Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Microglia-drive IRF8 upregulates complement pathway in Parkinson's disease","authors":"Hongkai Yao ,&nbsp;Chenming Liu ,&nbsp;Lingjing Jin ,&nbsp;Yunping Song","doi":"10.1016/j.bbadis.2025.167928","DOIUrl":"10.1016/j.bbadis.2025.167928","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a widespread degenerative disorder of the central nervous system. The gradual degeneration of dopaminergic neurons in the substantia nigra region is one of the primary pathological features of PD. Glial cells in SN are also linked to the pathological PD alterations. To discern the role of neurons and glial cells as well as their corresponding genetic modifications in PD, we utilized diverse bioinformatics techniques and performed biological experiments on cell and animal models. Several transcriptome datasets of the substantia nigra region were collected from the Gene Expression Omnibus dataset. Cibersort was used to deconvolute the data into proportions of brain cell types. WGCNA was used to analyze the association between modules and traits. Machine learning was used to select the hub genes from WGCNA results. Based on the results of transcriptome analysis, microglia were the most related cell type. Through machine learning, IRF8 was identified as the hub gene associated with PD and microglia. Furthermore, an increased ratio of IRF8+ microglia was observed in PD mice, along with an elevated expression of IRF8 in primary microglia cultures treated with α-synuclein preformed fibril (PFFs). To explore the function of IRF8 in microglia under disease condition, we conducted siRNA of IRF8 and found it was highly associated with complement pathway, which may cause the activation of microglia. In conclusion, our research indicated IRF8 may be involved in the functional regulation of microglia in PD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167928"},"PeriodicalIF":4.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicle-dependent crosstalk between hepatic stellate cells and Kupffer cells promotes their mutual activation","authors":"Junyu Wang ,&nbsp;Jia Li ,&nbsp;Manon Buist-Homan ,&nbsp;Martin C. Harmsen ,&nbsp;Han Moshage","doi":"10.1016/j.bbadis.2025.167914","DOIUrl":"10.1016/j.bbadis.2025.167914","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Hepatic fibrosis results from hepatic stellate cell (HSC) activation and excessive extracellular matrix (ECM) deposition, driven by chronic inflammation. Kupffer cells (KCs) play a central role in HSC activation. We previously showed that HSC-secreted factors, particularly extracellular vesicles (EVs), activate KCs. However, the reciprocal effects of activated KCs on HSCs remain poorly understood. This study investigates the bidirectional crosstalk between HSCs and KCs, focusing on the role of KC-derived EVs in regulating HSC activation and fibrosis progression.</div></div><div><h3>Methods</h3><div>Primary HSCs and KCs were isolated from male Wistar rats. HSCs were co-cultured with KCs for 24 h to assess inflammatory and activation markers. LPS-stimulated KC-derived EVs and controls were administered to HSCs on day 1. LPS and the Toll-like receptor 4 (TLR4) inhibitor TAK-242 were used to investigate the intercellular communication in detail.</div></div><div><h3>Results</h3><div>Co-cultured HSCs and KCs showed mutual activation, demonstrated by elevated inflammatory markers in both cell types and enhanced HSC pro-fibrotic activation. Pro-inflammatory (LPS)-activated KCs amplified HSC activation in a TLR4-dependent fashion. Part of this augmented HSC activation was attributed to EVs.</div></div><div><h3>Conclusions</h3><div>In co-culture, KCs and HSCs show mutual activation in a TLR4-dependent fashion. This bidirectional activation is augmented by pro-inflammatory mediators. KC-derived EVs (partially) activate HSCs, which might contribute to progression of liver fibrosis <em>in vivo</em>. Modulating KC activation, such as by blocking TLR4 signaling, may alter EV secretion or cargo composition, reducing HSC activation and fibrosis progression. Targeting this EV-mediated crosstalk could provide novel therapeutic strategies for liver fibrosis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167914"},"PeriodicalIF":4.