Life sciences最新文献

{"title":"Roflumilast attenuates doxorubicin and cyclophosphamide combination-induced chemobrain in rats through modulation of NLRP3/ASC/caspase-1/GSDMD axis","authors":"Georgette Eskander ,&nbsp;Sherihan G. Abdelhamid ,&nbsp;Sara A. Wahdan ,&nbsp;Sara M. Radwan","doi":"10.1016/j.lfs.2025.123378","DOIUrl":"10.1016/j.lfs.2025.123378","url":null,"abstract":"<div><h3>Aim</h3><div>The aim of this study is to investigate the neuroprotective effect of roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor on cognitive impairment induced by doxorubicin (DOX)/cyclophosphamide (CP) combination therapy and to elucidate its modulatory effect on the pyroptosis pathway.</div></div><div><h3>Materials and methods</h3><div>Rats were allocated into five groups: a control group, a DOX/CP-intoxicated group, two groups receiving DOX/CP plus low-dose (0.5 mg/kg/day) or high-dose (1 mg/kg/day) roflumilast, and a roflumilast-only group. Behavioral assessments and brain tissue analyses were conducted, including histopathological staining and the measurement of inflammatory and oxidative stress markers.</div></div><div><h3>Findings</h3><div>DOX/CP treatment resulted in cognitive impairment, abnormal brain histology. It significantly elevated the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and malondialdehyde (MDA). Concurrently, superoxide dismutase (SOD) activity was reduced. Pyroptosis-associated markers, including nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1, gasdermin-D (GSDMD), and interleukin-18 (IL-18) were upregulated. Apoptotic marker caspase-3 also exhibited increased expression. Conversely, administration of roflumilast (1 mg/kg/day) for four weeks ameliorated these pathological changes. Roflumilast improved cognitive function, reduced oxidative stress, and modulated inflammatory signaling. Additionally, it suppressed pyroptotic and apoptotic pathways within hippocampal tissue.</div></div><div><h3>Significance</h3><div>These results suggest that roflumilast exerts neuroprotective effects against chemotherapy-induced cognitive dysfunction and neurodegeneration through inhibition of the NLRP3/ASC/caspase-1/GSDMD pyroptosis pathway.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123378"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951018","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":"Insight into a multifunctional potassium channel Kv1.3 and its novel implication in chronic kidney disease","authors":"Zac Dragan,&nbsp;Carol A. Pollock,&nbsp;Chunling Huang","doi":"10.1016/j.lfs.2024.123338","DOIUrl":"10.1016/j.lfs.2024.123338","url":null,"abstract":"<div><div>Chronic kidney disease (CKD), a global public health problem, causes substantial morbidity and mortality worldwide. Innovative therapeutic strategies to mitigate the progression of CKD are needed due to the limitations of existing treatments. Kv1.3, a voltage-gated potassium ion channel, plays a crucial role in multiple biological processes, including cell proliferation, apoptosis, energy homeostasis, and migration. Inhibition of the Kv1.3 channels has shown beneficial effects in the therapy of a wide range of human diseases such as cancer, autoimmune and neuroinflammatory diseases. Increasing evidence reveals a close link between Kv1.3 and CKD. This review summarises the most recent insights into the physiological functions of the Kv1.3 channel and its pharmacological modulators. Furthermore, the therapeutic potential of targeting Kv1.3 for CKD is also discussed. Collectively, these studies suggested that Kv1.3 channels may serve as a novel target for CKD therapy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123338"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined analysis of bulk, single-cell RNA sequencing, and spatial transcriptomics reveals the expression patterns of lipid metabolism and ferroptosis in the immune microenvironment of metabolic-associated fatty liver disease","authors":"Zhihao Fang ,&nbsp;Changxu Liu ,&nbsp;Yue Cheng ,&nbsp;Yanchao Ji ,&nbsp;Chang Liu","doi":"10.1016/j.lfs.2025.123377","DOIUrl":"10.1016/j.lfs.2025.123377","url":null,"abstract":"<div><h3>Aims</h3><div>This study aims to identify key biomarkers associated with ferroptosis and lipid metabolism and investigate their roles in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD). It further explores interactions between these biomarkers and the immune-infiltration environment, shedding light on how ferroptosis and lipid metabolism influence immune dynamics in MAFLD.