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

{"title":"Nitroxoline upregulates low-density lipoprotein receptors expression, enhances lipid metabolism, and reduces hepatic steatosis and atherosclerosis in Apoe−/− mice","authors":"Rou-Ling Cho ,&nbsp;Yu-Lueng Shih ,&nbsp;Chih-Feng Lien ,&nbsp;Yi-Jhen Huang ,&nbsp;Pei-Yu Lien ,&nbsp;Chin-Sheng Lin ,&nbsp;Feng-Yen Lin ,&nbsp;Chien-Sung Tsai ,&nbsp;Sy-Jou Chen","doi":"10.1016/j.bbadis.2025.168016","DOIUrl":"10.1016/j.bbadis.2025.168016","url":null,"abstract":"<div><div>Low-density lipoprotein receptors (LDLRs) play a critical role in maintaining cholesterol homeostasis. Dysregulation of lipid metabolism contributes to atherosclerosis and steatohepatitis. This study investigated the effects of nitroxoline on LDLR expression and its protective role in lipid dysregulation, hepatic steatosis, and atherosclerosis. Through comprehensive screening of FDA-approved clinical drugs, nitroxoline was identified as a promising candidate for modulating LDLR. Functional validation in Huh7 cells using quantitative reverse transcription polymerase chain reaction, western blotting, flow cytometry, and RNA-seq analysis showed that nitroxoline significantly upregulated <em>LDLR</em> mRNA and protein expression, enhancing LDL uptake and binding capacity. Mechanistically, nitroxoline promoted <em>SREBF2</em> expression via <em>PPP2CA</em> suppression and stabilized <em>LDLR</em> mRNA through AMPK- and JNK-dependent repression of the RNA-binding proteins, notably <em>HNRNPD</em>. Transcriptomic profiling revealed increased expression of genes related to cholesterol homeostasis and decreased expression of genes involved in triglyceride biosynthesis, including <em>GPAT</em>, <em>AGPAT</em>, and <em>PNPLA3</em>. In <em>Apoe</em>^{<em>−/−</em>} mice, nitroxoline reduced serum levels of total cholesterol, triglycerides, and LDL-C without affecting HDL<img>C. Histological analyses demonstrated significant reductions in hepatic steatosis, fibrosis, and stellate cell activation, along with a modest attenuation of atherosclerotic plaque formation in the aortic root. These molecular and phenotypic effects were consistent with improved lipid clearance and hepatocellular protection. These findings suggest that nitroxoline exerts dual actions by upregulating LDLR expression and improving hepatic lipid metabolism. Given its established clinical safety and oral bioavailability, nitroxoline may offer repurposing potential as a therapeutic agent for treating lipid-related metabolic disorders and preventing atherosclerotic cardiovascular disease.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168016"},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879851","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":"Post-translational modifications of huntingtin's N17 region: implications for self-association and membrane binding","authors":"Mariana Gallo ,&nbsp;Raffaele Ingenito ,&nbsp;Marco Finotto ,&nbsp;Sara Di Marino ,&nbsp;Daniel Cicero ,&nbsp;Elisabetta Bianchi ,&nbsp;Tobias Neudegger ,&nbsp;Michael Blaesse ,&nbsp;Stefan Steinbacher ,&nbsp;Becka M. Warfield ,&nbsp;Elizabeth H. Frush ,&nbsp;Leticia Toledo-Sherman ,&nbsp;Celia Dominguez ,&nbsp;Edith Monteagudo ,&nbsp;Matthew R. Lee ,&nbsp;Elizabeth M. Doherty","doi":"10.1016/j.bbadis.2025.168019","DOIUrl":"10.1016/j.bbadis.2025.168019","url":null,"abstract":"<div><div>Huntington's disease is a neurodegenerative disorder associated with a polyglutamine expansion within the first exon of the huntingtin protein (HTT exon 1). This mutation results in HTT dysfunction and the production of N-terminal HTT aggregates. The dimerization of the HTT exon 1 fragment through self-association of the first 17 residues (N17) is considered the initial step in the HTT exon 1 aggregation pathway. The association of N17 with membranes has been proposed to catalyze aggregation by increasing the local concentration of exon 1, and post-translational modifications (PTMs) in N17 are known to influence membrane interaction and the aggregation rate of exon 1. To elucidate the influence of N17 PTMs on both self-association and membrane interaction, thereby gaining insight into HTT function and exon 1 aggregation, we used solution nuclear magnetic resonance and circular dichroism spectroscopies to address loss of initial methionine, subsequent acetylation, and phosphorylation of threonine and serines. Our findings indicate that modifications to N17 that enhance helicity correspond to increased self-association and membrane interaction. We then conducted X-ray crystallographic studies that led to a proposed HTT exon 1 dimerization model consistent with the association of N17 dimers. This provides insight into the impact of PTMs on HTT aggregation. The experimental methods and N17 self-association model we describe may serve as a foundation for further experiments exploring the influence of N17 PTMs on HTT function and pathogenicity.