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

{"title":"Pathological forms of TDP-43 in amyotrophic lateral sclerosis (ALS) promote aberrant telomere elongation","authors":"Anna Konopka ,&nbsp;Md Shafi Jamali ,&nbsp;Megan Fowler ,&nbsp;Prachi Mehta ,&nbsp;Sonam Parakh ,&nbsp;Zeinab Takalloo ,&nbsp;Fabiha Farzana ,&nbsp;Naima Mumtaz ,&nbsp;Julie Hunter ,&nbsp;Sina Shadfar ,&nbsp;Mary-Louise Rogers ,&nbsp;Julie D. Atkin","doi":"10.1016/j.bbadis.2025.167906","DOIUrl":"10.1016/j.bbadis.2025.167906","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. TAR DNA-binding protein 43 (TDP-43) mis-localisation from the nucleus to the cytoplasm is the major pathological characteristic of ALS. Telomeres are repetitive DNA sequences found in complex with proteins at chromosomal ends. The shelterin protein complex protects telomeres from DNA damage by producing characteristic t-loop structures, and telomere repeat binding factor 2 (TRF2) has an essential role in this process. Telomere dysregulation is reported in ALS, but conflicting findings have been obtained. Here we examined if telomere dysregulation is present in cortical neurons in a mouse model with pathological mis-localisation of TDP-43 to the cytoplasm - TDP-43 rNLS - compared to controls, and in cortical primary neurons expressing TDP-43 ALS associated mutations (A315T, A90V). We demonstrate that telomeres are significantly longer and of more variable in length in the TDP-43 rNLS model compared to controls. This was proceeded by downregulation of TRF2 in early disease stages with subsequent upregulation of TRF2 at advanced disease in TDP-43 rNLS mice. Longer telomeres were also present in primary cortical neurons expressing mutant TDP-43. A trend towards TRF2 upregulation was also present in human ALS spinal cord lysates. We detected dysregulation of catalytic subunit of telomerase, TERT, and a trend towards upregulation of telomere interacting protein, Rif 1 in these mice and human ALS spinal cord lysates. The longer telomeres were independent of the alternative lengthening of telomeres (ALT) mechanism of maintaining telomere length. Similarly, no DNA damage at telomere sites was detected. Our findings imply that telomere protection is compromised in ALS, leading to longer telomeres in neurons in ALS associated with TDP-43 pathology.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167906"},"PeriodicalIF":4.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086806","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":"METTL3 promotes human amniotic epithelial stem cells differentiation into insulin-producing cells by regulation of MaFA expression","authors":"Yunfei Luo ,&nbsp;jin-E Li ,&nbsp;Shan Xu ,&nbsp;Haixia Zeng ,&nbsp;Yuying Zhang ,&nbsp;Shiqi Yang ,&nbsp;Xiaoju He ,&nbsp;Jianping Liu","doi":"10.1016/j.bbadis.2025.167904","DOIUrl":"10.1016/j.bbadis.2025.167904","url":null,"abstract":"<div><h3>Objective</h3><div>Generating mature β-cells from stem cells remains a significant challenge in diabetes cell therapy. Human amniotic epithelial stem cells (hAESCs) have made their mark in regenerative medicine, and provide several advantages compared to other stem cells. Methyltransferase-like 3 (METTL3), an essential RNA methyltransferase participating in N6-methyladenosine (m6A) mRNA methylation, plays a critical role in the normal development of β-cells, yet its deletion in β-cells leads to β-cell dysfunction and hyperglycemia.</div></div><div><h3>Methods</h3><div>In this study, we isolated and characterized hAESCs from human amniotic membranes, differentiated these hAESCs into insulin-producing cells (IPCs), and explored the role of METTL3 in such differentiation. We examined the expression of METTL3 and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2, a decodes m6A methylation “reader”) in the generated IPCs. Subsequently, we suppressed METTL3 using an inhibitor (STM2457) and overexpressed METTL3 via plasmid transfection (METTL3-OE). The differentiated STM2457 and METTL3-OE IPCs were compared to normal induction (WT) IPCs regarding the expression of β-cell markers by RT-qPCR and western blotting, immunofluorescence, C-peptide release, and glucose-stimulated insulin secretion (GSIS). Methylated RNA immunoprecipitation (MeRIP)-qPCR was used to examine the molecular mechanism underlying METTL3/m6A signaling axis in MaFA (endocrine pancreatic β-cells marker) expression. We examined the potential therapeutic uses and efficacy of IPCs through streptozotocin (STZ)-induced C57BL/6 DM.