</div></div><div><h3>Main methods</h3><div>Single-cell RNA sequencing data from liver samples were analyzed to evaluate expression variations related to ferroptosis and lipid metabolism in MAFLD patients. Gene scores were assessed to explore their impact on the immune microenvironment, particularly hepatocyte-macrophage communication. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to Bulk-RNA-Seq data to identify gene clusters associated with ferroptosis and lipid metabolism. The analyses were integrated into a risk assessment system and predictive model, with validation conducted through in vivo experiments.</div></div><div><h3>Key findings</h3><div>Integration of single-cell and WGCNA data identified 11 key genes linked to ferroptosis and lipid metabolism (e.g., IER5L, SOCS2, KLF9), significantly influencing the liver's immune microenvironment. The risk assessment system and predictive model achieved an AUC of 0.92 and revealed distinct immune and biological characteristics in MAFLD patients across risk levels. The expression patterns and biological roles of these genes were confirmed in in vivo studies.</div></div><div><h3>Significance</h3><div>This study establishes a strong link between ferroptosis- and lipid metabolism-related gene expression and MAFLD's complexity. It provides novel insights into disease mechanisms, supporting personalized prognosis and targeted therapeutic strategies for MAFLD patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123377"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965592","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 many faces of DGAT1","authors":"Ewa Oleszycka ,&nbsp;Kamila Kwiecień ,&nbsp;Beata Grygier ,&nbsp;Joanna Cichy ,&nbsp;Patrycja Kwiecińska","doi":"10.1016/j.lfs.2024.123322","DOIUrl":"10.1016/j.lfs.2024.123322","url":null,"abstract":"<div><div>Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a multifaced enzyme with a wide spectrum of substrates, from lipids through waxes to retinoids, which makes it an interesting therapeutic target. DGAT1 inhibitors are currently at various stages of preclinical and clinical trials, mostly related to metabolic diseases. Interestingly, in recent years, a growing amount of research has shown the influence of DGAT1 on immune cell metabolism and functions, highlighting its important role during infections and tumorigenesis. In this review, we aim to elucidate the potential immunomodulatory effect of DGAT1 in physiological and pathological conditions.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123322"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872474","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":"Probing the familial ties between serpin members Kallistatin and PEDF: A comparative analysis review","authors":"Jingnan Chen ,&nbsp;Zihan Wang ,&nbsp;Simin Wang ,&nbsp;Jiayi Lyu ,&nbsp;Zhenzhen Fang ,&nbsp;Weiwei Qi ,&nbsp;Xia Yang ,&nbsp;Guoquan Gao ,&nbsp;Ti Zhou","doi":"10.1016/j.lfs.2024.123333","DOIUrl":"10.1016/j.lfs.2024.123333","url":null,"abstract":"<div><div>The serine protease inhibitors (Serpins) represent a diverse protein superfamily that holds paramount significance in governing vital pathophysiological processes. Their influence on critical biological pathways renders serpins highly coveted targets for drug discovery endeavors. Among the numerous members of this family, two distinct proteins, Kallistatin (encoded by the <em>SERPINA4</em> gene) and Pigment Epithelium-Derived Factor (PEDF, encoded by the <em>SERPINF1</em> gene), stand out as secreted proteins that are abundantly present in peripheral blood. Kallistatin is a serine protease inhibitor that specifically inhibits human tissue kallikrein, while PEDF is a non-inhibitory member of the serine protease inhibitors superfamily (Lin et al., 2015a; Chao and Chao, 1995 [<span><span>1</span></span>,<span><span>2</span></span>]). Instead, they exhibit notable anti-angiogenic effects and play pivotal roles in the pathogenesis of metabolic disorders. Extensive research, including our own investigations, has revealed intriguing similarities as well as noteworthy differences between these two proteins. Despite their shared characteristics, the distinctive features of Kallistatin and PEDF render them unique in their respective functions and mechanisms of action. However, a comprehensive literature review comparing their similarities and differences remains elusive. Therefore, the present review aims to systematically delve into and summarize the comparable and contrasting aspects of Kallistatin and PEDF. We will delve into their expression patterns, structural features, and mechanisms of expression regulation. Furthermore, this review will delve into their physiological functions and roles in diseases, the signaling pathways they influence, and their potential clinical applications. By comparing and contrasting these two proteins, we hope to provide a comprehensive understanding of their functions and potential in biomedical research and clinical practice.