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168019"},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903289","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":"Hepcidin/HIF-1α is involved in the endogenous recovery and ferroptosis after cerebral ischemia in mice","authors":"Jingru Zhao ,&nbsp;Lipeng Dong ,&nbsp;Xin Gong ,&nbsp;Shuo Hui ,&nbsp;Xinyao Wang ,&nbsp;Siyu Tian ,&nbsp;Yuanyuan Liu ,&nbsp;Tiantian Huo ,&nbsp;Yanzhao Xie ,&nbsp;Yanzhong Chang","doi":"10.1016/j.bbadis.2025.168022","DOIUrl":"10.1016/j.bbadis.2025.168022","url":null,"abstract":"<div><div>It is common to witness a spontaneous endogenous recovery process with the potential mechanisms involving the remyelination, nerve regeneration, and synaptic plasticity, which might be vital for the neurological rehabilitation after cerebral ischemic stroke. Iron homeostasis is considered to be crucial for myelination and neuronal metabolic processes, and Hepcidin is an important factor in regulating iron homeostasis and ferroptosis. Hypoxia-inducible factor (HIF) is an important hypoxia tolerance factor and can regulate cell survival in hypoxia environment, which is critical to regulate iron homeostasis as well. Nevertheless, the effect of Hepcidin on endogenous injury repair during cerebral ischemia recovery period and whether Hepcidin could regulate ferroptosis via HIF-1α remain unclear. Here, we established the distal middle cerebral artery occlusion (dMCAO) mice model to investigate the effect of Hepcidin on endogenous injury repair and ferroptosis during cerebral ischemia recovery and HIF-1α-associated mechanisms. Our results indicated that Hepcidin/HIF-1α pathway played a crucial role in regulating ferroptosis as well as endogenous injury repair and subsequent neurological recovery after cerebral ischemia, serving as a possible target for the treatment of recovery after stroke.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168022"},"PeriodicalIF":4.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144852084","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":"2-Chloroethanol induces hepatic toxicity by disrupting endoplasmic reticulum homeostasis ameliorated by dimethyl sulfoxide","authors":"Tzung-Hsin Chou ,&nbsp;Min-Hsiu Hu ,&nbsp;Kuo-Tai Hua ,&nbsp;Cheng-Chung Fang","doi":"10.1016/j.bbadis.2025.168017","DOIUrl":"10.1016/j.bbadis.2025.168017","url":null,"abstract":"<div><div>2-Chloroethanol (2CE), a metabolite of ethylene oxide, vinyl chloride, and 1,2-dichloroethene, induces acute liver injury, but its mechanisms remain poorly defined. In this study, we demonstrate that 2CE disrupts endoplasmic reticulum (ER) homeostasis and activates unfolded protein response (UPR) signaling in both mouse liver and H4IIEC3 hepatoma cells. While in vivo eIF2α–CHOP signaling predominated, all three canonical UPR branches—IRE1α–XBP1s, PERK–eIF2α–CHOP, and ATF6—were activated in vitro. Notably, 2CE-induced XBP1s expression was transient, whereas pro-apoptotic UPR signaling persisted, suggesting an imbalance. Among several ER stress modulators tested, only dimethyl sulfoxide (DMSO) significantly improved cell viability and increased the 24-h LD₅₀ of 2CE in mice. Mechanistically, DMSO sustained XBP1s expression while reducing eIF2α phosphorylation, CHOP expression, and cleaved ATF6, indicating a rebalancing of UPR signaling toward a pro-survival state. Pharmacologic inhibition of IRE1α with 4μ8C abolished the protective effect of DMSO, suppressed XBP1s, and elevated cleaved caspase-3, confirming the critical role of the IRE1α–XBP1s axis in cytoprotection. These findings highlight UPR signaling dynamics as a central feature of 2CE-induced ER stress and identify IRE1α–XBP1s as a promising therapeutic target.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168017"},"PeriodicalIF":4.