</div></div><div><h3>Results</h3><div>Isolated hAESCs displayed all characteristics of ESCs and could generate IPCs. METTL3 and IGF2BP2 were elevated during differentiation. Overexpressing METTL3 improved the expression of β-cell markers in the final differentiated IPCs, improved C-peptide release, and demonstrated increased insulin secretion upon challenging with high glucose conditions, whereas inhibiting METTL3 attenuated these effects. Moreover, METTL3 modulated the MaFA expression in an m6A-dependent manner.</div></div><div><h3>Conclusions</h3><div>These findings suggest METTL3 as a promoting factor of IPCs generation, with its up-regulation potentially generating more mature IPCs for hAESCs therapy of diabetes mellitus.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167904"},"PeriodicalIF":4.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071013","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":"Novel LBR pathogenic variants with loss of sterol reductase activity participate in the pathogenesis of skeletal dysplasia via dysregulating canonical Wnt pathway","authors":"Yilin Chen ,&nbsp;Ying Bai ,&nbsp;Dan Deng ,&nbsp;Yiheng Liu ,&nbsp;Linyang He ,&nbsp;Mengru Wang ,&nbsp;Mengchen Zhou ,&nbsp;Xiangyi Wang ,&nbsp;Chenguang Yu ,&nbsp;Yue Wang ,&nbsp;Feifei Zhao ,&nbsp;Chengying Hai ,&nbsp;Bo Wang ,&nbsp;Junyi Liu ,&nbsp;Xiangdong Kong ,&nbsp;Xin Tu ,&nbsp;Hui Li","doi":"10.1016/j.bbadis.2025.167901","DOIUrl":"10.1016/j.bbadis.2025.167901","url":null,"abstract":"<div><div>Biallelic pathogenic variants in the lamin B receptor (LBR) with impaired sterol reductase function are associated with the development of perinatal lethal Greenberg dysplasia (GRBGD) and mild nonfatal skeletal dysplasia with or without Pelger-Huet anomaly (PHASK), as well as other related hereditary skeletal dysplasia. However, the underlying molecular mechanism remains unclear. In this study, we found two novel pathogenic variants of LBR, namely missense mutation (c.1011 T &gt; G, NM_002296.4; p.Cys337Trp, NP_002287.2) and LBR gene deletion (Chr1q42.12 (225,515,082-225,633,464), NC_000001.10). LBR is a novel substrate of FBW7, which is degraded by GSK3β/FBW7-mediated proteasome pathway and whose C337W mutation promotes its degradation through enhanced interaction with FBW7. Wild-type but not C337W mutant LBR is upregulated by WNT3A-mediated inactivation of GSK3β/FBW7 axis and then participated in WNT3A-activated Wnt pathway through its mediated cholesterol synthesis. MC3T3-E1 cells with Lbr knockdown or cholesterol removal exhibited reduced mineralized nodules in the presence of WNT3A, but addition of cholesterol in the culture medium reversed this phenotype. Collectively, we detected two novel variants in LBR and our study revealed for the first time that disruption of cholesterol synthesis by LBR impairs Wnt pathway and thus disrupts the cell osteogenic differentiation, providing new insights into the pathogenesis of skeletal dysplasia caused by LBR variation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167901"},"PeriodicalIF":4.2,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061731","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":"Characterization and targeting of chemoresistant triple-negative breast cancer subtypes using amino-pyridine compounds","authors":"Santiago Ruiz-Martínez ,&nbsp;Xavi Ribas ,&nbsp;Miquel Costas ,&nbsp;Göran Landberg ,&nbsp;Teresa Puig","doi":"10.1016/j.bbadis.2025.167899","DOIUrl":"10.1016/j.bbadis.2025.167899","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with limited