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123333"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884831","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":"Altering phosphorylation of dystrophin S3059 to attenuate cancer cachexia","authors":"Kristy Swiderski ,&nbsp;Jennifer Trieu ,&nbsp;Annabel Chee ,&nbsp;Timur Naim ,&nbsp;Christopher J. Brock ,&nbsp;Dale M. Baum ,&nbsp;Audrey S. Chan ,&nbsp;Justin P. Hardee ,&nbsp;Wenlan Li ,&nbsp;Andrew J. Kueh ,&nbsp;Marco J. Herold ,&nbsp;Kate T. Murphy ,&nbsp;Paul Gregorevic ,&nbsp;Gordon S. Lynch","doi":"10.1016/j.lfs.2024.123343","DOIUrl":"10.1016/j.lfs.2024.123343","url":null,"abstract":"<div><h3>Aims</h3><div>Cancer cachexia affects up to 80 % of patients with advanced cancer and accounts for &gt;20 % of all cancer-related deaths. Sarcolemmal localization of dystrophin, a key protein within the dystrophin-glycoprotein complex (DGC), is perturbed in multiple muscle wasting conditions, including cancer cachexia, indicating a potential role for dystrophin in the maintenance of muscle mass. Strategies to preserve dystrophin expression at the sarcolemma might therefore combat muscle wasting. Phosphorylation of dystrophin serine 3059 (S3059) enhances the interaction between dystrophin and β-dystroglycan and attenuates atrophy of mouse muscle myotubes <em>in vitro</em> when cultured in the presence of colon-26 (C-26) cancer cells. Whether dystrophin S3059 phosphorylation can attenuate cachexia in tumor-bearing mice has not been determined.</div></div><div><h3>Materials and methods</h3><div>Mice with systemic mutations of serine 3059 to alanine (DmdS3059A; phospho-null) or glutamate (DmdS3059E; phosphomimetic) were generated to investigate the impact of S3059 phosphorylation on survival and skeletal muscle health in the C-26 tumor-bearing mouse model of cancer cachexia using measures of skeletal muscle function <em>in situ</em> combined with biochemical and histological assessments.</div></div><div><h3>Key findings</h3><div>In a model of mild cachexia, loss of skeletal muscle mass and function was greater in DmdS3059A mice. Conversely, in a model of severe cachexia, overall survival was prolonged, and markers of protein degradation were decreased in skeletal muscles of DmdS3059E mice. Thus, manipulating dystrophin S3059 phosphorylation can alter the progression of cachexia in tumor-bearing mice.</div></div><div><h3>Significance</h3><div>Strategies to increase phosphorylation of this site, and/or increase dystrophin protein expression, have therapeutic potential for cancer cachexia.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123343"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcranial alternating current stimulation inhibits ferroptosis and promotes functional recovery in spinal cord injury via the cGMP-PKG signalling pathway","authors":"Ke Huang ,&nbsp;Jing Fang ,&nbsp;Shining Xiao ,&nbsp;Wansong Wang ,&nbsp;Guodong Zhang ,&nbsp;Weiming Sun ,&nbsp;Lang Shuai ,&nbsp;Haidi Bi","doi":"10.1016/j.lfs.2024.123341","DOIUrl":"10.1016/j.lfs.2024.123341","url":null,"abstract":"<div><h3>Aims</h3><div>This study explores the potential of neuromodulation, specifically transcranial alternating current stimulation (tACS), as a promising rehabilitative therapy in spinal cord injury (SCI).</div></div><div><h3>Main methods</h3><div>By meticulously optimizing treatment parameters and durations, our objective was to enhance nerve regeneration and facilitate functional recovery. To assess the efficacy of tACS, our experiments used the rat T10 SCI model. Motor function outcomes were measured using the Basso-Beattie-Bresnahan (BBB) scoring scale and footprint analysis. To thoroughly understand the impact of tACS, we conducted a series of histological evaluations two weeks post-injury. These included q-PCR, enzyme-linked immunosorbent assays (ELISA), transmission electron microscopy (TEM), immunofluorescence staining, and Western blotting. The mechanisms underlying the role of tACS will be elucidated through comprehensive analyses.