-(1–7), I-I/R+ Ang-(1–7)+ A779 and I-I/R+ Ang-(1–7)+ ML-385. Serum C reactive protein level (CRP) and markers of intestinal barrier malfunction were assessed. Measurements of the intestinal levels of Ang-(1–7), Angiotensin II (Ang II), angiotensin converting enzyme 2 (ACE2), in addition to the markers of oxidation, inflammation and apoptosis were taken. Also, Gene expression of heme oxygenase-1 (HO-1), Western blotting test of NOD-like receptor protein 3 (NLRP3) and immunoexpression of Nrf-2 and nuclear factor kappa B P56 (NF-κB P65) were assessed in the intestinal tissues.</div></div><div><h3>Key findings</h3><div>Ang-(1–7) secured against I-I/R injury through its suppressive action on oxidative stress, inflammation and apoptosis, but this protective effect was completely blocked with Mas receptor blocker and partially blocked with Nrf-2 inhibitor.</div></div><div><h3>Significance</h3><div>Ang-(1–7)/Mas receptors axis gave its protective influence <em>via</em> augmenting Nrf-2/HO-1 pathway and attenuating NF-κB/NLRP3 inflammasome pathway.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123898"},"PeriodicalIF":5.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841669","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":"Role of MYC inhibition in overcoming resistance to HER2-targeted therapies for breast cancer","authors":"Tamanna Tanwisa ,&nbsp;Alan Raj ,&nbsp;Aradhana Puttiga ,&nbsp;Adarsh Gopinathan ,&nbsp;Angel Treasa Alex","doi":"10.1016/j.lfs.2025.123902","DOIUrl":"10.1016/j.lfs.2025.123902","url":null,"abstract":"<div><div>HER2-positive breast cancer is a distinct subtype of breast cancer defined by the overexpression of the human epithelial growth factor receptor 2 (HER2). HER2 promotes aggressive tumor growth and shows poor prognosis. HER2-targeted therapies, like trastuzumab and pertuzumab, have sufficiently improved patient outcomes, but eventually, most patients face resistance to HER2 therapies, resulting in ineffective clinical action. Recent knowledge has pointed to the oncogene MYC (as gene) as a major contributor to intrinsic and acquired resistance toward HER2-targeted therapies. Myc (as protein) overexpression promotes cell proliferation, survival, and metabolism reprogramming, permitting an escape from HER2 inhibition. Furthermore, Myc activation induces cellular reprogramming and activates downstream signalling pathways, including PI3K/AKT/mTOR and MAPK, which collectively contribute to resistance against HER2-targeted therapies. This review assesses the mechanistic role MYC plays in HER2-positive breast cancer progression and resistance, emphasizing preclinical studies that highlight the ability of Myc inhibition to restore sensitivity to HER2-directed therapeutics. Additionally, MYC targeting through small molecules, siRNA, or to enhance the delivery using nanoformulations, is a rapidly evolving strategy that may overcome resistance in the HER2-positive clinical context and improve therapeutic response. Furthermore, targeting Myc represents a logical and natural strategy to combine with HER2 therapies currently in use, and could potentially be a pivotal step forward in the development of effective combinatorial therapies. This review emphasizes the necessity of incorporating Myc-targeted strategies to address resistance and improve the durability of HER2-targeted therapy in breast cancer.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123902"},"PeriodicalIF":5.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855721","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":"Triple-phase VPA administration in Sprague-Dawley rats: A cost-effective ASD model unveiling the synaptic-mitochondrial-inflammatory axis as a therapeutic target","authors":"Zhaoming Liu ,&nbsp;Caixia Wu ,&nbsp;Zuoxian Lin ,&nbsp;Heying Li ,&nbsp;Yujie Liu ,&nbsp;Nouman Amjad ,&nbsp;Muhammad Majid ,&nbsp;Rajesh Basnet ,&nbsp;Zhiyuan Li","doi":"10.1016/j.lfs.2025.123900","DOIUrl":"10.1016/j.lfs.2025.123900","url":null,"abstract":"<div><h3>Aims</h3><div>To overcome limitations of traditional single-dose valproic acid (VPA) models in autism spectrum disorder (ASD) research—including severe maternal toxicity and imprecise embryonic exposure—this study established a cost-effective ASD model using a three-phase sequential VPA strategy in Sprague-Dawley (SD) rats.</div></div><div><h3>Materials and methods</h3><div>Pregnant SD rats received VPA (400 → 450 → 400 mg·kg⁻¹) on gestational days 11.5, 12.5, and 13.5. Maternal/neonatal survival, neurodevelopmental milestones, and behavioral phenotypes (open field, three-chamber sociability, repetitive grooming) were assessed. Synaptic ultrastructure (transmission electron microscopy), neuroinflammation (ELISA for IL-1β, IL-6, TNF-α, IL-10), and oxidative stress (CAT, SOD, GSH-Px, MDA) in the prefrontal cortex were analyzed.</div></div><div><h3>Key findings</h3><div>The optimized protocol eliminated maternal mortality (<em>p &lt; 0.01</em>) and resorption (<em>p &lt; 0.0001</em>), while enhancing neonatal survival (<em>p &lt; 0.01</em>) and litter size (12–16 pups). Model rats exhibited core ASD phenotypes: social deficits (<em>p &lt; 0.0001</em>), repetitive grooming (<em>P &lt; 0.01</em>), and delayed neurodevelopment. Synaptic vesicle depletion, mitochondrial cristae disruption, proinflammatory cytokine upregulation (<em>p &lt; 0.01</em>), and antioxidant suppression (<em>p &lt; 0.01</em>) confirmed synaptic-mitochondrial-inflammatory axis dysregulation. SD rats outperformed C57BL/6 mice in phenotypic fidelity and modeling efficiency.</div></div><div><h3>Significance</h3><div>This study pioneers a three-phase VPA strategy that balances high ASD phenotyping fidelity with animal welfare. The synaptic-mitochondrial-inflammatory axis is identified as a novel therapeutic target. SD rats provide a superior, cost-effective platform for ASD mechanism and intervention studies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123900"},"PeriodicalIF":5.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841645","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}