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-secreted TNF induces NCoA3 upregulation in breast cancer-associated adipocytes via TNFR1/NF-κB signaling","authors":"María Cecilia Lira ,&nbsp;Francisco D. Rosa ,&nbsp;Juliana Lourdes Bernacchia ,&nbsp;Alejandra G. Palma ,&nbsp;Natalia Paladino ,&nbsp;Mónica A. Costas ,&nbsp;María Fernanda Rubio","doi":"10.1016/j.bbadis.2025.167931","DOIUrl":"10.1016/j.bbadis.2025.167931","url":null,"abstract":"<div><div>In breast cancer, adipocytes are the predominant cell type in the microenvironment, and the continuous communication between these tissues alters the adipose phenotype. However, molecular mechanisms promoting these changes are still poorly understood. Previously, we demonstrated that NCoA3 expression is increased in adipose tissue adjacent to breast cancer and that this increase is associated with an inflammatory profile. This study aimed to investigate the mechanisms underlying NCoA3 expression in adipocytes within the breast tumor microenvironment.</div><div>We demonstrated that breast cancer-secreted TNF increases NCoA3 expression in adipocytes, and this upregulation is dependent on NF-κB transcriptional activity. Furthermore, the use of a TNF blocker prevented both coactivator overexpression and macrophages recruitment, mimicking the effects observed when NCoA3 expression was downregulated using a short hairpin RNA.</div><div>These findings shed light on the molecular mechanisms by which breast cancer cells modulate adipocyte behavior, identifying NCoA3 as a key mediator in the tumor-adipose tissue crosstalk. Targeting this pathway through TNF inhibition offers promising therapeutic strategy to attenuate tumor-associated inflammation and potentially improve outcomes in breast cancer patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167931"},"PeriodicalIF":4.2,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-assisted multi-OMICS analysis reveals new markers for the prediction of AD","authors":"Hamid Latifi-Navid ,&nbsp;Saeedeh Mokhtari ,&nbsp;Sepideh Taghizadeh ,&nbsp;Fatemeh Moradi ,&nbsp;Dorsa Poostforoush-Fard ,&nbsp;Sakineh Alijanpour ,&nbsp;Mohamad-Reza Aghanoori","doi":"10.1016/j.bbadis.2025.167925","DOIUrl":"10.1016/j.bbadis.2025.167925","url":null,"abstract":"<div><div>Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline. Early and accurate diagnosis is crucial for improving patient outcomes, yet current diagnostic methods remain invasive, costly, and limited in accessibility. This study leverages artificial intelligence (AI) and machine learning approaches to perform a multi-omics analysis, integrating proteomics and transcriptomics data to identify potential biomarkers for early AD prediction. Using multiple AD-related databases and AI-powered literature review tools, we extracted and analyzed gene expression profiles from various tissues, including brain, cerebrospinal fluid (CSF), and plasma. A protein-protein interaction (PPI) network was reconstructed to determine key hub genes using centrality analysis. Our findings revealed 13 common hub genes, including APP, YWHAE, YWHAH, SOD1, UQCRFS1, ATP5F1B, AP2M1, MMAB, INA, RPL6, HADHB, CD63, and CTNNB1, that are significantly implicated in both early and advanced AD. Furthermore, pathway enrichment analysis identified critical pathways such as oxidative phosphorylation, metabolic pathways, and synaptic transmission, which are associated with AD progression. Additionally, nine common miRNAs and eight key molecular axes were determined, highlighting potential mechanistic links between early and advanced AD. These findings offer novel insights into AD pathophysiology and provide a foundation for developing non-invasive biomarkers for early detection. Future experimental validation of these biomarkers is essential to translate these findings into clinical applications.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167925"},"PeriodicalIF":4.