</div></div><div><h3>Key findings</h3><div>Simultaneously, tACS reduced the levels of reactive oxygen species (ROS), Fe, and malondialdehyde (MDH), and increased the levels of glutathione (GSH) after SCI. Additionally, tACS significantly enhanced motor function, reduced fibrotic scar tissue formation, and provided substantial neuroprotection. It also contributed to the restoration of the blood-spinal cord barrier and supported the regeneration of essential neural components, including axons, myelin, and synapses. The cGMP-PKG signalling pathway was identified as playing a crucial role in these processes.</div></div><div><h3>Significance</h3><div>Our findings suggest that tACS inhibits ferroptosis and necrotic degeneration by modulating the cGMP-PKG signalling pathway. This highlights the importance of tACS in promoting neural repair and functional recovery in SCI patients. Overall, tACS emerges as a highly effective and cost-efficient rehabilitative approach for SCI, offering new hope for improving patient outcomes.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123341"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909778","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":"Inhibition of peptidyl arginine deiminase-4 ameliorated pulmonary fibrosis via modulating M1/M2 polarisation of macrophages","authors":"Biswajit Panda,&nbsp;Shrilekha Chilvery,&nbsp;Priyanka Devi,&nbsp;Radha Kalmegh,&nbsp;Chandraiah Godugu","doi":"10.1016/j.lfs.2024.123354","DOIUrl":"10.1016/j.lfs.2024.123354","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) arises from dysregulated wound healing, leading to excessive extracellular matrix (ECM) deposition and impaired lung function. Macrophages exhibit high plasticity, polarizing to pro-inflammatory M1 during early inflammation and anti-inflammatory, fibrosis-inducing M2 during later stages of PF. Additionally, neutrophils and neutrophil extracellular traps (NETs) release mediated by peptidyl arginine deiminase (PAD-4), also play a key role in PF progression. PAD-4 inhibitor chloro-amidine (CLA) has shown anti-fibrotic effects in bleomycin (BLM) induced PF mouse model in our earlier study. Here, we have demonstrated that CLA also exhibited inhibition of macrophage polarisation in in-vitro in THP-1 monocytes and in-vivo in BLM induced PF. THP-1 monocytes were exposed to NETs isolated from phorbol 12-myristate-13-acetate (PMA) stimulated and PMA plus CLA treated differentiated HL-60 (dHL-60) cells. Monocytes exposed to stimulated NETs resulted in increased oxidative stress, disrupted mitochondrial membrane potential and increased M1 and M2 macrophage markers. These alterations were abrogated in THP-1 cells upon exposure to CLA treated NETs. Further, CLA treatment in BLM induced mice improved abnormal BALF, biochemical, and histological parameters in line with our previous findings. Additionally, CLA also reduced M1 and M2 markers time-dependently, as shown by immunofluorescence (IF), western blot, and RT-PCR analysis. CLA treatment led to decreased expression of PAD-4, M1-related pro-inflammatory cytokines and M2-related pro-fibrotic cytokines and mediators, as confirmed by western blot and ELISA analysis. Thus, it is established that inhibition of PAD-4 lead to mitigation of macrophage polarisation and a combined anti-fibrotic effect is achieved which can be explored further.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123354"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927462","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":"Pediococcus acidilactici CECT 9879 (pA1c®) and heat inactivated pA1c® (pA1c® HI) ameliorate gestational diabetes mellitus in mice","authors":"Deyan Yavorov-Dayliev ,&nbsp;Fermín I. Milagro ,&nbsp;Josune Ayo ,&nbsp;María Oneca ,&nbsp;Ignacio Goyache ,&nbsp;Miguel López-Yoldi ,&nbsp;Jamie A. FitzGerald ,&nbsp;Fiona Crispie ,&nbsp;Paul D. Cotter ,&nbsp;Paula Aranaz","doi":"10.1016/j.lfs.2024.123359","DOIUrl":"10.1016/j.lfs.2024.123359","url":null,"abstract":"<div><h3>Aims</h3><div>Gestational diabetes mellitus (GDM) is the most common complication of pregnancy and is known to be associated with an increased risk of postpartum metabolic disease. Based on the important role that the intestinal microbiota plays in blood glucose regulation and insulin sensitivity, supplementation of probiotic and postbiotic strains could improve glucose metabolism and tolerance in GDM.