treatment options and high relapse rates due to chemoresistance and the presence of cancer stem cells (CSCs). This study explores the molecular profile and invasive properties of two TNBC cell lines, MDA-MB-231 (Basal-Like 1; BL1 subtype) and HCC1806 (BL2 subtype), as well as their chemotherapy-resistant derivatives (doxorubicin and paclitaxel). Both cell lines exhibited CD44⁺ and CD24^−/low profiles with significant differences in epithelial-mesenchymal transition (EMT) markers. Chemoresistant variants exhibited significant changes in CSC markers, EMT genes, and ALDH activity, particularly the upregulation of CD133, suggesting its role in chemoresistance. Analysis of embryonic pathways revealed a prominent role of Sonic Hedgehog signaling, particularly in the BL2 subtype. Resistant models also exhibited increased Notch receptor expression.</div><div>This study also examined novel polyamine compounds with an amino-pyridine structure. These compounds showed significant cytotoxicity against both sensitive and resistant TNBC cells, enhancing the efficacy of standard chemotherapeutics (paclitaxel and doxorubicin). Additionally, they reduced stem-like properties and self-renewal capacity of CSCs.</div><div>This comprehensive characterization of TNBC cell lines and their chemoresistant variants underscores the molecular heterogeneity of TNBC and highlights potential therapeutic targets and strategies to enhance treatment efficacy and overcome resistance.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167899"},"PeriodicalIF":4.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051951","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":"Empagliflozin attenuates DOX-induced cardiotoxicity by inhibiting RIPK1-mediated endoplasmic reticulum stress and autophagy","authors":"Yinan Wang ,&nbsp;Zi Wang ,&nbsp;Xinning Guo ,&nbsp;Zhengyu Tao,&nbsp;Chen Wu,&nbsp;Meng Jiang,&nbsp;Jun Pu","doi":"10.1016/j.bbadis.2025.167898","DOIUrl":"10.1016/j.bbadis.2025.167898","url":null,"abstract":"<div><h3>Background</h3><div>Doxorubicin (DOX), a classical chemotherapeutic agent, remains indispensable in cancer treatment but is limited by dose-dependent cardiotoxicity. Investigating strategies to mitigate DOX-induced cardiac damage is critical. Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, exhibits anti-inflammatory and antioxidant effects in cardiovascular disease. This study investigated empagliflozin's protective effects against DOX-induced cardiotoxicity and underlying mechanisms.</div></div><div><h3>Methods</h3><div>DOX-induced cardiotoxicity models were established in male C57BL/6 J mice, with cardiac-specific RIPK1 overexpression achieved via adeno-associated virus (AAV9) technology. Cardiac function was assessed using echocardiography, and heart tissue was analyzed for injury, inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and autophagy through various biochemical and molecular assays.</div></div><div><h3>Results</h3><div>Empagliflozin alleviated DOX-induced cardiac dysfunction, reduced fibrosis, and suppressed systemic inflammation and oxidative stress in mice. Mechanistic studies revealed that empagliflozin mitigated DOX-induced cardiotoxicity by inhibiting ER stress and autophagy, as evidenced by the downregulation of BIP, p-IRE1, and ATF6 expression, alongside elevated p62 and reduced LC3BII/LC3BI levels. RIPK1 was identified as a crucial mediator of empagliflozin's cardioprotective effects, with similar protection observed using the RIPK1 inhibitor Nec-1. RIPK1 knockdown in cardiomyocytes mimicked empagliflozin's antioxidant effects, while its protective effects were abolished in RIPK1-deficient cells. Importantly, RIPK1 overexpression reduced empagliflozin's benefits in DOX-treated mice. In addition, empagliflozin enhanced DOX-induced cytotoxicity in 4 T1 breast cancer cells.