Life sciences最新文献

{"title":"Carnosinase inhibition enhances reactive species scavenging in high fat diet","authors":"Charlie Jr. Lavilla ,&nbsp;Merell P. Billacura ,&nbsp;Suniya. Khatun ,&nbsp;Daniel P. Cotton ,&nbsp;Vivian.K. Lee ,&nbsp;Sreya. Bhattacharya ,&nbsp;Paul W. Caton ,&nbsp;Craig Sale ,&nbsp;John D. Wallis ,&nbsp;A. Christopher Garner ,&nbsp;Mark D. Turner","doi":"10.1016/j.lfs.2025.123448","DOIUrl":"10.1016/j.lfs.2025.123448","url":null,"abstract":"<div><h3>Aims</h3><div>Life expectancy is typically reduced by 2–4 years in people with a body mass index (BMI) of 30–35 kg/m² and by 8–10 years in people with a BMI of 40–50 kg/m². Obesity is also associated with onset, or exacerbation of, multiple chronic diseases. Mechanistically, this, in part, involves formation of advanced glycation and lipidation end-products that directly bond with proteins, lipids, or DNA, thereby perturbing typical cellular function. Here we seek to prevent these damaging adduction events through inhibition of carnosinase enzymes that rapidly degrade the physiological reactive species scavenger, carnosine, in the body.</div></div><div><h3>Main methods</h3><div>Herein we performed in silico computational modelling of a compound library of ∼53,000 molecules to identify carnosine-like molecules with intrinsic resistance to carnosinase turnover.</div></div><div><h3>Key findings</h3><div>We show that leading candidate molecules reduced reactive species in C2C12 myotubes, and that mice fed <em>N</em>-methyl-[6-(2-furyl)pyrid-3-yl]methylamine alongside a high fat diet had significantly decreased amounts of damaging plasma 4-hydroxynonenal and 3-nitrotyrosine reactive species. Oral administration of <em>N</em>-methyl-[6-(2-furyl)pyrid-3-yl]methylamine to high fat-fed mice also resulted in a modest ∼10 % reduction in weight gain when compared to mice fed only high fat diet.</div></div><div><h3>Significance</h3><div>Our findings suggest that inhibition of carnosinase enzymes can increase the life-span, and thereby enhance the efficacy, of endogenous carnosine in vivo, thereby offering potential therapeutic benefits against obesity and other cardiometabolic diseases characterised by metabolic stress.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123448"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349640","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":"Carboxyaminotriazole: A bone savior in collagen-induced arthritis—Halting osteoclastogenesis via interleukin-1β downregulation","authors":"Mei Yang ,&nbsp;Shan Lu ,&nbsp;Juan Li ,&nbsp;Lei Zhu","doi":"10.1016/j.lfs.2025.123440","DOIUrl":"10.1016/j.lfs.2025.123440","url":null,"abstract":"<div><h3>Aims</h3><div>Rheumatoid arthritis (RA), a prevalent autoimmune disease, features inflammation and bone erosion, correlating with osteoclast hyperactivation and enhanced responsiveness to inflammatory factors. Reducing osteoclast formation and inflammatory mediator expression might avert bone erosion in RA. Carboxyaminotriazole (CAI) holds potential for treating autoinflammatory disorders and impeding cancer-related bone metastases. Yet, its bone-protective role and mechanism remain elusive. This study targets to explore the impacts and underlying mechanisms of CAI in preventing bone erosion in RA.</div></div><div><h3>Materials and methods</h3><div>A collagen-induced arthritis (CIA) rat model was utilized to evaluate the anti-RA potential of CAI. CCK-8, TRAP staining, TRAP activity assay, pit formation assay, RT-qPCR, Western blotting, immunofluorescence, and ELISA, were conducted to assess the effects and potential mechanisms of CAI in the management of RA.</div></div><div><h3>Key findings</h3><div>CAI not only reduces inflammatory symptoms, but it also offers superior bone protection compared to methotrexate (MTX) and works synergistically with MTX, the preferred anchoring agent for the treatment of RA. <em>In vitro</em> studies show that CAI inhibits osteoclast differentiation and function, as well as the expression of specific genes, by inhibiting NF-κB/MAPK pathways and reducing IL-1β levels. The deletion of <em>Il-1</em> and the application of IL-1β inhibitors suggest that CAI retards osteoclastogenesis through the downregulation of IL-1β.</div></div><div><h3>Significance</h3><div>CAI may have therapeutic value in treating RA-related bone erosion, likely due to its inhibition of overactive osteoclasts by suppressing the NF-κB/MAPK pathways and the subsequent expression of IL-1β.