</div></div><div><h3>Main methods</h3><div>56 4-week-old female C57BL/6J-mice were divided into 4 groups (<em>n</em> = 14 animals/group): control (CNT), high-fat/high-sucrose (HFS), pA1c® alive (pA1c®) and heat-inactivated pA1c® (pA1c®HI). Serum biochemical parameters were analyzed, gene expression analyses were conducted, and fecal microbiota composition was evaluated by shot-gun sequencing.</div></div><div><h3>Key findings</h3><div>pA1c®- and pA1c® HI-supplemented groups presented reduced fasting blood glucose levels and reduced insulin resistance during gestation and exhibited lower visceral adiposity and increased muscle tissue, together with an improvement in intrahepatic TGs content and ALT levels. Liver gene expression analyses demonstrated that pA1c® and pA1c® HI activities were mediated by modulation of the insulin receptor, but also by an overexpression of beta-oxidation genes, and downregulation of fatty acid biosynthesis genes. Shot-gun metagenomics demonstrated that <em>Pediococcus acidilactici</em> was detected in the feces of all the pA1c® and pA1c® HI-group after the supplementation period (75 % of the microbial profile was <em>Pediococcus acidilactici</em>) in only nine weeks of supplementation, and modulated gut microbiota composition.</div></div><div><h3>Significance</h3><div>These results may be considered as future perspectives for the development of preventive, even therapeutic options for GDM based on hyperglycemia reduction, blood glucose regulation, hepatic steatosis attenuation and insulin resistance alleviation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123359"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dissociated glucocorticoid receptor modulator mitigates glucolipotoxicity in the endocrine pancreas and peripheral tissues: Preclinical data from a mouse model of diet-induced type 2 diabetes","authors":"Miranda Sol Orellano ,&nbsp;Andrea Scelza-Figueredo ,&nbsp;Lucía Lameroli Mauriz ,&nbsp;Carolina Sétula ,&nbsp;Milagros Argañarás ,&nbsp;Catalina Atorrasagasti ,&nbsp;Marcelo Javier Perone ,&nbsp;Luz Andreone","doi":"10.1016/j.lfs.2024.123363","DOIUrl":"10.1016/j.lfs.2024.123363","url":null,"abstract":"<div><h3>Aims</h3><div>Type 2 diabetes (T2D) is a prevalent metabolic disease linked to obesity and metabolic syndrome (MS). The glucolipotoxic environment (GLT) impacts tissues causing low-grade inflammation, insulin resistance and the gradual loss of pancreatic β-cell function, leading to hyperglycemia. We have previously shown that Compound A (CpdA), a plant-derived dissociative glucocorticoid receptor-modulator with inflammation-suppressive activity, displays protective effects on β-cells in type 1 diabetes murine models. This study aimed to evaluate whether the administration of CpdA can attenuate GLT effects and improve pathophysiological parameters in a murine model of T2D/MS.</div></div><div><h3>Main methods</h3><div>Eight-week-old male C57BL/6NCrl mice were fed either a standard chow diet or a high-fat/high-sucrose diet (HFHS) for 15 weeks. From week 5 of feeding, each group received i.p. injections of CpdA (2.5 μg/g) or vehicle three times a week. We also examined CpdA in vitro effect against GLT using the insulinoma cell line INS-1E and naïve isolated mouse islets.</div></div><div><h3>Key findings</h3><div>CpdA administration in HFHS fed mice improved glucose homeostasis and insulin sensitivity with no apparent side effects. CpdA treatment also preserved pancreatic islet architecture and insulin expression, while reducing hepatic steatosis and visceral adipose tissue inflammation induced by HFHS diet. In vitro assays in INS-1E cells and naïve isolated mouse islets demonstrated that CpdA counteracted GLT-induced inhibition of glucose-stimulated insulin secretion and supported the expression of key β-cell identity genes under GLT conditions.</div></div><div><h3>Significance</h3><div>These findings highlight the potential protective effect of CpdA in preserving β-cell functionality and peripheral tissue physiology in the context of T2D/MS.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123363"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950420","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}