Life sciences最新文献

{"title":"LEAP2 modulates β-adrenergic triggered cardiac responses and provokes antihypertensive effects.","authors":"Sixta Isabel Atencio Berrio, Jhulle Horrane Carvalho, João Batista Dutra, Marcos Eliezeck, Sergio Scalzo, Juliana Vila Verde Ribeiro, Michelle Mendanha Mendonça, Rodrigo Mello Gomes, Gustavo Rodrigues Pedrino, Eduardo Colombari, Daniel Castrogiovanni, Sisti Maria Milagros, Maria Florencia Racioppi, Martin Vila Petroff, Sonia Cantel, Jean-Alain Fehrentz, Silvia Guatimosim, Mario Perelló, Carlos Henrique de Castro, Carlos Henrique Xavier","doi":"10.1016/j.lfs.2026.124243","DOIUrl":"10.1016/j.lfs.2026.124243","url":null,"abstract":"<p><p>Receptors for orexigenic hormones are broadly expressed in different tissues. Growth hormone secretagogue receptor (GHSR) is the receptor for the gastric peptide hormone ghrelin, although it further displays an intrinsic ligand-independent activity. The liver-expressed antimicrobial peptide 2 (LEAP2) has been recently identified as GHSR endogenous antagonist and inverse agonist. To understand LEAP2 effects on cardiac performance, we assessed (in-vivo) Wistar (WT) and spontaneously hypertensive rats (SHR), isolated hearts (ex-vivo) and cardiomyocytes (in-vitro). Intravenous LEAP2 injection reduced arterial pressure, with a greater effect in SHR. LEAP2 also reduced cardiac inotropism in both WT and SHR, whereas a negative chronotropy was observed only in SHR. LEAP2 perfusion reduced intraventricular pressure in isolated SHR hearts and attenuated the responses to isoproterenol on coronary flow, whereas responses to acetylcholine were almost unaffected by LEAP2. Fluorescent LEAP2 or ghrelin labeled cardiomyocytes. LEAP2 or the synthetic inverse agonist PF04628935 produced an equipotent reduction in maximum contraction speed, reduced cardiomyocyte shortening area, and attenuated the responses to isoproterenol, but not to acetylcholine. Plasma levels of ghrelin and LEAP2 were not different between strains, but higher GHSR levels were found in SHR hearts. In conclusion, LEAP2 exerted marked cardiovascular effects, reducing arterial pressure and left ventricular systolic performance in both WT and SHR, with a greater impact in hypertensive animals. However, GHSR involvement in SHR cardiac abnormalities is unrelated to the circulating levels of its endogenous ligands and instead seems to depend on altered cardiac GHSR expression and function. The cardiac LEAP2 interaction with β-adrenergic receptors reveals an important cardioprotective potential.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"124243"},"PeriodicalIF":5.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096945","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":"2026-01-29","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":"Dose-dependent effects of vildagliptin (DPP-4 inhibitor) in a scopolamine-induced memory impairment model in rats","authors":"Fazilet Şen Metin ,&nbsp;Elif Aksöz","doi":"10.1016/j.lfs.2026.124245","DOIUrl":"10.1016/j.lfs.2026.124245","url":null,"abstract":"<div><h3>Aims</h3><div>Cognitive decline and dementia are closely linked with metabolic disorders such as type 2 diabetes mellitus, sharing common pathophysiological mechanisms including insulin resistance, inflammation, and oxidative stress. This study investigated the neuroprotective potential of vildagliptin, an antidiabetic medication, in a rat model of scopolamine-induced acute memory impairment, focusing on its effects on learning and memory as well as its association with cholinergic activity, inflammatory responses, and lipid peroxidation as an indicator of oxidative stress.</div></div><div><h3>Materials and methods</h3><div>Male Wistar Albino rats were orally administered vildagliptin (0.5, 5, or 50 mg/kg/day) or physiological saline for 4 weeks. Spatial learning and memory were assessed using the Morris water maze (MWM) test. Memory impairment was induced by intraperitoneal injection of scopolamine (1 mg/kg, <em>i.p.