Life sciences最新文献

{"title":"MLN4924, neddylation inhibitor suppresses hypoxia induced retinal angiogenesis by targeting Human Antigen R signaling","authors":"Sruthi Priya Mohan ,&nbsp;RN NareshKumar ,&nbsp;Sai Shreya Cheruvu ,&nbsp;Hemavathy Nagarajan ,&nbsp;Nishath Fathima Majid ,&nbsp;Sampathkumar Ranganathan ,&nbsp;Jayabalan Nirmal ,&nbsp;Sharada Ramasubramanyan","doi":"10.1016/j.lfs.2025.123927","DOIUrl":"10.1016/j.lfs.2025.123927","url":null,"abstract":"<div><h3>Purpose</h3><div>Retinal hypoxia is a key pathological stimulus for neovascularization, leading to abnormal proliferation of blood vessels and vascular endothelial dysfunction leading to vision threatening conditions. The anti-angiogenic potential of MLN4924, a specific inhibitor of neddylation signaling has been evidenced in cancer cells, but remains abstract as therapy for ocular angiogenesis in normal retinal cells. The current work intended to delineate a novel molecular signaling cascade of combating retinal angiogenesis by inhibiting the neddylation-Human Antigen R (HuR) signaling pathway using MLN4924.</div></div><div><h3>Methods</h3><div>The effect of neddylation inhibition on hypoxia-induced HRMVEC was demonstrated by the real-time PCR, western blotting, immunofluorescence, and functional assays. <em>In silico</em> analysis was used to study the impact of the mutation of the RNA binding protein, HuR neddylation sites on its binding affinity towards <em>VEGF</em> mRNA. RNA immunoprecipitation and Actinomycin D experiments were performed to evidence the effect of neddylation inhibition on HuR binding and stabilization of <em>VEGF</em> mRNA in hypoxic HRMVECs.</div></div><div><h3>Results</h3><div>Functional angiogenic assays revealed that treatment with MLN4924 could suppress hypoxia-induced angiogenesis by reducing secretory VEGF levels without altering the barrier integrity of HRMVECs. <em>In silico</em> analysis revealed that mutation of two of the HuR neddylation sites decreased its binding affinity to 3′UTR region of <em>VEGF</em> mRNA. Indeed, HuR preferentially bound and stabilized <em>VEGF</em> mRNA upon hypoxia, which was significantly inhibited using MLN4924 in HRMVECs.</div></div><div><h3>Conclusion</h3><div>Neddylation inhibition could suppress hypoxia-induced angiogenesis through HuR signaling without compromising the barrier integrity of HRMVECs.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123927"},"PeriodicalIF":5.1,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144921639","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":"Single-cell transcriptomics reveal oxidative phosphorylation and oxidative stress in the superior temporal plane of non-syndromic cleft lip and palate fetuses","authors":"Changle Fang ,&nbsp;Xinwei Huang ,&nbsp;Qiulin Wang ,&nbsp;Yeqing Fei ,&nbsp;Xingcheng Wang ,&nbsp;Yinggang Zheng ,&nbsp;Qiuxia Xiao ,&nbsp;Zongjin Gan ,&nbsp;Tinghua Wang ,&nbsp;Liulin Xiong","doi":"10.1016/j.lfs.2025.123922","DOIUrl":"10.1016/j.lfs.2025.123922","url":null,"abstract":"<div><h3>Aim</h3><div>Non-syndromic cleft lip and palate (NSCLP) is a common congenital disability that causes morphological and functional abnormalities in the craniofacial region. Many studies have focused on clinical treatments and surgical aspects, but there has been limited investigation into the neural mechanisms in individuals with NSCLP. Therefore, it remains unclear whether developmental abnormalities in the brains of NSCLP fetuses exist.</div></div><div><h3>Materials and methods</h3><div>To investigate the presence of developmental abnormalities in the brains of NSCLP fetuses, we performed single-nucleus RNA sequencing (snRNA-seq) on the superior temporal plane (STP) from three NSCLP fetuses and three normal fetuses. Samples were collected at 17–23 gestational weeks. Real-time quantitative PCR (RT-qPCR) and immunofluorescence were performed to validate further phenotypes identified in the sequencing data.