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123440"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348643","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 effect of proteasome in heart transplantation: From mechanisms to therapeutic potential","authors":"Ye Zhou ,&nbsp;Yu Chen ,&nbsp;Mengyao Xu ,&nbsp;Ying Zhang ,&nbsp;Xiaoning Wan ,&nbsp;Yudong Xia ,&nbsp;Hongjie Wang ,&nbsp;Hesong Zeng","doi":"10.1016/j.lfs.2025.123446","DOIUrl":"10.1016/j.lfs.2025.123446","url":null,"abstract":"<div><div>Heart transplantation is a critical treatment for end-stage heart failure. However, its clinical efficacy is hindered by some challenges, such as ischemia-reperfusion injury (IRI) and post-transplant rejection. These complications significantly contribute to graft dysfunction and compromise patient survival. Emerging evidence underscores the involvement of proteasome in the pathophysiology of both IRI and post-transplant rejection. Proteasome inhibition has demonstrated potential in attenuating IRI by limiting oxidative damage and apoptosis while also mitigating rejection through the regulation of adaptive and innate immune responses. Recent advances in the development of proteasome inhibitors, particularly in optimizing specificity and minimizing adverse effects, have further strengthened their prospects for clinical application. This review focuses on the roles of the proteasome and its inhibitors in heart transplantation, with an emphasis on their mechanisms and therapeutic applications in managing IRI and rejection.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123446"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143339746","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 effect of modulation Piezo2 by IGF-1 on tactile hypersensitivity in BTBR model mice","authors":"Jinhe Zhai ,&nbsp;Haiying Hao ,&nbsp;Zihan Xu ,&nbsp;Akemi Tomoda ,&nbsp;Xinyi Zhang ,&nbsp;Xinxin Wang ,&nbsp;Yutong Liu ,&nbsp;Xuan Cao ,&nbsp;Dongxin Li ,&nbsp;Yuying Zhang ,&nbsp;Xueke Yao ,&nbsp;Lili Fan ,&nbsp;Jia Wang","doi":"10.1016/j.lfs.2025.123449","DOIUrl":"10.1016/j.lfs.2025.123449","url":null,"abstract":"<div><h3>Aims</h3><div>Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder. Individuals with ASD exhibit a higher incidence of tactile hypersensitivity. However, the underlying mechanisms remain unclear. The dorsal root ganglion (DRG) plays a crucial role in influencing tactile processing. This study aims to integrate RNA sequencing (RNA-seq) and molecular biology experiments to identify key molecules involved in tactile hypersensitivity in ASD, further investigate related mechanisms, and develop effective intervention strategy.</div></div><div><h3>Main methods</h3><div>Using BTBR as the ASD model mouse and wild-type C57BL/6J as the control mouse, the differences in tactile sensitivity between them was compared. DRG were collected for RNA-seq analysis. Immunofluorescence and Enzyme-linked immunosorbent assay (ELISA) techniques were employed to validate the identified key molecules. And combined western blot to investigate the associated regulatory pathways.</div></div><div><h3>Key findings</h3><div>BTBR mice exhibit tactile hypersensitivity, which are associated with the upregulation of IGF-1 in the DRG. IGF-1 regulates the expression of Piezo2 ion channels. Inhibition of the IGF-1/Piezo2 pathway can significantly alleviate tactile hypersensitivity and social deficits in BTBR mice. Additionally, gentle touch intervention has been shown to reduce the overexpression of IGF-1/Piezo2 in the DRG, thereby ameliorating ASD symptoms.</div></div><div><h3>Significance</h3><div>The upregulation of the IGF-1/Piezo2 pathway in DRG may serve as a potential mechanism for tactile hypersensitivity observed in BTBR mice. Restoring the normalization of the IGF-1/Piezo2 is crucial for alleviating tactile hypersensitivity and synergistically rescues social deficits. Gentle touch intervention has the potential to ameliorate these behaviors through regulating IGF-1/Piezo2, positioning it as a promising strategy for ASD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123449"},"PeriodicalIF":5.