</em>) before the probe trial of the MWM. Following behavioral testing, rats were sacrificed, and hippocampal tissues were isolated for biochemical analysis.</div></div><div><h3>Key findings</h3><div>Vildagliptin significantly enhanced spatial learning performance in a dose-dependent manner during the acquisition phase of the MWM. Scopolamine administration markedly impaired memory performance in rats. Pretreatment with vildagliptin at all tested doses prevented these memory deficits during the MWM probe trial. In addition, vildagliptin robustly prevented scopolamine-induced increases in hippocampal acetylcholinesterase (AChE) activity and elevated levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and malondialdehyde (MDA).</div></div><div><h3>Significance</h3><div>These findings suggest that vildagliptin may exert protective effects against cognitive impairment by modulating cholinergic activity, inflammatory responses, and lipid peroxidation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124245"},"PeriodicalIF":5.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097032","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":"Gestational sevoflurane exposure induces amino acid metabolic reprogramming and cognitive deficits in offspring","authors":"Jieyu Ma ,&nbsp;Li Xu ,&nbsp;Nai Sun ,&nbsp;Jianqiang Song ,&nbsp;Jie Wang ,&nbsp;Jingjing Wang ,&nbsp;Liumei Li ,&nbsp;Qinjun Chu ,&nbsp;Lin-jian Wang ,&nbsp;Qiong Song","doi":"10.1016/j.lfs.2026.124246","DOIUrl":"10.1016/j.lfs.2026.124246","url":null,"abstract":"<div><h3>Background</h3><div>Sevoflurane is one of the most widely used anesthetics in pediatric medicine; however, accumulating evidence raises critical concerns regarding its potential to induce long-term neurodevelopmental deficits. Despite extensive research, the underlying systemic molecular mechanisms driving these outcomes remain elusive.</div></div><div><h3>Methods</h3><div>Pregnant C57BL/6J mice were exposed to 2.5% sevoflurane for 2 h at embryonic day 14 (E14). Offspring were assessed for spatial learning and anxiety-related behaviors. To reconstruct the molecular landscape of toxicity, we employed an integrative multi-omics approach combining transcriptomics, proteomics, and paired brain–serum metabolomics, complemented by ELISA validation and histopathology.</div></div><div><h3>Results</h3><div>Sevoflurane-exposed offspring exhibited persistent spatial learning deficits and anxiety-like behaviors. These functional impairments were mirrored by histopathological damage, characterized by disordered neuronal arrangement and reduced Nissl-positive cells in the hippocampus. Consistently, ELISA analysis revealed a pronounced systemic inflammatory response (elevated IL-1β, IL-6, TNF-α). Integrated multi-omics profiling uncovered the molecular basis of these phenotypes, revealing a landscape of neurodevelopmental gene suppression alongside the activation of oxidative stress and inflammatory signaling. Underpinning these multidimensional pathologies, we identified a convergent reprogramming of amino acid metabolism, defined by glutamate depletion and lysine accumulation—metabolic shifts previously implicated in neuroinflammation and cognitive decline. Finally, ectoine and 5-OPPA were consistently depleted in both brain and serum, identifying them as novel concordant biomarkers of anesthetic neurotoxicity.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that gestational sevoflurane exposure induces persistent neurocognitive dysfunction in offspring driven by amino acid metabolic reprogramming. The concordant depletion of ectoine and 5-OPPA highlights their potential as minimally invasive biomarkers for anesthetic induced neurodevelopmental injury.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124246"},"PeriodicalIF":5.