</div></div><div><h3>Key findings</h3><div>Following dimensionality reduction and clustering, we identified seven distinct cell types. Cell abundance changes revealed that excitatory neurons, inhibitory neurons, and astrocytes varied dramatically. We further identified the abnormally increased levels of oxidative phosphorylation (OXPHOS) and oxidative stress in the STP of NSCLP fetuses. Further investigation determined that a specific subpopulation of inhibitory neurons, InN6, is closely associated with altered OXPHOS and oxidative stress, potentially contributing to abnormal brain development in NSCLP. Finally, immunofluorescence and RT-qPCR results confirmed the abnormal increase in OXPHOS and oxidative stress in the NSCLP fetuses' brain.</div></div><div><h3>Significance</h3><div>This study provides a single-cell atlas of STP in the NSCLP fetuses, revealing increased OXPHOS and oxidative stress in the NSCLP fetal brain. These findings provide new insights into the pathological mechanisms of the brain in NSCLP.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 123922"},"PeriodicalIF":5.1,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959526","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":"Heart saver: Comprehensive investigation of (redox-) proteomic and thiol metabolite changes induced by Cana-, Dapa-, Empagliflozin treatment in 2D and 3D heart cell models reveals increased mitochondrial activity and glutathione redox defense and involvement of redox signaling","authors":"Julia Hoehlschen ,&nbsp;Émilie Gosset ,&nbsp;Dominik Hofreither ,&nbsp;Stefan Jahnel ,&nbsp;Sasha Mendjan ,&nbsp;Matthias Schittmayer ,&nbsp;Tamara Tomin ,&nbsp;Ruth Birner-Gruenberger","doi":"10.1016/j.lfs.2025.123923","DOIUrl":"10.1016/j.lfs.2025.123923","url":null,"abstract":"<div><h3>Aims</h3><div>Antidiabetic drugs, sodium-glucose co-transporter-2 inhibitors (SGLT-2i), have demonstrated heart-saving properties independently of the diabetes status of a patient. We aimed to discover SGLT-2i-specific cardiac targets.</div></div><div><h3>Materials and methods</h3><div>Two cardiac cell lines (AC16 and HCM) were treated with low-end therapeutic and 100- or 1000-fold dose of cana-, dapa and empagliflozin to investigate their influence on the (redox) proteome and thiol metabolome. Furthermore, we mimicked reperfusion injury (RI) on stem-cell derived cardioids to examine if and how SGLT-2i help to cope with RI.</div></div><div><h3>Key findings</h3><div>We show that gliflozins increase glutathione synthesis and trigger autophagy already at low drug concentration, visible through increase in ATG13. On the (redox) proteome level, several potential targets could be identified: 10 proteins affected by low concentration across all three drugs (including TXN and NAPRT) in HCM cells and 16 downregulated proteins shared between all high drug treatments in HCM cells and cardioids. Among the latter were GSR, PRDX2, LAMTOR5 and the catalytic subunit of PP2A. On the redox proteome level, we found among others, PKM, PPP1CA, PRDX5 and MDH2 with redox affected cysteine sites in both HCM and AC16 cells, and additionally, PKM, MDH2 and PPP2CA in both HCM and cardioids.</div></div><div><h3>Significance</h3><div>Our data suggest that gliflozin treatments affect the cells' capacity to buffer redox stress by increasing glutathione and altering redox state of key cysteine residues of proteins involved in the cellular defense against oxidative stress.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123923"},"PeriodicalIF":5.1,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917848","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":"Innovative therapeutic modalities of purified platelet-derived growth factors on PDX1, Neurog3, and renin expressions in STZ-induced diabetic nephropathy and pancreatic injury","authors":"Mohamed Elzallat ,&nbsp;Marwa Hassan ,&nbsp;Hossam M. Fahmy ,&nbsp;Eman El-Ahwany ,&nbsp;Nagwan M. Salama ,&nbsp;Hoda Abu-Taleb ,&nbsp;Tarek Aboushousha ,&nbsp;Mahmoud Balata ,&nbsp;Dina Mostafa Mohammed","doi":"10.1016/j.lfs.2025.123921","DOIUrl":"10.1016/j.lfs.2025.123921","url":null,"abstract":"<div><div>Diabetic nephropathy is the predominant etiology of advanced renal