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of antioxidant enzyme PRDX6 and mucosal chemokine CXCL17: unraveling the factors behind oxidative stress and mucosal homeostasis disruption in dry eye disease","authors":"Murat Akkurt Arslan ,&nbsp;Antoine Rousseau ,&nbsp;Hong Liang ,&nbsp;Solenne Chardonnet ,&nbsp;Cédric Pionneau ,&nbsp;Ghislaine Rabut ,&nbsp;Annabelle Réaux Le Goazigo ,&nbsp;Marc Labetoulle ,&nbsp;Christophe Baudouin ,&nbsp;Françoise Brignole-Baudouin ,&nbsp;Karima Kessal","doi":"10.1016/j.bbadis.2025.167911","DOIUrl":"10.1016/j.bbadis.2025.167911","url":null,"abstract":"<div><div>This study aimed to identify dysregulated proteins in Schirmer strip samples (ScS) from Sjögren's syndrome dry eye (SSDE) patients to uncover key biological processes using untargeted proteomics. The focus then shifted to two dysregulated proteins, PRDX6 and CXCL17, due to their roles in oxidative stress and mucosal immunity, with the goal of exploring their potential as therapeutic targets. Their involvement was further investigated in vitro and validated in a larger SSDE cohort, assessing their relationship with clinical signs. ScS from 12 SSDE patients and 6 healthy controls underwent untargeted proteomic analysis. PRDX6 and CXCL17 levels in ScS from 39 SSDE patients were quantified using ELISA. In vitro, human corneal epithelial cells (HCEc) were exposed to hyperosmolarity or IFN-γ, and PRDX6 and CXCL17 expression was assessed by RT-qPCR for gene expression and by ELISA and immunocytochemistry for protein expression. Untargeted proteomics identified 111 dysregulated proteins in SSDE, highlighting alterations in oxidative stress, cell metabolism, cytoskeleton organization, and programmed cell death. Targeted proteomics showed positive correlations between PRDX6 levels and TBUT/Schirmer tests, and negative correlations with OSDI/Oxford scores. CXCL17 levels negatively correlated with the Oxford score. In vitro, PRDX6 and CXCL17 expression increased under hyperosmotic or inflammatory stress, displaying inverse trends compared to ScS from SSDE patients. This study elucidates the biological processes driving epithelial cell alterations in SSDE, focusing on oxidative stress and mucosal homeostasis. It underscores the significant roles of PRDX6 and CXCL17 in these processes, suggesting their potential as biomarkers or therapeutic targets for SSDE.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167911"},"PeriodicalIF":4.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate inhibits T-cell activation in sepsis through CD40LG downregulation and SOCS3-mediated JAK1/STAT3 pathway suppression","authors":"Hui Zhang ,&nbsp;Fanbing Meng ,&nbsp;Jinxuan Tang ,&nbsp;Meixian Zhang ,&nbsp;Qi Jing ,&nbsp;Guotao Peng ,&nbsp;Xiaoxiao Sun ,&nbsp;Cheng Li","doi":"10.1016/j.bbadis.2025.167923","DOIUrl":"10.1016/j.bbadis.2025.167923","url":null,"abstract":"<div><h3>Objectives</h3><div>Lactate, an indicator of sepsis severity, affects kinase activity and is often associated with immunosuppression. This study investigates the impact of lactate on kinases and immune cells and identifies pivotal genes governing their interactions.</div></div><div><h3>Methods</h3><div>Differentially expressed genes (DEGs) between sepsis and control groups were screened using the limma package. The correlation between lactate-related DEGs (lrDEGs) and kinase-related DEGs (krDEGs) was then assessed. Hub genes were identified using the algorithms in CytoHubba and weighted gene co-expression network analysis (WGCNA). The aberrant immune status of sepsis patients was evaluated using xCell. The findings were ultimately validated through cellular experiments.</div></div><div><h3>Results</h3><div>In sepsis, a stronger correlation between lrDEGs and krDEGs was observed among the 998 identified DEGs compared to controls. Eight hub genes were identified through CytoHubba and WGCNA. The correlation between lrDEGs (or krDEGs) and T lymphoid cell score was particularly strong among the hub genes. CD40LG and SOCS3 were identified as key regulators of T cell function. These genes were closely associated with lrDEGs. Cellular experiments demonstrated that lactate inhibits T cell activation through downregulation of CD40LG and suppression of the SOCS3-mediated JAK1/STAT3 pathway.</div></div><div><h3>Conclusion</h3><div>Lactate-induced inhibition of T lymphocyte activation in sepsis is associated with altered expression of kinase-related genes. Elevated lactate levels downregulate CD40LG and SOCS3 expression, leading to T cell suppression by inhibiting the JAK-STAT signaling pathway.