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841590","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":"Augmented recruitment of host Grb2 by Helicobacter pylori tyrosine phosphorylated CagA EPIYA-D motif promotes cellular oncogenic transformation","authors":"Huilin Zhao ,&nbsp;Shuzhen Liu ,&nbsp;Jiangfan Shan ,&nbsp;Juan Zhang ,&nbsp;Qianwen Wu ,&nbsp;Jianhui Zhang ,&nbsp;Zekun Sun ,&nbsp;Xinying Cao ,&nbsp;Shu Chen ,&nbsp;Mingzhu Feng ,&nbsp;Yinuo Zhang ,&nbsp;Xiang Cheng ,&nbsp;Boqing Li ,&nbsp;Xiaofei Ji","doi":"10.1016/j.bbadis.2025.168018","DOIUrl":"10.1016/j.bbadis.2025.168018","url":null,"abstract":"<div><div>CagA, one of the key virulence factors of <em>Helicobacter pylori</em>, plays a significant role in <em>H. pylori</em>-associated gastric cancer by actively participating in neoplastic transformation. Among CagA variants, East Asian type CagA (CagA^E) bearing the EPIYA-D motif exhibits a higher risk than the Western-type (CagA^W) with EPIYA-C motifs. In this study, we investigated the interactions of CagA^E and CagA^W and host intracellular Grb2 and found a pronouncedly greater recruitment of Grb2 by CagA^E compared to CagA^W. Our findings revealed the phosphorylated tyrosine in the EPIYA motif is very important for the binding of CagA to Grb2. Phe at Y + 5 position in EPIYA-D, which interacts with Trp¹²¹ in SH2 domain of Grb2, established the higher affinity than the interaction of EPIYA-C and Grb2-SH2. The substitute of Phe to Asp/Ala in CagA^E EPIYA-D reduced the recruitment of Grb2 by CagA^E, and neutralized the stronger induced malignant characteristics of the recipient cells. These findings provide additional insights into the distinct regulatory mechanisms employed by CagA^E and CagA^W, contributing to a better understanding of the higher oncogenic risk associated with <em>H. pylori</em> CagA^E.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168018"},"PeriodicalIF":4.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841554","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":"An Ile to Met polymorphism in ADCY9 promotes airway obstruction and remodeling in asthma","authors":"Li-Mei Liang ,&nbsp;Peng-Cheng Cai ,&nbsp;Fan Yu ,&nbsp;Xin-Liang He ,&nbsp;Lin-Jie Song ,&nbsp;Yu-Zhi Lu ,&nbsp;Qian Niu ,&nbsp;Ya-Ya Zhou ,&nbsp;Li-Juan Jiang ,&nbsp;Ye-Han Jiang ,&nbsp;Zi-Heng Jia ,&nbsp;Li-Qin Zhao ,&nbsp;Meng Wang ,&nbsp;Pei-Pei Cheng ,&nbsp;Shuai-Jun Chen ,&nbsp;Xiao Feng ,&nbsp;Qian Li ,&nbsp;Xiao-Lin Cui ,&nbsp;Liang Xiong ,&nbsp;Fei Xiang ,&nbsp;Wan-Li Ma","doi":"10.1016/j.bbadis.2025.168015","DOIUrl":"10.1016/j.bbadis.2025.168015","url":null,"abstract":"<div><div>Airway remodeling is a key point in asthma. Airway smooth muscle cells (ASMCs) play a pivotal role in airway remodeling. Cyclic AMP (cAMP) provides energy which is necessary for airway relaxation. Lack of energy in ASMCs results in dysregulation of airway relaxation as well as airway remodeling. The type 9 adenylyl cyclase (ADCY9) is a widely distributed adenylyl cyclase and contributes to basal cAMP production. However, the role of ADCY9 in asthma was still poorly understood. In this study, firstly ADCY9 rs2230739 gene polymorphism in asthma patients was investigated. There was a single nonsynonymous sequence variant at nucleotide 2316 where it was noted an A (wild-type) or G which was corresponding an Ile changed to Met at position 772 (Ile772Met). Next, we found this Ile to Met polymorphism in ADCY9 decreased reversibility of FEV1/FVC%. Moreover, changes of the Ile to Met in ADCY9 predicted further decline of FEV1/FVC% and FEV1% by Cox proportional hazard regression model. Then mechanisms of ADCY9 in asthma were explored. Asthma-related cytokines decreased ADCY9 expression and cellular cAMP levels which reduced airway relaxation ability and promoted airway remodeling. On the contrary, over-expression of ADCY9 protein attenuated airway remodeling. However, ADCY9 over-expression with missense mutant protein (ADCY9-772Met) failed to prevent airway smooth muscle remodeling. Taken together, An Ile to Met polymorphism in ADCY9 promoted airway obstruction and remodeling in asthma.