disease, and its prevalence has increased significantly over recent years. The primary management strategy focuses on controlling identified risk factors; however, this approach only slows disease progression and cannot halt or reverse it. Therefore, novel therapeutic strategies are urgently needed. Forty-eight male rats were used in this study. After the experiment, kidney and pancreas tissues were removed and maintained for histopathological examination and gene expression analysis, and blood samples were taken to evaluate biochemical markers. Nutritional parameters were also evaluated. The diabetic nephropathy + PRP group and the diabetic nephropathy + L-GFs group showed reduced blood glucose levels and renin expression, alongside increased PDX1 and Neurog3 expression compared to the diabetic nephropathy group. Additionally, these groups exhibited decreased cytokine and malondialdehyde (MDA) levels, with significant improvements in superoxide dismutase (SOD) activity, hepatic function, and renal function biomarkers. Histopathological analysis of the kidneys and pancreas from both treatment groups showed significant improvements compared to the diabetic nephropathy group. In conclusion, administering platelet-rich plasma (PRP) and lyophilized growth factors (L-GFs) represents an innovative and promising treatment strategy for diabetic nephropathy and accompanying consequences.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123921"},"PeriodicalIF":5.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144866500","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":"Neuropilin-1: A critical regulator and potential therapeutic target in fibrotic diseases","authors":"Xia Chen ,&nbsp;Yajuan Jiang ,&nbsp;Chunyan Tan ,&nbsp;Xiaojun Deng ,&nbsp;Hong Zhao","doi":"10.1016/j.lfs.2025.123917","DOIUrl":"10.1016/j.lfs.2025.123917","url":null,"abstract":"<div><div>Fibrosis is a chronic and progressive pathologic condition. Neuropilin-1 (NRP1) is a transmembrane non-tyrosine-kinase glycoprotein receptor. It has emerged as a key regulator of progressive fibrosis through binding to diverse ligands including SEMA3, VEGF, TGF-β, and PDGF. A large amount of evidence suggests that NRP1 is responsible for fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis, and renal fibrosis. NRP1 induces pulmonary fibrosis mainly via the TGF-β1/Smad2/3, TGF-β1–NRP1, PDGFRα/NRP1, and SEMA3B/NRP1/plexin signaling pathways. However, the expression of SEMA3B and NRP1 is reduced in the lung tissues of pulmonary fibrosis mouse models. NRP1 triggers the development of renal fibrosis via multiple pathways such as NRP1/RACK1, SEMA3A/NRP1/plexin, and TGF-β1/Smad3 signaling. Conversely, miR-128-3p/NRP1 may potentially postpone the progression of acute kidney injury. NRP1 participates in the development of hepatic fibrosis by activating hepatic stellate cells. In this review, we focus on the current understanding of NRP1, including its structure, subcellular localization, ligand–receptor interactions, and tissue distribution. We also review the roles of NRP1 in different fibrotic diseases, highlighting its regulatory mechanism. Finally, we present several compounds targeting NRP1 and explore their anti-fibrotic effects. In summary, our review indicates that NRP1 is a potential therapeutic target for fibrotic diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123917"},"PeriodicalIF":5.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144880179","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":"Liraglutide attenuates doxorubicin-induced cardiomyocyte ferroptosis via DHHC7-mediated STAT3 palmitoylation","authors":"Ge Gao ,&nbsp;Cheng Shen ,&nbsp;Manman Wang ,&nbsp;Cuiling Ji ,&nbsp;Fang Fang ,&nbsp;Yu Jiang ,&nbsp;Lihong Shi ,&nbsp;Wenqiang Chen ,&nbsp;Jinguo Zhang","doi":"10.1016/j.lfs.2025.123912","DOIUrl":"10.1016/j.lfs.2025.123912","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to investigate liraglutide's protective effects against doxorubicin (DOX)-induced cardiotoxicity and ferroptosis, and to elucidate the underlying mechanisms involving signal transducer and activator of transcription 3 (STAT3) signaling and its post-translational palmitoylation.