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080719","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":"HHcy promotes hypertension by activating ferroptosis via suppression of the renal H₂S-SLC7A11/GPX4 axis","authors":"Pan Huang ,&nbsp;Kexin Zhang ,&nbsp;Ying Chen ,&nbsp;Jiaxin Cheng ,&nbsp;Shuangshuang Yang ,&nbsp;Lin Shi ,&nbsp;Yajuan Wang ,&nbsp;Qin Zhang","doi":"10.1016/j.lfs.2026.124247","DOIUrl":"10.1016/j.lfs.2026.124247","url":null,"abstract":"<div><div>Elevated homocysteine (Hcy) is an independent risk factor for hypertension, and kidney is an important organ for Hcy metabolism and blood pressure regulation, and its damage is closely related to the process of hypertension. Recent evidence suggests that ferroptosis, an oxidative stress-related form of cell death, contributes significantly to hypertensive organ damage. However, whether Hcy aggravates renal injury in H-type hypertension by destroying renal hydrogen sulfide (H₂S) metabolism and driving ferroptosis is still lack of direct evidence. In this study, the H-type hypertensive rat model induced by high methionine diet combined with HK-2 cell model was studied. We observed a significant increase in blood pressure and plasma Hcy in the Hcy group, accompanied by renal dysfunction and renal tubular injury. Specifically, in the renal tissue of Hcy group rats, the levels of KIM-1, Fe²⁺ and malondialdehyde (MDA) were increased, glutathione/glutathione disulfide (GSH/GSSG) ratio decreased, SLC7A11 expression was down-regulated, and GPX4 activity was inhibited. Concurrently, H₂S levels and cystathionine-beta-synthase (CBS) activity were decreased. In vitro experiments using HK-2 cells confirmed that Hcy could down-regulate the expression of CBS, cystathionine-gamma-lyase (CSE), SLC7A11, GPX4 and GSH/GSSG ratio, and up-regulate MDA and reactive oxygen species (ROS) levels. Treatment with H₂S donor (NaHS) or ferroptosis inhibitors (Ferrostatin-1, Fer-1) could rescue these changes. Collectively, our results demonstrate that high Hcy promotes hypertension by suppressing endogenous H₂S generation, downregulating the SLC7A11/GPX4 signaling axis, and inducing ferroptosis. These findings reveal a new mechanism by which Hcy aggravates hypertension by inhibiting H₂S synthesis and inducing ferroptosis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124247"},"PeriodicalIF":5.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092860","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 alleviates the obesity-related dysfunction of skeletal muscle and heart caused by Akh gene knockdown in Drosophila","authors":"Ying Lin ,&nbsp;Deng-tai Wen ,&nbsp;Qing-yao Sun ,&nbsp;Shou-zhi Lv ,&nbsp;Ji-ying Wang ,&nbsp;Xing-feng Ma","doi":"10.1016/j.lfs.2026.124237","DOIUrl":"10.1016/j.lfs.2026.124237","url":null,"abstract":"<div><div>The Adipokinetic hormone (Akh), a functional analog of mammalian glucagon, plays a key role in regulating energy metabolism in <em>Drosophila</em>. Although exercise is recognized as an important intervention for preventing and alleviating obesity-related complications, its efficacy against obesity induced by <em>Akh</em> gene deficiency remains unclear. In this study, the <em>Akh</em> gene was knocked down systemically and specifically in the corpora cardiaca (CC) using <em>Act-gal4/Akh-UAS-RNAi</em> and <em>Akh-gal4/Akh-UAS-RNAi</em> systems in flies, and these flies were followed by a two-week exercise intervention. The results showed <em>Akh</em> knockdown induced obesity phenotypes, including significantly increased body weight and triglyceride levels, and concurrently impaired skeletal muscle and cardiac function—manifested as reduced climbing speed, climbing endurance, and cardiac shortening fraction, along with elevated heart rate. Mechanistically, these effects were associated with upregulated systemic <em>FASN1</em>/<em>Mdy</em>/triglyceride process and lipotoxicity (MDA), as well as downregulated mitochondrial (<em>PGC-1α</em>) and contractile (<em>Mhc</em>) markers in muscle. Exercise intervention ameliorated the obesity phenotype and was correlated with increased <em>Akh</em> expression. These findings confirm that <em>Akh</em> gene deficiency contributes to hereditary obesity and obesity-related dysfunction of skeletal muscle and heart, and demonstrate that exercise can serve as a therapeutic strategy to counteract impairments resulting from <em>Akh</em> knockdown, suggesting its potential relevance for treating human obesity linked to glucagon-related genetic defects.