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167923"},"PeriodicalIF":4.2,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole exome sequencing identified three novel mutations of RTEL1 in Chinese patients with idiopathic pulmonary fibrosis","authors":"Lv Liu ,&nbsp;Cheng-Feng Hu ,&nbsp;Chen-Yu Wang ,&nbsp;Jie-Yi Long ,&nbsp;Hong Peng ,&nbsp;Liang-Liang Fan","doi":"10.1016/j.bbadis.2025.167924","DOIUrl":"10.1016/j.bbadis.2025.167924","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>Previous studies have revealed that mutations in <em>regulator of telomere elongation helicase 1</em> (<em>RTEL1</em>) can lead to idiopathic pulmonary fibrosis (IPF).</div></span></li><li><span>•</span><span><div>Here, we identified three novel mutations (NM_001283009.1: p.G201R, p.D266H and p.S798T) of <em>RTEL1</em> in IPF patients. Functional studies suggested that these three variants disrupted the protein stability and nucleocytoplasmic distribution of the RTEL1 protein, which further decreased the expression of dyskerin and finally reduced the length of telomere and led to IPF and related disorders.</div></span></li><li><span>•</span><span><div>Our study may broaden the mutation and phenotype spectrum of RTEL1 deficiency, offering insights into the mechanisms underlying IPF.</div></span></li></ul></div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167924"},"PeriodicalIF":4.2,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endolysosomal cation channel MCOLN as the novel regulator of redox homeostasis","authors":"Yahao Gao,&nbsp;Lei Xu,&nbsp;Ying Chen","doi":"10.1016/j.bbadis.2025.167910","DOIUrl":"10.1016/j.bbadis.2025.167910","url":null,"abstract":"<div><div>Reactive oxygen species (ROS) production and antioxidant levels are out of equilibrium, which leads to oxidative stress. When ROS levels rise, tissues are destroyed by protein oxidation, lipid peroxidation, DNA oxidation, and mutagenesis, which activates the cell death pathway. Low levels of ROS can regulate cell survival and metabolic pathways to stimulate cell proliferation. Normal cells don't create as much ROS as cancer cells do. The endolysosomal cation channel MCOLN channels have been shown to integrate multiple processes of cell growth, division, and metabolic activities, according to recent investigations. Dysregulation of MCOLN channels activity is associated with cancer development. This review aims to discuss the current role of MCOLN channels in cancer as novel regulators of redox homeostasis, with the aim of exploiting the oncogenic potential of MCOLN channels to inspire therapeutic interventions.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167910"},"PeriodicalIF":4.2,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ertugliflozin attenuates atherosclerosis in nondiabetic ApoE−/− mice by upregulating ABCA1 and LDLR via the PPARγ/LXRα pathway","authors":"Jing Yang ,&nbsp;Baixue Zhang ,&nbsp;Faming Zhao ,&nbsp;Yue Wang ,&nbsp;Bo Li ,&nbsp;Yuanbao Dong","doi":"10.1016/j.bbadis.2025.167927","DOIUrl":"10.1016/j.bbadis.2025.167927","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;Ertugliflozin is a potent, selective, and orally active inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2), which is beneficial to cardiovascular health. We aimed to study the effect of Ertugliflozin on atherosclerosis (AS) in nondiabetic ApoE&lt;sup&gt;−/−&lt;/sup&gt; mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Eight-week-old apolipoprotein E knockout (ApoE&lt;sup&gt;−/−&lt;/sup&gt;) mice were randomly divided into two groups. Control group mice were fed high-fat diet (HFD), and the experimental group was fed HFD combined with Ertugliflozin (3.075 μg/g/d). Three months later, blood samples from all mice were collected to detect serum low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL&lt;img&gt;C). Aortic arch plaques were used for the assessment of plaque burden by hematoxylin-eosin staining (H&amp;E staining). The relative lipid and macrophage contents of atherosclerotic plaques in two groups were assessed using Oil Red O staining and immunohistochemistry with an anti-MOMA2 (monocyte/macrophage) antibody. In the cell experiment, RAW264.7 cells were divided into 3 groups: a control group, induced with oxidized LDL (ox-LDL) group (50 μg/ml), and induced with ox-LDL combined with Ertugliflozin group (100 μM). Lipid accumulation was evaluated by Oil Red O staining; several adipogenesis markers were analyzed by real-time quantitative PCR (RT-qPCR) and western blotting (WB). Later, a specific inhibitor of this pathway (GW9662, 10 μM) was used to block its effect. The genes and proteins identified to be involved in this pathway were verified using RT-qPCR and WB.