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

{"title":"Exercise-induced irisin attenuates ferroptosis in polycystic ovary syndrome by modulating the NCOA4-FTH pathway","authors":"Yaling Zhang ,&nbsp;Yi Zhang ,&nbsp;Daojuan Wang ,&nbsp;Yajing Weng ,&nbsp;Shanmei Shen ,&nbsp;Yanting Wen ,&nbsp;Jianguo Ruan ,&nbsp;Yong Wang","doi":"10.1016/j.bbadis.2025.168108","DOIUrl":"10.1016/j.bbadis.2025.168108","url":null,"abstract":"<div><h3>Objective</h3><div>Hyperandrogenism is a central pathological feature of polycystic ovary syndrome (PCOS) that disrupts granulosa cell function. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, may contribute to ovarian injury. This study aimed to clarify the pathways of hyperandrogenic-induced granulosa cells ferroptosis, elucidating the molecular mechanism of exercise and its secretory factor, irisin, through the NCOA4-FTH pathway.</div></div><div><h3>Methods</h3><div>DHEA-induced PCOS model and in vitro granulosa cells were constructed to systematically evaluate the effects of exercise and irisin on ovarian function and ferroptosis. In vivo experiments included treadmill training in PCOS mice, assessment of estrous cycles, glucose/insulin tolerance, ovarian morphology, oxidative stress, ferroptosis, and NCOA4-FTH pathway proteins. In vitro, granulosa cells were treated with DHT and co-exposed to irisin or the ferroptosis inhibitor Ferrostatin-1 (Fer-1), with siRNA-mediated <em>NCOA4</em> knockdown for functional verification.</div></div><div><h3>Results</h3><div>DHEA-induced PCOS mice exhibited disrupted estrous cycles, abnormal follicular morphology, glucose intolerance, insulin resistance, and ferroptosis activation, characterized by oxidative stress, Fe²⁺ overload, and dysregulated ferroptosis-related proteins. Fer-1 reversed DHT-induced <em>GPX4</em> downregulation, suggesting ferroptosis involvement. Eight-week aerobic exercise improved metabolic parameters and ovarian morphology, suppressed ferroptosis by modulating <em>NCOA4</em> and <em>GPX4</em> expression, and alleviated oxidative stress. Mechanistically, exercise-induced irisin inhibited ferritinophagy and restored iron metabolism via the NCOA4-FTH pathway. <em>NCOA4</em> knockdown further validated its central role in regulating ferritinophagy.</div></div><div><h3>Conclusion</h3><div>Hyperandrogenism triggers granulosa cells ferroptosis in PCOS, while exercise and irisin protect ovarian function by regulating the NCOA4–FTH pathway, suggesting a potential therapeutic target for PCOS.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168108"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524847","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":"Vitamin D attenuates PCSK9-driven phenotypic switch of vascular smooth muscle cells and neointimal hyperplasia via SIRT6 activation","authors":"Sushmitha Duddu ,&nbsp;Yash T. Katakia ,&nbsp;Nivedha Suresh ,&nbsp;Rituparna Chakrabarti ,&nbsp;Syamantak Majumder ,&nbsp;Praphulla Chandra Shukla","doi":"10.1016/j.bbadis.2025.168135","DOIUrl":"10.1016/j.bbadis.2025.168135","url":null,"abstract":"<div><div>Pathologically activated vascular smooth muscle cells (VSMCs) upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), contributing to vascular inflammation and remodeling. Although both PCSK9 and 25-hydroxyvitamin D (25OHD), the active form of Vitamin D, are linked to inflammatory regulation, their interaction in modulating VSMC phenotype remains unclear. Here, we investigated the effect of 25OHD on PCSK9 expression in human aortic SMCs (HASMCs) under lipopolysaccharide (LPS)-induced inflammatory stress. LPS stimulation increased PCSK9 mRNA &gt;2-fold, while 25OHD pre-treatment significantly reduced this induction and restored expression of contractile markers (<em>Acta2, Cnn1, Myocd, Tagln</em>). Functional assays revealed that both 25OHD and PCSK9 knockdown attenuated LPS-induced proliferation and migration in HASMCs. In vivo, 25OHD supplementation in C57BL/6 mice for six weeks prior to partial carotid artery ligation suppressed injury-induced PCSK9 expression in SMCs and reduced neointimal hyperplasia. Supporting these findings, reanalysis of RNA-seq data revealed that airway SMCs (ASMCs) derived from asthma patients and treated with Vitamin D exhibited lower PCSK9 expression and concomitantly elevated sirtuin expression relative to untreated asthmatic controls. Mechanistically, 25OHD enhanced SIRT6 activation, and inhibition of SIRT6 with nicotinamide reversed 25OHD-mediated PCSK9 downregulation, identifying SIRT6 as a key regulator. Together, these findings reveal a novel SIRT6-dependent mechanism by which Vitamin D suppresses PCSK9-driven VSMC phenotypic switching, exerting protective effects against vascular inflammation and remodeling.