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168015"},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841597","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":"Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells","authors":"Luisa Amato ,&nbsp;Caterina De Rosa ,&nbsp;Daniela Omodei ,&nbsp;Camilla C. Tufano ,&nbsp;Rossella Buono ,&nbsp;Concetta Tuccillo ,&nbsp;Giovanni N. Roviello ,&nbsp;Michele Spinelli ,&nbsp;Carolina Fontanarosa ,&nbsp;Federica Papaccio ,&nbsp;Rosa Camerlingo ,&nbsp;Floriana Morgillo ,&nbsp;Andrea Carpentieri ,&nbsp;Angela Amoresano ,&nbsp;Virginia Tirino ,&nbsp;Francesca Iommelli ,&nbsp;Carminia Maria Della Corte ,&nbsp;Silvana Del Vecchio ,&nbsp;Viviana De Rosa","doi":"10.1016/j.bbadis.2025.168014","DOIUrl":"10.1016/j.bbadis.2025.168014","url":null,"abstract":"<div><div>The metabolic reprogramming of tumor cells plays a critical role in cancer progression, contributing to drug resistance and tumor survival. Tyrosine kinase inhibitors (TKIs) have shown promising clinical results by targeting specific signaling pathways in cancer cell proliferation, survival, and metastasis and are now standard of care for NSCLC with actionable mutations. However, secondary resistance to TKIs remains a significant challenge. Here, we explored the rationale behind combining TKIs with an inhibitor of glucose metabolism (dichloroacetate, DCA), focusing on the synergistic effects from dual inhibition of oncogenic and metabolic reprogramming. We selected three NSCLC cell line models (H1975, H1993, A549) with EGFR/MET/KRAS mutations and determined the optimal DCA dose (500 μM) to reverse the Warburg effect. TKIs in combination with DCA (CI &lt; 1, indicating synergy) altered cell metabolism, by improving oxidative phosphorylation via reduced glucose consumption (~50 %, <em>p</em> &lt; 0.05) and increased ATP (~50 %, <em>p</em> &lt; 0.0001), particularly mitoATP, confirmed by metabolite levels. The combination also reduced cell proliferation (S phase <em>p</em> &lt; 0.001), increased cell death (~40 %, p &lt; 0.0001 less MMP, ~1.6 fold more BIM, 2.5-fold more autophagy) and blocked invasion (~3 fold fewer protrusions). Our findings show DCA potentiates TKIs at lower doses, likely via Warburg effect reversal. These changes in tumor behaviour leads to a higher pro-apoptotic status responsible for an increased tumor response and, in parallel, the lower doses reduced alternative evasion pathways contributing to decrease of tumor invasion and resistance mechanism. This study shed light on a new potential combined therapeutic approach to improve clinical outcomes in targeted cancer therapy scenarios.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168014"},"PeriodicalIF":4.2,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810109","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":"Glioma cells produce soluble PD-L1 via the Wnt/β-catenin signaling pathway to suppress CD8+ T cell activity","authors":"Zihan Zhou ,&nbsp;Yao Wang ,&nbsp;Ying Wang ,&nbsp;Chunhui Yuan ,&nbsp;Junjian Lin ,&nbsp;Xinbin Bai ,&nbsp;Yunhao Chen ,&nbsp;Man Hu ,&nbsp;Xingchen Ding","doi":"10.1016/j.bbadis.2025.168013","DOIUrl":"10.1016/j.bbadis.2025.168013","url":null,"abstract":"<div><div>Soluble programmed death ligand 1 (sPD-L1) is emerging as a novel prognostic marker, potentially replacing PD-L1 for assessing prognosis and immunotherapy effectiveness. However, little is known about sPD-L1. This study aimed to assess sPD-L1's potential as a biomarker and explore its origin and biological function. The study found sPD-L1 concentration in plasma is linked to worse overall survival (OS) in glioma. Patients with high Ki-67 expression, IDH-wild type or high-grade have higher level of sPD-L1. Notably, sPD-L1 concentration is positive correlations with tumor volume in patients and mice. Mice plasma with varying sPD-L1 concentration was co-cultured with CD8⁺ T cells to investigate sPD-L1 activity and function. We conclude that glioma cells produce sPD-L1 through the Wnt/β-catenin signaling pathway, which interacts with the PD-1 receptor on CD8⁺ T cells, inhibiting their function by reducing IFN-γ levels. Wnt inhibitors combined with PD-L1 inhibitors can enhance the anti-tumor effect by further reducing sPD-L1 levels.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168013"},"PeriodicalIF":4.2,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810440","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":"Defective collagen VI-NG2 axis impairs pericyte balance between proliferation and quiescence in COLVI-related myopathies","authors":"Antonietta Fazio ,&nbsp;Patrizia Sabatelli ,&nbsp;Cesare Faldini ,&nbsp;Alberto Di Martino ,&nbsp;Maria Vittoria Marvi ,&nbsp;Irene Neri ,&nbsp;Foteini Dionysia Koufi ,&nbsp;Luciano Merlini ,&nbsp;Lucia Manzoli ,&nbsp;Stefano Ratti ,&nbsp;Camilla Evangelisti","doi":"10.1016/j.bbadis.2025.168012","DOIUrl":"10.1016/j.bbadis.2025.168012","url":null,"abstract":"<div><div>Collagen VI-related myopathies (COLVI-RMs) are rare genetic disorders caused by impaired assembly and secretion of COLVI, a key extracellular matrix (ECM) protein. COLVI deficiency alters ECM architecture and biomechanics, leading to progressive muscle fiber damage and connective tissue abnormalities. While pericytes are emerging as key players in muscle regeneration due to their myogenic potential, their role in COLVI-RMs remains unclear.