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124237"},"PeriodicalIF":5.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096947","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":"Loss of Galectin-3 in the epidermis exacerbates psoriasis pathogenesis via inhibiting autophagy","authors":"Shanshan Han ,&nbsp;Meiqi Cheng ,&nbsp;Shengtao Jiang ,&nbsp;Pei Liu ,&nbsp;Yue Hu ,&nbsp;Qiong Wang ,&nbsp;Yu Cai ,&nbsp;Yinhong Song ,&nbsp;Xuan Xia ,&nbsp;Yuxin Wang ,&nbsp;Yang Li ,&nbsp;Jin Chao ,&nbsp;Decheng Wang","doi":"10.1016/j.lfs.2026.124238","DOIUrl":"10.1016/j.lfs.2026.124238","url":null,"abstract":"<div><h3>Aims</h3><div>Galectin-3 (Gal3) is linked to psoriasis pathophysiology, however, the detailed mechanism of Gal3 involved in this course still needs further addressing. This study aimed to elucidate the role of Gal3 in psoriasis.</div></div><div><h3>Materials and methods</h3><div>Imiquimod (IMQ)-induced psoriasis model in wild-type (WT) as well as Gal3 knockout (<em>Gal3</em>^−/−) mice were established to investigate the impact of Gal3 expression on the development of psoriasis. Autophagy markers LC3 and P62 (SQSTM1) were detected. In vitro, HaCaT cells with Gal3 knockdown were established to detect the effect on the autophagic flux. Then the Sirt1 agonist SRT1720 was used to demonstrate whether Gal3 affects autophagy via Sirt1. The regulation of Sirt1 by Gal3 was demonstrated through half-life experiments.</div></div><div><h3>Key findings</h3><div>Gal3 was significantly reduced in the epidermis in IMQ-induced psoriasis model. The skin inflammation in <em>Gal3</em>^−/− mice more severe than that in WT controls. A deficiency of Gal3 not only reduced the autophagy in psoriatic lesions of the mice model but also effectively inhibited autophagy in a cultured HaCaT cell model. Gal3 was demonstrated to be involved in the assembly of autophagosomes by regulating autophagic flux. In Gal3-depleted mouse skin and HaCaT cells, Sirt1 was downregulated, and SRT1720 could compensate for the impaired autophagy caused by Gal3 deficiency. Gal3 may be involved in the regulation of Sirt1 protein stability.</div></div><div><h3>Significance</h3><div>Gal3 loss exacerbates psoriasis by impairing the autophagic process. These findings position Gal3 as a key protective factor against psoriasis, providing new insights into its role in the pathogenesis of this disease.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124238"},"PeriodicalIF":5.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080720","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":"High-intensity interval training attenuates the progression of diastolic and skeletal muscle dysfunction in the two-hit mouse model of HFpEF","authors":"Francisco Pino-De la Fuente ,&nbsp;Mayarling F. Troncoso ,&nbsp;Sebastián Urquiza-Zurich ,&nbsp;David Silva ,&nbsp;Magda C. Díaz-Vesga ,&nbsp;Danica Jiménez-Gallegos ,&nbsp;Rocío Bascuñan ,&nbsp;Angélica Ortega-Muñoz ,&nbsp;Raúl Vivar ,&nbsp;Claudia Muñoz-Rodriguez ,&nbsp;Raúl Flores-Vergara ,&nbsp;Alejandra Hernández ,&nbsp;Alejandra Guerrero-Moncayo ,&nbsp;Ximena Calle-Chalco ,&nbsp;Pablo F. Castro ,&nbsp;Luigi Gabrielli ,&nbsp;Mario Chiong ,&nbsp;Rodrigo Troncoso ,&nbsp;Luis Michea ,&nbsp;Sergio Lavandero","doi":"10.1016/j.lfs.2026.124248","DOIUrl":"10.1016/j.lfs.2026.124248","url":null,"abstract":"<div><h3>Background</h3><div>Heart failure with preserved ejection fraction (HFpEF) is a multifactorial syndrome characterized by diastolic dysfunction, metabolic disturbances, and skeletal muscle impairments. Exercise training has been recommended as non-pharmacological therapy for HFpEF. Yet its effects on cardiac, renal, skeletal muscle, and metabolic homeostasis remain incompletely understood.</div></div><div><h3>Aim</h3><div>We investigated the systemic effects of exercise training in the “two-hit” mouse model of HFpEF.