</div></div><div><h3>Materials and methods</h3><div><em>In vivo</em> models of chronic DOX-induced cardiotoxicity were established in male C57BL/6 J mice. Cardiac function was assessed <em>via</em> echocardiography. Ferroptosis markers such as malondialdehyde (MDA), glutathione (GSH), iron (Fe²⁺), reactive oxygen species (ROS), mitochondrial ultrastructure) were evaluated in myocardial tissue and H9c2 cardiomyocytes. Bioinformatics analysis of the GSE193861 dataset identified ferroptosis-related differentially expressed genes. STAT3 and DHHC7 were modulated using short hairpin RNA (shRNA) knockdown and cardiomyocyte-specific adeno-associated virus 9 (AAV9)-mediated overexpression. Molecular interactions were assessed <em>via</em> co-immunoprecipitation, acyl-biotin exchange assays, and western blotting.</div></div><div><h3>Key findings</h3><div>Liraglutide administration significantly attenuated DOX-induced cardiac dysfunction and cardiomyocyte ferroptosis. Bioinformatics identified STAT3 as a central regulator, with liraglutide restoring DOX-impaired STAT3 phosphorylation and nuclear translocation, thereby enhancing transcription of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4). STAT3 knockdown abolished liraglutide's protection. Mechanistically, liraglutide upregulated the palmitoyltransferase DHHC7, rescuing DOX-suppressed STAT3 palmitoylation. DHHC7 knockdown and palmitoylation inhibition abrogated liraglutide-mediated STAT3 phosphorylation and anti-ferroptotic effects. Crucially, cardiomyocyte-specific DHHC7 overexpression replicated liraglutide's cardioprotection, mitigating DOX-induced ferroptosis and dysfunction.</div></div><div><h3>Significance</h3><div>We demonstrate a novel cardioprotective axis wherein liraglutide enhances DHHC7-dependent STAT3 palmitoylation, facilitating its phosphorylation, nuclear translocation, and transcriptional activation of GPX4 to suppress ferroptosis. This study provides the first evidence that DHHC7-mediated STAT3 palmitoylation is essential for liraglutide's efficacy, identifying a promising therapeutic target for DOX cardiotoxicity.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123912"},"PeriodicalIF":5.1,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851950","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":"Celecoxib inhibits skin fibrosis via suppressing adipocyte progenitor–myofibroblast transdifferentiation by attenuating the YAP/TAZ signaling pathway","authors":"Masaki Arioka ,&nbsp;Hiroaki Matsunaga ,&nbsp;Shin Ishikane ,&nbsp;Kazuma Ito ,&nbsp;Kohei Hashimoto ,&nbsp;Yi Wang ,&nbsp;Kazunobu Igawa ,&nbsp;Fumi Takahashi-Yanaga","doi":"10.1016/j.lfs.2025.123914","DOIUrl":"10.1016/j.lfs.2025.123914","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Excessive fibrosis and abnormal scarring, such as hypertrophic scars and keloids, pose significant challenges in wound healing. Myofibroblasts derived from various cell types, including adipocyte progenitors, play a crucial role in driving fibrotic tissue formation. This study aimed to investigate the anti-fibrotic potential of celecoxib, a selective cyclooxygenase-2 inhibitor, and elucidate its underlying mechanisms.</div></div><div><h3>Experimental approach</h3><div>We utilized a bleomycin-induced sclerosis mouse model to evaluate the in vivo effects of topically administered celecoxib on skin fibrosis. In vitro experiments were conducted using the 3T3-L1 adipocyte progenitor cell line to investigate the impact of celecoxib on transforming growth factor-β (TGF-β1)-induced myofibroblast transdifferentiation and the involvement of the Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway.</div></div><div><h3>Key results</h3><div>Topical celecoxib treatment significantly attenuated dermal thickening and preserved the intradermal adipose tissue in the bleomycin-induced fibrosis model. In vitro, celecoxib suppressed TGF-β1-induced myofibroblast transdifferentiation in 3T3-L1 cells, as evidenced by reduced α-smooth muscle actin expression and extracellular matrix production. Mechanistically, celecoxib inhibited the TGF-β1-induced activation of the YAP/TAZ signaling pathway by suppressing YAP and TAZ protein expressions and preventing their nuclear translocation, without affecting the canonical TGF-β/SMAD signaling pathway.</div></div><div><h3>Conclusion and implications</h3><div>Celecoxib exhibited anti-fibrotic effects by targeting the YAP/TAZ signaling pathway, inhibiting adipocyte progenitor–myofibroblast transdifferentiation, and suppressing extracellular matrix production. These results suggest that celecoxib could serve as a promising therapeutic agent for abnormal scarring and fibrosis, offering valuable insights into novel anti-fibrotic strategies for wound healing.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123914"},"PeriodicalIF":5.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144860411","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":"Exercise improves aging-induced cardiac dysfunction and prolongs lifespan via Hmgcr","authors":"Zhengwen Yu ,&nbsp;Qiufang Li ,&nbsp;Meng Ding ,&nbsp;Xu Ping ,&nbsp;Wenzhi Gu ,&nbsp;Qin Yi ,&nbsp;Jin Dai ,&nbsp;Rui Tian ,&nbsp;Zhihao Pan ,&nbsp;Lan Zheng","doi":"10.1016/j.lfs.2025.123897","DOIUrl":"10.1016/j.lfs.2025.123897","url":null,"abstract":"<div><div>Since the incidence of cardiovascular disease increases dramatically with age, it is crucial to understand the molecular mechanisms of heart damage in aging and how to reduce the damage caused by aging to the heart. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to mevalonate (MVA). <em>Hmgcr</em> not only affects cholesterol synthesis during the development process, but also regulates primordial germ cell migration and affects heart development. We investigated the expression and function of <em>Hmgcr</em> during cardiac development and aging. Changes during cardiac development may affect its entire life cycle. We used the Drosophila aging model to explore the expression changes of <em>Hmgcr</em> in the aging heart. The results showed that aging led to a significant decrease in the expression level of <em>Hmgcr</em> in cardiac tissue, accompanied by impaired cardiac function. Specific upregulation of cardiac <em>Hmgcr</em> expression can significantly improve aging-related cardiac dysfunction and extend lifespan. Interestingly, exercise can improve cardiac function and extend lifespan by upregulating <em>Hmgcr</em> expression levels in the aging heart. This finding provides a new theoretical basis for exercise to improve aging heart function and lifespan.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123897"},"PeriodicalIF":5.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862323","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":"GPR41 and GPR43 modulate rodent pancreatic α-cell function and growth","authors":"A. Sánchez-Roncero ,&nbsp;T. Fernández-Marcelo ,&nbsp;A.A. Pérez-Serna ,&nbsp;P. Martínez-Oca ,&nbsp;O. Alberquilla-Fernández ,&nbsp;R. Sánchez-Domínguez ,&nbsp;J.C. Segovia ,&nbsp;F. Escrivá ,&nbsp;B.G. Gálvez ,&nbsp;C. Álvarez ,&nbsp;L. Marroqui ,&nbsp;E. Fernández-Millán","doi":"10.1016/j.lfs.2025.123913","DOIUrl":"10.1016/j.lfs.2025.123913","url":null,"abstract":"<div><h3>Objective</h3><div>While SCFA receptors GPR41 and GPR43 regulate β-cell insulin secretion, their role in α-cells remains unknown despite hyperglucagonemia in type 2 diabetes (T2D). Thus, the current study aims to investigate the ability of synthetic GPR41 and GPR43 agonists to modulate α-cell physiology and responsiveness to nutrient challenge.</div></div><div><h3>Methods</h3><div>Using αTC1.9 cells and primary rat islets we investigated the role of SCFA receptors in glucagon expression and secretion under physiological and insulin resistant conditions associated with high-fat feeding (HFD) and lactation (L). The specific agonists AR420626 (AR) and (<em>S</em>)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl) butanamide (PA) were employed to study the mechanisms involved.