</div><div>News and Noteworthy: This study highlights the crucial role of PCSK9 in the inflammation and phenotypic modulation of VSMCs. The active Vitamin D metabolite, 25OHD, suppresses inflammation-induced PCSK9 expression and restores contractile gene markers in HASMCs. In vivo, Vitamin D supplementation reduces PCSK9 levels and neointimal hyperplasia following flow-mediated vascular injury. Mechanistically, 25OHD activates SIRT6, establishing a novel 25OHD–SIRT6–PCSK9 regulatory axis with promising therapeutic implications for vascular inflammation and remodeling.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168135"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758700","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":"Neutrophil-derived thrombospondin-1 (THBS1) drives type 2 diabetes-induced osteoporosis via CD36-PPARγ-POU2F2 signaling","authors":"Weibo Huang ,&nbsp;Chenghao Zhou ,&nbsp;Rong Wu ,&nbsp;Kangcheng Zhao ,&nbsp;Jianfeng Wu ,&nbsp;Dianwen Song","doi":"10.1016/j.bbadis.2025.168139","DOIUrl":"10.1016/j.bbadis.2025.168139","url":null,"abstract":"<div><h3>Objective</h3><div>Type 2 diabetes (T2D) is associated with osteoporosis. Although chronic inflammation and immune dysregulation are implicated in T2D-induced bone loss, the specific roles of immune cells remain poorly understood. This study aimed to investigate how neutrophils in T2D contribute to osteoporosis and to identify the underlying molecular mechanisms and potential therapeutic targets.</div></div><div><h3>Methods</h3><div>We utilized a combination of in vivo and in vitro approaches, including T2D and control mouse models, primary cell cultures, and publicly available single-cell RNA sequencing data from the GEO database. Osteoporosis was assessed through TRAP staining, micro-CT imaging, and quantitative PCR. Molecular interactions were examined using Western blotting, chromatin immunoprecipitation followed by qPCR, and flow cytometry. Additionally, virtual screening was employed to identify potential inhibitors of thrombospondin-1(THBS1).</div></div><div><h3>Results</h3><div>Neutrophils isolated from T2D mice promoted osteoclast activity and bone loss when transferred into wild-type mice, as evidenced by increased TRAP-positive cells and deteriorated bone microarchitecture. We identified THBS1, a glycoprotein secreted at higher levels by T2D neutrophils, as a mediator of osteoclast differentiation. THBS1 engaged the CD36 receptor on macrophages, activating PPARγ, which transcriptionally upregulates POU2F2—a transcription factor that enhances osteoclastogenesis via c-FOS induction. Genetic ablation of THBS1 attenuated osteoclast formation and bone loss in T2D mice. Virtual screening identified nasunin as a potent THBS1 inhibitor. Treatment with nasunin suppressed the CD36–PPARγ–POU2F2–c-FOS axis, reduced osteoclast differentiation in vitro, and ameliorated T2D-induced osteoporosis in vivo.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a novel pathway through which neutrophil-derived THBS1 exacerbates diabetic osteoporosis by promoting osteoclastogenesis via CD36–PPARγ–POU2F2 signaling.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168139"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776762","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":"Swimming exercise attenuates diabetic myopathy and is associated with histological and mitochondrial changes in pregnant rats (Rattus norvegicus)","authors":"Bruna Bologna Catinelli ,&nbsp;Angélica Mércia Pascon Barbosa ,&nbsp;Aline Medolago Carr ,&nbsp;Rafael Guilen de Oliveira ,&nbsp;Fernanda Cristina Bergamo Alves ,&nbsp;Franciele Mosele ,&nbsp;Agnaldo Bruno Chies ,&nbsp;Sérgio Luis Felisbino ,&nbsp;Luis Sobrevia ,&nbsp;Patrícia de Souza Rossignoli ,&nbsp;Marilza Vieira Cunha Rudge ,&nbsp;Diamater Study Group","doi":"10.1016/j.bbadis.2025.168126","DOIUrl":"10.1016/j.bbadis.2025.168126","url":null,"abstract":"<div><h3>Aim</h3><div>Diabetic-induced myopathy (DiM) is reversed by swimming exercise (SE) in diabetic pregnant rats. This study aims to characterise the role of muscle stem cells (MuSCs), mitochondrial adaptations, and inflammation in this process.