</div></div><div><h3>Methods</h3><div>Male C57BL/6 N mice were assigned to either a sedentary HFpEF group (20 weeks) (<em>n</em> = 10) or a high-intensity interval training (HIIT) intervention for five weeks (training was initiated in the 15th week of the protocol) (n = 10), and a control group (<em>n</em> = 8). Cardiac function was assessed via echocardiography, while glucose metabolism, renal function, and skeletal muscle adaptations were evaluated through metabolic assays, histological analyses, and molecular studies.</div></div><div><h3>Results</h3><div>HIIT reduced diastolic dysfunction, as indicated by a slightly lower E/e′ ratio and reduced myocardial collagen deposition. Skeletal muscle integrity was improved, with a higher proportion of oxidative fibers in the gastrocnemius, while the quadriceps showed hypertrophy in both oxidative and less oxidative fibers. It also promotes an anabolic environment and mitochondrial enhancement. Force generation was also increased. Furthermore, HIIT reduced insulin levels without affecting renal function but decreased markers of kidney damage.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that HIIT attenuates diastolic and skeletal muscle dysfunction in the two-hit HFpEF mice model. Understanding how exercise training influences HFpEF phenotypes could provide novel insights into therapeutic strategies for patients with cardiovascular and metabolic comorbidities.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124248"},"PeriodicalIF":5.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081260","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":"Enhanced antiproliferative and anti-inflammatory effects of combined metformin, tadalafil, and tamsulosin in a rat model of testosterone-induced benign prostatic hyperplasia","authors":"Samar S. Khalaf ,&nbsp;Aya M. Sherif ,&nbsp;Eman T. Mehanna ,&nbsp;Ranwa A. Elrayess ,&nbsp;Noha M. Mesbah ,&nbsp;Dina M. Abo-Elmatty ,&nbsp;Mohamed M. Hafez","doi":"10.1016/j.lfs.2026.124240","DOIUrl":"10.1016/j.lfs.2026.124240","url":null,"abstract":"<div><h3>Aims</h3><div>Benign prostatic hyperplasia (BPH) is a common condition in aging men, associated with hormonal imbalances, oxidative stress, and inflammation. This study evaluated the effects of metformin, tadalafil, and tamsulosin administered individually or in combination on testosterone-induced BPH.</div></div><div><h3>Materials and methods</h3><div>Following BPH induction, 48 male Wistar rats were divided into six groups: normal control, BPH control, and four treatment groups receiving metformin (500 mg/kg/day), tadalafil (2 mg/kg/day), tamsulosin (10 μg/kg/day), or their combination for two weeks. Serum levels of urea, creatinine, uric acid, reduced glutathione (GSH), and malondialdehyde (MDA) were measured using enzymatic colorimetric assays. Prostate tissue levels of prostate-specific antigen (PSA), estradiol, dihydrotestosterone (DHT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed via ELISA. mRNA expression of cyclooxygenase-2 (COX-2), transforming growth factor β-2 (TGFβ-2), insulin growth factor-2 (IGF-2), and bone morphogenetic protein 5 (BMP5) was assessed by quantitative real-time PCR.</div></div><div><h3>Key findings</h3><div>Histopathological examination confirmed BPH induction through increased prostate weight and prostate index. While monotherapies alleviated BPH-related changes, com-bination therapy showed superior antioxidant activity and significantly improved kidney function markers. It also markedly reduced PSA, estradiol, and DHT levels, along with significant downregulation of COX-2, TGFβ-2, IGF-2, BMP5, NF-κB, and TNF-α.</div></div><div><h3>Significance</h3><div>although individual treatments provided benefits, their combined use enhanced therapeutic outcomes through modulation of oxidative stress, inflammation, and androgenic activity in BPH management.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124240"},"PeriodicalIF":5.1,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080721","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":"2026-01-27","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}