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143339842","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":"Identification of biomarkers associated with macrophage polarization in diabetic cardiomyopathy based on bioinformatics and machine learning approaches","authors":"Yi Liu ,&nbsp;Juan Zhang ,&nbsp;Quancheng Han ,&nbsp;Yan Li ,&nbsp;Yitao Xue ,&nbsp;Xiujuan Liu","doi":"10.1016/j.lfs.2025.123443","DOIUrl":"10.1016/j.lfs.2025.123443","url":null,"abstract":"<div><h3>Background</h3><div>Numerous studies have investigated the role of macrophages in the pathogenesis of diabetic cardiomyopathy (DCM); however, the underlying mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>The DCM dataset (GSE62203) was downloaded from the GEO database. DEGs and WGCNA key module genes were identified. Macrophage polarization-associated genes were obtained from the GeneCards database. GO and KEGG functional enrichment were constructed. Two machine learning techniques, LASSO logistic regression and random forest, were further used to identify hub genes. The diagnostic efficiency was evaluated using ROC curves. Single-gene GSEA investigated the biological functions. Then, the relationship between hub genes and macrophage pathways was explored. Predicted Transcription factor (TF), miRNA, and lncRNA. Single cell sequencing analysis was performed. Finally, experimental validation of the hub genes using the DCM rat model.</div></div><div><h3>Results</h3><div>Three hub genes (PGK1, LDHA, EDN1) were identified through machine learning approaches. All three hub genes were found to be associated with the HIF-1 signaling pathway. Functional enrichment analysis revealed that the HIF-1 signaling pathway and Glycolysis/Gluconeogenesis are potentially linked to DCM-induced macrophage polarization. The mRNA and protein expression levels of the hub genes were consistent with the bioinformatics analysis. Furthermore, mRNA expression of the hub genes showed a positive correlation with CD80 and CD86.</div></div><div><h3>Conclusion</h3><div>PGK1, LDHA, and EDN1 represent potential biomarkers for M1 macrophage polarization in DCM. These genes may facilitate M1 macrophage polarization in DCM. Targeting macrophage polarization could represent a novel therapeutic strategy for DCM.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123443"},"PeriodicalIF":5.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143164161","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":"KLK8 modulates macrophage function following myocardial infarction by promoting the paracrine of epidermal growth factor from cardiac fibroblasts","authors":"Jinchao Song ,&nbsp;Jiankui Du ,&nbsp;Qian Zhao ,&nbsp;Yuan Gao ,&nbsp;Xing Tan ,&nbsp;Binhai Cong","doi":"10.1016/j.lfs.2025.123445","DOIUrl":"10.1016/j.lfs.2025.123445","url":null,"abstract":"<div><h3>Aims</h3><div>Tissue kallikrein-related peptidase 8 (KLK8) plays a significant role in the regulation of cardiac remodeling following myocardial infarction (MI). However, the impact of KLK8 on macrophage (MΦ) function in the context of MI remains to be elucidated.</div></div><div><h3>Materials and methods</h3><div>MI was induced through the ligation of the left anterior descending coronary artery for a duration of 1 h, followed by reperfusion. The morphological and molecular alterations in the heart were assessed at 24 h and 14 days post-ischemic injury. Adult rat cardiac fibroblasts and bone marrow-derived macrophages were employed to explore the underlying molecular mechanisms <em>in vitro</em>.</div></div><div><h3>Key findings</h3><div>In the acute phase of MI (24 h post-MI), KLK8 was observed to diminish the inflammatory response and mitigate tissue damage within the ischemic ventricle. Conversely, during the reparative phase of MI (14 days post-MI), KLK8 was found to enhance the accumulation of the M2 MΦs, elevate pro-fibrotic factors, and intensify cardiac fibrosis. The <em>in vitro</em> analysis revealed that KLK8 did not exert a direct effect on MΦs; rather, it facilitated the paracrine secretion of epidermal growth factor (EGF) from the cardiac fibroblasts. This EGF may play a role in inhibiting the pro-inflammatory activation of the MΦs and promoting their polarization towards the M2 phenotype under conditions of inflammatory stress.</div></div><div><h3>Significance</h3><div>In summary, KLK8 modulates MΦ function through the paracrine of EGF derived from cardiac fibroblasts, which may have implications for cardiac injury and remodeling following MI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123445"},"PeriodicalIF":5.