</div></div><div><h3>Methods</h3><div>A mild hyperglycaemic pregnant rat model was created by administering 100 mg/kg streptozotocin to Wistar female newborns on the first day of life. In adulthood, after mating, the rats were assigned to either a sedentary or exercise group. The SE protocol involved 60 min of daily swimming, 6 days per week, from gestational day 0 to 20. On gestational day 21, blood samples, rectus abdominis muscle (RAM), and soleus muscle were collected for analysis of fiber type, MuSCs count, mitochondrial adaptations, and inflammation markers.</div></div><div><h3>Results</h3><div>The diabetic group showed a lower number of fast and slow-twitch fibers. SE increased the number of MuSCs, the MuSCs/myonuclei ratio, mitochondrial area, and count, and restored citrate synthase activity. SE also increased the MuSCs/fiber and myonuclei/fiber ratios, as well as the mitochondria number/fiber and mitochondria area/fiber ratios, showing a positive relationship between mitochondrial count and fiber number in the diabetic group. Inflammation analysis revealed no differences in pro-inflammatory marker expression or quantification.</div></div><div><h3>Conclusion</h3><div>These results highlight a new combined effect of SE, increasing MuSCs and mitochondrial number and area, as well as restoring citrate synthase activity, suggesting that changes in muscle histology, MuSCs abundance, and mitochondrial adaptations with SE in diabetic animals may be key mechanisms in attenuating RAM DiM in diabetic pregnant rats.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168126"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615692","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":"Vitexin targets USP49-GRPR deubiquitination axis in medullary thyroid carcinoma therapy","authors":"Qing Xia ,&nbsp;Shuai Dong ,&nbsp;Wenjun Xu ,&nbsp;Qinmei Lai ,&nbsp;Hanlin Song ,&nbsp;Wei Zhang","doi":"10.1016/j.bbadis.2025.168128","DOIUrl":"10.1016/j.bbadis.2025.168128","url":null,"abstract":"<div><div>Medullary thyroid carcinoma (MTC) is a rare, aggressive neuroendocrine malignancy with limited therapeutic options, often exhibiting resistance to targeted therapies. This study demonstrates that the natural flavonoid vitexin suppresses MTC progression by disrupting the deubiquitination axis involving USP49 and the gastrin-releasing peptide receptor (GRPR). GRPR, known to drive tumor growth in neuroendocrine cancers, promotes cell survival via the PI3K/AKT signaling pathway. We identified USP49 as a key regulator of GRPR protein stability in MTC, a previously unrecognized interaction where USP49 counteracts GRPR ubiquitination. Vitexin inhibits USP49, destabilizing GRPR. Consequently, vitexin treatment significantly reduced MTC cell proliferation, enhanced apoptosis, and impaired migration and invasion in vitro. Furthermore, vitexin markedly inhibited tumor growth in nude mouse xenograft models, correlating with decreased Ki67 expression and increased apoptotic markers (Tunel). Mechanistically, USP49 stabilizes GRPR by preventing its ubiquitin-mediated degradation; inhibiting USP49 with vitexin resensitizes tumors to apoptosis by destabilizing GRPR. These findings highlight the therapeutic potential of targeting post-translational modification pathways, specifically deubiquitination, in MTC. Vitexin represents a promising candidate agent for overcoming therapeutic resistance by disrupting GRPR-driven survival mechanisms. This work underscores the critical role of deubiquitination in MTC progression and offers a rationale for utilizing natural compounds to modulate GPCR stability in aggressive cancers.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168128"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681565","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":"Inhibition of BRG1 suppresses the progression of glioblastoma via repressing oligodendrocyte genes","authors":"Huanwen Rui ,&nbsp;Bo Chen ,&nbsp;Min Wang ,&nbsp;Xing Xue ,&nbsp;Yangyang Ma ,&nbsp;Chenyang Zhang ,&nbsp;Ying Xu ,&nbsp;Zai Song ,&nbsp;Feifei Ji ,&nbsp;Weijun Feng ,&nbsp;Hao Li","doi":"10.1016/j.bbadis.2025.168118","DOIUrl":"10.1016/j.bbadis.2025.168118","url":null,"abstract":"<div><div>Glioblastoma, the most lethal and pervasive subtype of glioma, has been classified according to both molecular signatures and cell identity. However, the promise of subtype-specific therapy for GBM has yet to be realized. We hypothesize that epigenetic compounds could be effective due to the