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Ertugliflozin reduces lipid accumulation and arterial plaque formation in nondiabetic ApoE&lt;sup&gt;−/−&lt;/sup&gt; mice. H&amp;E staining and Oil Red O staining of the two groups of mouse tissues indicated that the degree of AS in experimental mice was reduced, and the lipid components within the plaques were diminished following Ertugliflozin intervention. Histological staining showed plaque size in mouse aortic arch and abdominal aorta sections. Additionally, immunohistochemistry revealed that the expression of MOMA2 in the experimental mice plaques was significantly lower compared to that in the HFD group, suggesting that the plaques in the experimental mice were more stable. In vitro, Ertugliflozin upregulated the expression of low density lipoprotein receptor (LDLR) and ATP-binding cassette transporterA1 (ABCA1), upregulated the activity of the peroxisome proliferators-activated receptor γ/liver X receptor α (PPARγ/LXRα) pathway and downregulated the expression of cluster of differentiation 36 (CD36). When the PPARγ inhibitor (GW9662, 10 μM) was used to block the pathway, the effects of Ertugliflozin were also weakened.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;In summary, our results indicated that Ertugliflozin not only may reduce the area of atherosclerotic plaques in ApoE&lt;sup&gt;−/−&lt;/sup&gt; mice but also upregulate ABC","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167927"},"PeriodicalIF":4.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise improves glucose and lipid metabolism in high fat diet feeding male mice through androgen/androgen receptor-mediated metabolism regulatory factors","authors":"Jing Hu ,&nbsp;Yanan Yang ,&nbsp;Shaoting Fu ,&nbsp;Xiaohan Yu ,&nbsp;Xiaohui Wang","doi":"10.1016/j.bbadis.2025.167926","DOIUrl":"10.1016/j.bbadis.2025.167926","url":null,"abstract":"<div><div>Exercise alleviates high fat diet (HFD)-induced glycolipid metabolism disorders, but the mechanisms are not discovered totally. Low androgen/androgen receptor (AR) levels are associated with glycolipid metabolism disorders in males, and androgen/AR modulate glycolipid metabolism-related regulators such as peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α), Forkhead box O1 (FoxO1), phosphoenolpyruvate carboxy kinase (PEPCK) and stearyl-coenzyme A desaturase 1 (SCD1). In the present study, we blockaded androgen (by castration) and inhibited or activated AR activity (by AR antagonist flutamide and agonist S4, respectively) to clarify androgen/AR's roles in exercise-induced alleviation of glycolipid metabolism disorders in male high fat diet (HFD) feeding mice and the underlying mechanisms. We found that: (1) exercise reversed HFD-induced glycolipid metabolism disorders, including restoring fasting blood glucose (FBG), glucose tolerance, TC and TG, accompanied with the increases of serum testosterone and AR in muscle and liver. (2) castration exacerbated HFD-induced impairment of glucose tolerance and increases of TC and TG, and abolished the lowering effect of exercise on FBG and TC. Flutamide further impaired glucose tolerance, increased plasm LDL content, and attenuated exercise-induced improvements of FBG and TG content. (3) exercise reduced the levels of FoxO1 and SCD1, increased PGC-1α in muscle and liver of HFD mice; whereas castration and flutamide reversed exercise-induced improvements of these indicators. Furthermore, S4 rectified the levels of FoxO1, PGC-1α and SCD1 in HFD mice even in absence of androgen. In conclusion, androgen/AR, especially AR, play important roles in alleviating glycolipid metabolism disorders in HFD mice at sedentary and exercise states, which might fulfill through FOXO1, PGC-1α and SCD1.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167926"},"PeriodicalIF":4.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}