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143102175","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":"CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer","authors":"Seungheon Shin ,&nbsp;Steve K. Cho","doi":"10.1016/j.lfs.2025.123444","DOIUrl":"10.1016/j.lfs.2025.123444","url":null,"abstract":"<div><div>CRBN (Cereblon), a substrate receptor of the CRL4 (Cullin4-RING E3 ubiquitin ligase) complex, has emerged as a key player in cancer metabolism. While its role in influencing metabolic phenotypes has been suggested, the precise functions of CRBN in cellular metabolism and cancer progression remain underexplored. This study investigates the impact of CRBN downregulation in lung cancer, focusing on mitochondrial metabolism and cellular functions. Data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) revealed significant reductions in CRBN expression at both mRNA and protein levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This downregulation was further confirmed in most lung cancer cell lines examined. Functional analyses of CRBN knockout (KO) cells revealed substantial alterations in mitochondrial metabolism, including enhanced oxidative phosphorylation, increased mitochondrial membrane potential (ΔΨm), and elevated production of mitochondrial reactive oxygen species (mROS). CRBN deficiency also accelerated tricarboxylic acid (TCA) cycle flux and increased mitochondrial calcium accumulation, contributing to elevated ΔΨm and potentially compromised mitochondrial integrity. Additionally, CRBN KO cells demonstrated increased cell migration, which could be mitigated by inhibiting mitochondrial calcium import. These findings suggest that CRBN plays a pivotal role in regulating mitochondrial function and metabolic activity in non-small cell lung cancer. The loss of CRBN enhances mitochondrial metabolism and contributes to increased cancer cell migration, providing new insights into the metabolic adaptations associated with CRBN deficiency in cancer progression.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123444"},"PeriodicalIF":5.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143102576","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":"IL-4-primed human umbilical cord mesenchymal stem cells-derived extracellular vesicles facilitate recovery in spinal cord injury via the miR-21-5p/PDCD4-mediated shifting of macrophage M1/M2 polarization","authors":"Mi Li ,&nbsp;Tao Zhang ,&nbsp;Pengfei Li ,&nbsp;Zhiwei Luan ,&nbsp;Jingsong Liu ,&nbsp;Yangyang Wang ,&nbsp;Yubo Zhang ,&nbsp;Yishu Liu ,&nbsp;Yansong Wang","doi":"10.1016/j.lfs.2025.123441","DOIUrl":"10.1016/j.lfs.2025.123441","url":null,"abstract":"<div><div>Spinal cord injury (SCI) represents a significant neurological disorder that profoundly impacts human life. Transplantation of extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) has emerged as a promising therapeutic strategy. microRNA (miRNA) containing EVs serve as crucial mediators of intercellular communication, playing vital roles in physiological and pathological processes. Research indicates that EVs from hUC-MSCs could attenuate inflammation and facilitate recovery from SCI. Nevertheless, their application in clinical treatment necessitates further investigation. We are actively pursuing an effective approach to modulate the intensity of the inflammatory response, thereby addressing secondary SCI. Initially, we activated hUC-MSCs with interleukin-4 (IL-4) and subsequently harvested their EVs. We investigated the influences of A-hUC-MSCs-EVs compared to routinely acquired EVs on macrophage polarization phenotypes both in vitro and in vivo. Our results show that EVs originating from A-hUC-MSCs are more effective at promoting macrophage polarization from the M1 phenotype to the M2 phenotype than those derived from hUC-MSCs. Notably, we found that A-hUC-MSCs-derived EVs had a superior impact on motor function recovery in mice with SCI. Importantly, we observed that IL-4 activation significantly upregulated the expression of miR-21-5p within these EVs. More specifically, our data demonstrate that A-hUC-MSCs-EVs depend on miR-21-5p to inhibit the effects of PDCD4 on macrophage polarization. This mechanism regulates inflammatory responses while simultaneously reducing apoptosis. In summary, EVs derived from IL-4 primed hUC-MSCs are enriched with miR-21-5p, which exerts a pivotal influence in shifting macrophage polarization, alleviating inflammatory responses following SCI, and facilitating recovery.