crucial role of epigenetic regulation in maintaining individual GBM subtypes. We establish a mouse GBM model by expressing <em>AKT3</em>, <em>DN-p53</em> and <em>PDGFB</em> (ADP) in cortical neural progenitor cells via in utero electroporation. Gene expression analysis demonstrate that ADP glioma exhibits the oligodendrocyte precursor cell (OPC) signature. A small-scale compound screening conducted in cultured ADP tumor cells identify BRM014 (dual ATPase inhibitor of chromatin remodelers BRM/BRG1) as an effective compound. Mechanistically, acute treatment of ADP tumor cells with BRM014 specifically inhibits chromatin accessibility and the expression of oligodendrocyte genes. Importantly, genetic depletion of <em>Brg1</em> significantly delays tumor progression and prolongs the survival of ADP glioma-bearing mice. Importantly, BRM014 treatment selectively inhibits the growth of human GBM cells with the OPC signature. In sum, our findings demonstrate that the inhibition of ATPase activity of BRG1 is a promising epigenetic therapy for OPC-like GBM.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168118"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535136","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":"High-fat diet does not exacerbate aortic pathology and enhances metabolic function in Marfan syndrome Fbn1C1041G/+ mice","authors":"Carmen Yap ,&nbsp;Myrthe E. Hoogeland ,&nbsp;Siyu Li ,&nbsp;Iris Bakker ,&nbsp;Ela Yalcin ,&nbsp;Roelof Ottenhoff ,&nbsp;Maria P. Clemente-Olivo ,&nbsp;Sander Kooijman ,&nbsp;Yousef Morcos ,&nbsp;Gerhard Sengle ,&nbsp;Vivian de Waard","doi":"10.1016/j.bbadis.2025.168107","DOIUrl":"10.1016/j.bbadis.2025.168107","url":null,"abstract":"<div><h3>Background and aims</h3><div>Marfan syndrome (MFS) is a systemic disorder, caused by different pathogenic variants in the fibrillin-1 gene (<em>FBN1</em>). Interestingly, patients with MFS are often characterized with an asthenic body type, most likely associated with systemic metabolic alterations. We evaluate the effects of a high-fat diet (HFD) on aortic pathology and metabolism in a mouse model of MFS.</div></div><div><h3>Methods and results</h3><div>Male <em>Fbn1</em>^C1041G/+ MFS mice and wild-type littermates were fed a chow or a HFD for 13 weeks. Compared to chow, HFD-fed mice show increased body weight and white adipose tissue, developed glucose intolerance and increased the use of fat as a fuel source indicated by lower respiratory exchange ratio, independent of genotype. MFS mice showed an increased heart tissue weight, increase in aortic root diameter, and higher number of elastin breaks in the aorta compared to wild-type mice when fed a chow diet. The aortic diameter did not further increase upon HFD feeding in MFS mice, while HFD did promote aortic dilation of the ascending aorta of wild-type mice. In most examined tissues, the mitochondrial gene expression profile is altered in MFS mice on a chow diet. Especially <em>Sirt1</em> was reduced in all tissues, with HFD normalizing the MFS profile towards a wild-type profile. The latter may contribute to the observed increase in energy expenditure upon HFD in MFS mice.</div></div><div><h3>Conclusion</h3><div>In conclusion, <em>Fbn1</em>^C1041G/+ MFS aortic pathology is not aggravated by the HFD, most likely due to the increase of mitochondrial gene expression upon HFD in MFS mice.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168107"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515133","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":"MAIT cells accumulated via CXCL12-CXCR4 chemotaxis are involved in pathologic gastric inflammation among Helicobacter pylori-infected patients","authors":"Fang Zhang ,&nbsp;Youjian Zhou ,&nbsp;Tingting Xia ,&nbsp;Yue Xu ,&nbsp;Taojun He ,&nbsp;Bin Li ,&nbsp;Shasha Yang ,&nbsp;Ying Chen ,&nbsp;Honglei Chen ,&nbsp;Chao Wu","doi":"10.1016/j.bbadis.2025.168151","DOIUrl":"10.1016/j.bbadis.2025.168151","url":null,"abstract":"<div><h3>Background</h3><div><em>Helicobacter pylori</em> can cause gastritis, peptic ulcers, and even gastric cancer. In addition to conventional T cells, mucosal-associated invariant T (MAIT) cells may have an important immunologic role in mucosal infectious diseases. However, the phenotypic and effector characteristics of gastric MAIT cells and the relationship between mucosal MAIT cells and <em>H. pylori</em>-related diseases have not been established.