</div></div><div><h3>Conclusion</h3><div>Empagliflozin protects against DOX-induced cardiotoxicity by attenuating inflammation, oxidative stress, ER stress and autophagy, primarily through RIPK1 inhibition, providing insights into its cardioprotective mechanisms. Additionally, empagliflozin enhances DOX-induced cytotoxicity in vitro, providing support for its combination with DOX in cancer therapy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167898"},"PeriodicalIF":4.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037492","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":"HNF-1α promotes urethral fibrosis by up-regulating STAT3 transcriptional activity in mice hypospadias","authors":"Shibo Zhu,&nbsp;Weitang Sun,&nbsp;Zijie Ye,&nbsp;Wei Jia","doi":"10.1016/j.bbadis.2025.167893","DOIUrl":"10.1016/j.bbadis.2025.167893","url":null,"abstract":"<div><div>One of the most prevalent male urogenital anomalies is hypospadias. The general etiology of hypospadias is still not completely clear, despite the fact that the number of patients with the hypospadias is rising. HNF-1α was predicted as the most activated upstream regulator of severe hypospadias in our previous research. Our study aims to investigate the mechanism by which HNF-1α regulates hypospadias. We found that HNF-1α was highly expressed in hypospadias tissues, and was positively associated with fibrinogen related genes FGA and FGB, respectively. In animal experiments, silencing of HNF-1α resulted in a more narrow urethral groove, and a decreased periurethral pathologic fibrosis. Meanwhile, the inflammation cytokines and oxidative stress related factors were significantly reduced after inhibition of HNF-1α expression. In addition, the protein levels of STAT3, FGA and FGB were also depressed after HNF-1α knockdown. Mechanistically, we showed that the HNF-1α transcriptionally activated STAT3, and subsequently increased the expressions of FGA and FGB. Additionally, suppression of HNF-1α improved the murine hypospadias via inactivating the STAT3. Therefore, our findings confirmed that HNF-1α promoted hypospadias and periurethral fibrosis by activating STAT3. Targeting HNF-1α might the future direction for hypospadias treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167893"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031618","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":"The potential biological function of STARD8 in prostate cancer: A bioinformatic and experimental validation study","authors":"Zichuang Xu ,&nbsp;Xiaojian Chen ,&nbsp;Yeying He ,&nbsp;Jiaying Tong ,&nbsp;Chaoyue Chen ,&nbsp;Meiqing Ding ,&nbsp;Wei Chen ,&nbsp;Huiliang Zhou ,&nbsp;Xiaohui Zheng ,&nbsp;Yunbei Xiao","doi":"10.1016/j.bbadis.2025.167897","DOIUrl":"10.1016/j.bbadis.2025.167897","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) is one of the most prevalent malignancies among men, with its incidence and mortality rates rising globally, posing a significant threat to men's health. STARD8, an emerging tumor suppressor gene, has been reported to inhibit cancer cell proliferation and migration in certain cancers. However, its role in PCa remains inadequately understood.</div></div><div><h3>Methods</h3><div>Bioinformatic analyses utilizing the TCGA, GTEx, and MSigDB databases were conducted to investigate the biological functions of STARD8. Differential expression of STARD8 was confirmed through immunohistochemistry, western blotting (WB), and quantitative PCR (Q-PCR) using clinical samples and cell lines. Functional assays, including STARD8 silencing and overexpression in PC3, DU145, C4-2B, LNCaP and WPMY-1 cells, were performed using immunofluorescence staining, WB, EdU assays, and comet assays.</div></div><div><h3>Results</h3><div>Transcriptomic data and clinical samples revealed that STARD8 expression is significantly reduced in PCa. In PCa cells, silencing STARD8 enhanced cell adhesion, migration, and invasion, whereas overexpression of STARD8 significantly suppressed these processes. Furthermore, STARD8 expression was found to be closely associated with immune evasion and drug sensitivity in PCa. Functional assays demonstrated that upregulation of STARD8 in PCa cells enhanced the chemotherapeutic efficacy of cisplatin. Mechanistically, STARD8 negatively regulated total FAK and p-FAK protein levels, thereby modulating PCa cell migration, proliferation, immune responses, and drug sensitivity.