</div><div>This study investigates pericyte involvement in COLVI-RMs, focusing on the interaction between COLVI and neural/glial antigen 2 (NG2), a proteoglycan expressed on pericyte membranes.</div><div>Muscle biopsies from COLVI-RMs patients revealed abnormal pericyte distribution, reduced vessel coverage, and thickened capillary basement membranes. <em>In vitro</em>, healthy pericytes formed a dense COLVI network, while COLVI-RM-derived pericytes displayed a disrupted matrix and impaired cell-ECM interaction.</div><div>Proximity ligation assays demonstrated a significant reduction in COLVI-NG2 binding in COLVI-RM pericytes, correlating with altered balance between proliferative and quiescent states. In turn, defects in signaling pathways related to proliferation (Akt/mTOR and Wnt/β-catenin pathways) and quiescence (N-cadherin, Notch3, FOXO3A) were identified, revealing a marked quiescent state. <em>In vitro</em> inhibition of the COLVI-NG2 binding in healthy pericytes reproduced these pathological features, underscoring the functional relevance of this molecular axis.</div><div>Taken together, the data here reported revealed an unexpected role of NG2-COLVI binding on pericytes status. It follows that the impairment of functional binding between NG2 and COLVI could have important consequences on the pericytes myogenic potential in COLVI-RMs, and consequently on the muscle regeneration. Finally, targeting defective pericytes could provide potential therapeutic strategies for these debilitating diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168012"},"PeriodicalIF":4.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801219","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":"Ectopic laminin α2 accumulation in the glomerular basement membrane exacerbates podocyte injury in Alport syndrome","authors":"Kozue Uchio-Yamada ,&nbsp;Keiko Yasuda ,&nbsp;Osamu Suzuki ,&nbsp;Kentaro Oh-Hashi ,&nbsp;Takeshi Ohta ,&nbsp;Noboru Manabe","doi":"10.1016/j.bbadis.2025.168008","DOIUrl":"10.1016/j.bbadis.2025.168008","url":null,"abstract":"<div><div>Alport syndrome is a hereditary disease caused by mutations in <em>Col4a3</em>, <em>Col4a4</em>, and <em>Col4a5</em>, which encode the type IV collagen α3, α4, and α5 chains, respectively. Alport glomerular basement membrane (GBM), which predominantly consists of collagen α1α2α1 (IV) heterotrimers, provides less biomechanical strength than normal GBM with collagen α3α4α5 (IV) heterotrimers. In addition to type IV collagen abnormalities, laminin dysregulation is observed in Alport GBM. In this study, we aimed to investigate the mechanisms underlying laminin dysregulation in Alport GBM and their roles in disease progression using primary podocytes and <em>Col4a4</em>-deficient mice on DBA/2 background. Histological analysis of <em>Col4a4</em>-deficient mice revealed that ectopic laminin α2 deposition in GBM during postnatal nephrogenesis, followed by re-expression of laminin α1 and decreased expression of nephrin. The analysis of primary podocytes indicated that podocytes on low substrate stiffness overexpressed laminin α2. Moreover, podocytes cultured on laminin-α2β1γ1 exhibited higher laminin α1 levels and lower nephrin levels than those cultured on laminin-α5β2γ1. Cell adhesion assays showed that ectopic laminin α2 deposition in GBM may cause defective podocyte–GBM adhesion, leading to podocyte depletion. Overall, these findings suggest that insufficient GBM strength increases the mechanical stress on podocytes via daily transcapillary filtration pressures, resulting in ectopic laminin α2 deposition in GBM, which contributes to defective podocyte–GBM adhesion, GBM abnormalities, and podocyte injury in Alport syndrome.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168008"},"PeriodicalIF":4.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777192","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}