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123441"},"PeriodicalIF":5.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255782","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":"Molecular pathological characteristics and mechanisms of the liver in metabolic disease-susceptible transgenic pigs","authors":"Juan Du,&nbsp;Kaiyi Zhang,&nbsp;Jiakun Miao,&nbsp;Yu Yang,&nbsp;Yuying Tian,&nbsp;Tianwen Wu,&nbsp;Cong Tao,&nbsp;Yanfang Wang,&nbsp;Shulin Yang","doi":"10.1016/j.lfs.2024.123337","DOIUrl":"10.1016/j.lfs.2024.123337","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis.</div></div><div><h3>Materials and methods</h3><div>The triple-transgenic (<em>PNPLA3</em>^{<em>I148M</em>}<em>-GIPR</em>^<em>dn</em><em>-hIAPP</em>) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials. The transcriptome, metabolome, and lipidome were used to investigate the molecular mechanisms of the liver in pigs.</div></div><div><h3>Key findings</h3><div>The TG2 pigs presented mild metaflammation and insulin resistance (IR) which was similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as <em>ETNPPL</em>, <em>GABBR2</em>, and <em>BMP8B</em> might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury.</div></div><div><h3>Significance</h3><div><em>ETNPPL</em>, <em>GABBR2</em>, and <em>BMP8B</em> might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123337"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903343","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":"AAV2-mediated ABD-FGF21 gene delivery produces a sustained anti-hyperglycemic effect in type 2 diabetic mouse","authors":"Sen-lin Lu ,&nbsp;Zhi-hao Pan ,&nbsp;Zhi Cui ,&nbsp;Ji-li Wang ,&nbsp;Jian-lin Yang ,&nbsp;Ya-feng Lv ,&nbsp;Chun-yu Cao ,&nbsp;Xiao-fei Huang","doi":"10.1016/j.lfs.2024.123344","DOIUrl":"10.1016/j.lfs.2024.123344","url":null,"abstract":"<div><h3>Background</h3><div>Fibroblast Growth Factor 21 (FGF21) is a naturally occurring peptide hormone involved in the regulation of glycolipid metabolism, and it shows promise as a potential treatment for type 2 diabetes mellitus (T2DM). However, the short half-life and poor pharmacokinetics of native FGF21 limit its efficacy in reducing hyperglycemia in vivo. Therefore, maintaining stable and sustained blood concentrations of FGF21 is crucial for its role as an effective regulator of glycolipid metabolism in vivo. In this study, we developed an AAV2-mediated gene delivery system incorporating an Albumin-binding domain (ABD) fused to FGF21, and we evaluated its effects in a type 2 diabetic mouse model.</div></div><div><h3>Methods</h3><div>The plasmids pAAV-FGF21-Luciferase, pHelper, and the capsid plasmid were transfected into HEK293T cells to generate recombinant AAV (rAAV) virus. A type 2 diabetes mellitus (T2DM) mouse model was established for evaluation. The rAAV was administered via tail vein injection into the mice. The effects of rAAV injection on various parameters were assessed using commercial kits. Histological changes in the liver and adipose tissue of T2DM mice were examined using hematoxylin and eosin (H&amp;E) staining.</div></div><div><h3>Results</h3><div>The data showed that the inclusion of ABD significantly prolonged the half-life of FGF21 in the serum of mice. Additionally, AAV2-mediated delivery of ABD-FGF21 to the liver resulted in sustained gene expression and a significant increase in circulating FGF21 levels in mice. Treatment with AAV2-ABD-FGF21 led to several benefits, including reduced fasting glucose, improved insulin sensitivity, decreased triglyceride and total cholesterol levels, and improved body weight in T2DM mice. Furthermore, serum analysis and histological examination showed no significant liver damage at the study endpoint after seven weeks.</div></div><div><h3>Conclusion</h3><div>In conclusion, we have developed a novel strategy for producing long-acting FGF21 using the AAV vector, and AAV2-ABD-FGF21 shows promise as a therapeutic approach for type 2 diabetes mellitus and other glycolipid metabolic disorders.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"362 ","pages":"Article 123344"},"PeriodicalIF":5.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906559","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}