</div></div><div><h3>Conclusion</h3><div>This study identifies STARD8 as a critical tumor suppressor with significant roles in regulating cell proliferation, migration, immune evasion, and drug sensitivity in tumors.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167897"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922825","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":"Dehydrozingerone ameliorates renal structure compromised in diabetic nephropathy","authors":"Nivedita Singh ,&nbsp;Anuradha Kesharwani ,&nbsp;Harsha Sankar S H ,&nbsp;Rahul Laxman Gajbhiye ,&nbsp;Ramalingam Peraman ,&nbsp;Ruthrotha Selvi Bharathavikru ,&nbsp;Krishna Pandey ,&nbsp;Ravichandiran Velayutham ,&nbsp;Vipan K. Parihar","doi":"10.1016/j.bbadis.2025.167894","DOIUrl":"10.1016/j.bbadis.2025.167894","url":null,"abstract":"<div><div>Kidney structural integrity is critical for bodily excretory mechanism. Diabetes has been considered as one of the major risk factors for chronic kidney disease, but the underlying mechanism remains elusive. The present study investigates the transcriptomic and proteomic profiling of long-term impact of high-fat diet (HFD) on renal tissue in mice and role of dehydrozingerone (DH) in reinstating the normal kidney function. Animals were divided into four groups- healthy (NCD+Veh), diabetic (HFD-STZ+Veh), healthy+DH (NCD+DH) and treatment (HFD-STZ+DH). 65^th days of HFD-fed C57BL/6J mice developed diabetes and kidney dysfunction evident by albuminuria, proteinuria, and glucotoxicity with accumulation of glucose, triglyceride, cholesterol, albumin, and total protein in blood serum. The HFD-fed kidney showed renal injuries, including prominent defects in the glomerular filtration system by downregulation of proteins involved in transport, metabolic process, energy production, anti-oxidation, etc. Downregulation of lipid metabolism is the most impacted metabolic process under diabetic condition. Downregulation of transport proteins mainly impact the functioning of podocytes, cell adhesion and cytoskeletal rearrangement. HFD feeding also increased oxidative stress and induced mitochondrial dysfunction, and thereby activating the pro-apoptotic pathway which is evident by activation of BAX led mitochondrial apoptosis and mitochondrial dysfunction under diseased condition. Progression of DNA damage under diabetic condition triggered the epigenetic alteration and subsequent downstream changes which is evident by activation of HDAC1 under diseased condition. Both transcriptomic and proteomic studies revealed the potential of DH in attenuating the diabetic condition by positively regulating transport system, mitochondrial function, lipid metabolism, DNA damage and epigenetic alteration, and oxidative stress, which ameliorate the kidney function.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167894"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943415","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":"Multi-OMICs analysis on tridimensional fibroblast spheroids to model vascular Ehlers-Danlos syndrome pathogenesis","authors":"Lucia Micale ,&nbsp;Ester Di Muro ,&nbsp;Rossella De Cegli ,&nbsp;Barbara Tumaini ,&nbsp;Antonella Capuozzo ,&nbsp;Paolo Bernardi ,&nbsp;Silvia Morlino ,&nbsp;Carmela Fusco ,&nbsp;Grazia Nardella ,&nbsp;Elisabetta Mormone ,&nbsp;Lorenzo Vaccaro ,&nbsp;Eugenio Del Prete ,&nbsp;Daniela Giachino ,&nbsp;Michele Giuliani ,&nbsp;Chiara Leoni ,&nbsp;Francesca Mercadante ,&nbsp;Alice Moroni ,&nbsp;Carmelo Piscopo ,&nbsp;Marcella Zollino ,&nbsp;Davide Cacchiarelli ,&nbsp;Marco Castori","doi":"10.1016/j.bbadis.2025.167896","DOIUrl":"10.1016/j.bbadis.2025.167896","url":null,"abstract":"<div><div>Three-dimensional (3D) spheroids are an innovative cellular model mimicking tissue-like properties for a more effective replication of physiological cellular environment. Vascular