</div></div><div><h3>Results</h3><div>Histological and flow cytometry analysis of islets demonstrated that GPR41 and GPR43 localized in α-cells. Treatment of αTC1.9 cells with the GPR41-agonist AR or GPR43-agonist PA increased <em>Gcg</em> expression and glucagon secretion at low glucose, while AR also potentiated glucagon release at high glucose. This effect was recapitulated in isolated islets demonstrating pertussis toxin sensitivity for both agonist effects. HFD-fed animals showed glucose intolerance, early fasting hyperglucagonemia and islet resistance to glucose inhibition of glucagon secretion together with enhanced expression of islet <em>Gpr41/43</em>. Stimulation of HFD islets with the synthetic agonists further increased <em>Gcg</em> expression. Pancreatic <em>Gpr41/43</em> levels were also transiently induced during lactation although only GPR41 activation of lactating rat islets up-regulated <em>Gcg</em> expression via Gα_i and α-cell replication.</div></div><div><h3>Conclusions</h3><div>These findings position GPR41 as a promising therapeutic target for modulating hyperglucagonemia and improving glycemic control in T2D, supporting its translational relevance in diabetes intervention strategies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123913"},"PeriodicalIF":5.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144860396","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":"Cardioprotective role of phoenixin-14 in isoproterenol-induced myocardial injury: Involvement of AMPK, JAK2/STAT3, and Sema3E pathways","authors":"Raziye Akcılar ,&nbsp;Muhammed Taşar ,&nbsp;Fatih Kar ,&nbsp;Neziha Senem Arı ,&nbsp;Suna Karadeniz Saygılı ,&nbsp;Fatma Emel Koçak ,&nbsp;Cengiz Koçak","doi":"10.1016/j.lfs.2025.123896","DOIUrl":"10.1016/j.lfs.2025.123896","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to evaluate the cardioprotective effects of phoenixin-14 (PNX-14) in isoproterenol (ISO)-induced myocardial infarction (MI) in rats, comparing both preventive and therapeutic administration.</div></div><div><h3>Materials and methods</h3><div>Seventy adult male Wistar rats were divided into five groups: Control, PNX-14, ISO, ISO + PNX-14 (PNX-14 treatment after ISO), and PNX-14 + ISO (PNX-14 pretreatment before ISO). MI was induced by subcutaneous ISO (100 mg/kg/day) for two days. PNX-14 (5 nmol/kg, intraperitoneally) was administered once daily for 3 days. Biochemical, molecular, and histopathological analyses were performed to evaluate oxidative stress, inflammatory response, and apoptosis in cardiac tissue.</div></div><div><h3>Key findings</h3><div>PNX-14 treatment significantly reduced the ISO-induced increases in heart/body weight ratio (0.54 ± 0.05), infarct size (47.3 ± 2.51 %), apoptotic index (40.8 ± 2.99 %), and cardiac necrosis markers CK-MB and TnI (<em>p</em> &lt; 0.001). It improved antioxidant defenses by increasing glutathione (GSH) and total antioxidant status (TAS), while reducing total oxidant status (TOS) and oxidative stress index (OSI). Pro-inflammatory cytokines TNF-α and IL-6 were lowered, and anti-inflammatory IL-10 increased. PNX-14 also attenuated apoptosis in cardiac tissue by downregulating cytochrome <em>c</em>, APAF-1, caspase-3, and Bax, and upregulating the anti-apoptotic marker Bcl-2. These effects were linked to modulation of Gpr173, AMPK/Nrf2/HO-1, and Sema3E/PlexinD1 pathways, alongside suppression of JAK2/STAT3 and NF-κB signaling. Furthermore, PNX-14 improved hemodynamic stability and histopathologically reduced ISO-induced myocardial damage.</div></div><div><h3>Significance</h3><div>These results demonstrate that PNX-14, particularly when administered after injury, effectively attenuates myocardial damage through multi-pathway regulation of oxidative stress, inflammation, and apoptosis. PNX-14 may hold therapeutic potential for the prevention and treatment of cardiovascular diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"379 ","pages":"Article 123896"},"PeriodicalIF":5.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859307","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}