Ehlers-Danlos syndrome (vEDS) is a rare hereditary connective tissue disorder caused by heterozygous deleterious variants in <em>COL3A1</em>. Affected individuals are at increased risk of early death due to ruptures of arteries, large intestine, and gravid uterus. vEDS cellular pathogenesis is only partially understood and the disease remains without effective treatment. We integrated transcriptomic and proteomic data generated from 2D fibroblast cultures and 3D spheroids from ten patients and four controls. Transcriptomic analysis revealed upregulation of genes related to mitochondrial function, organellar ribosomal subunits, and biosynthesis processes, to indicate an augmented adaptive metabolic response, while downregulation of genes involved in cell migration, differentiation, and stress response highlighted abnormalities in cellular signaling and extracellular matrix maintenance. Proteomic analysis found that induced proteins were significantly enriched for the mitochondrial matrix and minichromosome maintenance complex as well as in biological processes involving low-density lipoprotein particles, and cellular response to catabolic processes and DNA damage stimuli. Ultrastructural analysis and high-content imaging documented an endoplasmic reticulum dilation, increased autophagosomes and lipofuscin deposits. Our findings expand current knowledge on the multi-OMIC profile of vEDS by highlighting potential convergent mechanisms and novel features acting as master regulators of the emerging phenotype. This study supports, for the first time, 3D fibroblast spheroids as a suitable experimental tool to dissect vEDS pathogenesis and a crucial model for identifying new therapeutic targets.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167896"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943416","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":"Tubular specific glutathione peroxidase 3 deletion exacerbates kidney damage in IRI-AKI mice","authors":"Jinrong He ,&nbsp;Xueqin Wu ,&nbsp;Jie Qiao ,&nbsp;Xian Xie ,&nbsp;Yu Wang ,&nbsp;Hao Zhang ,&nbsp;Wei Zhang","doi":"10.1016/j.bbadis.2025.167895","DOIUrl":"10.1016/j.bbadis.2025.167895","url":null,"abstract":"<div><div>Ischemia-reperfusion injury stands as a primary instigator of acute kidney injury (AKI), prominently driven by oxidative stress. Among the critical antioxidant defenses is glutathione peroxidase 3 (GPX3), an enzyme generated by renal tubular epithelial cells. Our prior investigations have unveiled a substantial downregulation of GPX3 in renal tissues gleaned from AKI patients and murine models. This study aims to investigate the role of tubular cell-specific <em>Gpx3</em> deletion on ischemia-reperfusion injury-induced AKI (IRI-AKI) in a murine model and delineate the potential underlying mechanisms.</div><div>By generating renal tubular epithelial cell-specific <em>Gpx3</em> knockout mice and inducing IRI-AKI, we assessed a spectrum of kidney injury indices including renal function, oxidative stress, apoptosis and mitochondrial dynamics. Additionally, we conducted transcriptome sequencing and bioinformatics analyses. The outcomes underscore that the deficiency of GPX3 in tubular cells exacerbates tubular injury, renal dysfunction, oxidative stress, apoptosis, and mitochondrial dynamic disturbances in the context of IRI-AKI. Sequencing and bioinformatics analysis suggest that the <em>Gpx3</em> deletion predominantly impacts pathways associated with metabolism and inflammation.</div><div>In conclusion, the tubular cell-specific deficiency of GPX3 exacerbates renal injury by intensifying oxidative stress, fostering mitochondrial impairment, perturbing metabolic processes and fueling inflammation. The targeted restoration of GPX3 in the renal tubular emerges as a potential therapeutic avenue for mitigating IRI-AKI.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167895"},"PeriodicalIF":4.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922824","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}