</div></div><div><h3>Methods</h3><div>We analyzed the phenotypes and cytokines of gastric and peripheral MAIT cells from <em>H. pylori</em>-infected patients by flow cytometry. CXCL12-mediated chemotaxis of MAIT cells was measured by Transwell assay. Relationship between MAIT cells and inflammation of <em>H. pylori</em>-infected gastric diseases was assessed with immunofluorescence staining and histopathological score.</div></div><div><h3>Results</h3><div>The number of gastric MAIT cells was significantly increased but the frequency of peripheral MAIT cells were decreased in patients with <em>H. pylori</em> infections. The gastric MAIT cells were activated with high expression of CD69 and CD38, and produced several pro-inflammatory cytokines. Furthermore, we observed the expression of CXCR4 and CXCL12 were upregulated in <em>H. pylori</em>-infected stomachs. CXCL12 promoted MAIT cells to migrate, which was blocked by a CXCR4 antagonist. Finally, we demonstrated that the number of gastric MAIT cells was positively correlated with severe inflammation in <em>H. pylori</em>-infected stomachs.</div></div><div><h3>Conclusions</h3><div>Gastric MAIT cells were accumulated and activated in <em>H. pylori</em>-infected stomachs, which may be involved in the pathologic inflammation of <em>H. pylori</em>-related gastric diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168151"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907225","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":"Prolyl-hydroxylase domain inhibition enhances collagen levels in oral mucosa-derived fibroblasts","authors":"Sivan Najar Hasson ,&nbsp;Itay Kilimnik ,&nbsp;Bar Shahar ,&nbsp;Lucia Adriana Lifshits ,&nbsp;Marina Sova ,&nbsp;Daniel Zvi Bar ,&nbsp;Lihi Adler-Abramovich ,&nbsp;Evgeny Weinberg ,&nbsp;Maayan Gal","doi":"10.1016/j.bbadis.2025.168124","DOIUrl":"10.1016/j.bbadis.2025.168124","url":null,"abstract":"<div><div>Fibroblast cells are a primary source of collagen, playing a vital role in maintaining the structural integrity of the oral mucosa. Given that hypoxia upregulates collagen levels in oral mucosa-derived fibroblasts (OMDFs), this study aims to investigate the effect of inhibiting prolyl-hydroxylase domain (PHD) enzymes, negative regulators of the transcription factor hypoxia-inducible factor (HIF), on collagen-I levels under normal oxygen levels. We examined three PHD inhibitors, IOX4, Enarodustat, and Daprodustat, for their effect on collagen levels in keratinized OMDFs. While IOX4 exhibited cellular cytotoxicity, Enarodustat and Daprodustat did not affect cell viability. Further treatment with Daprodustat at 12.5 or 25 μM significantly increased collagen I level more than twofold compared to non-treated cells, whereas Enarodustat had no significant effect. Additional mechanistic studies revealed that Daprodustat treatment induced the accumulation and nuclear translocation of HIF-1α and upregulated transcripts of key collagen-modifying enzymes, including P4HA1 and P4HA2, by more than twofold. This study demonstrates that direct PHD inhibition effectively enhances collagen biosynthesis in OMDFs. The mechanism involves HIF-1α-mediated upregulation of collagen-modifying enzymes. These findings highlight the potential of repurposing clinically approved PHD inhibitors as therapeutic agents for promoting the healing and regeneration of damaged gingiva and additional tissues.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168124"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650395","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-induced mitochondrial magnesium uptake and its metabolic implications in the McArdle disease model","authors":"Thiruvelselvan Ponnusamy ,&nbsp;Jeremy Mehta ,&nbsp;Haris Waseem ,&nbsp;Marianne Assogba ,&nbsp;Asha Parveen Sakkarai Mohamed ,&nbsp;Shibani Kudchadkar ,&nbsp;Paul Herold ,&nbsp;Kalimuthusamy Natarajaseenivasan ,&nbsp;Santhanam Shanmughapriya","doi":"10.1016/j.bbadis.2025.168130","DOIUrl":"10.1016/j.bbadis.2025.168130","url":null,"abstract":"<div><div>McArdle disease, caused by mutations in the <em>pygm</em> encoding myophosphorylase, impairs muscle glycogenolysis and lactate production during exercise, leading to severe energy deficits. Here, we report that the decreased lactate production in McArdle disease regulates mitochondrial magnesium (mMg²⁺) uptake, with major metabolic consequences in skeletal muscle. Using a CRISPR/Cas9-generated <em>pygm</em> knockout (KO) rat model, we demonstrate that KO rats fail to elevate lactate during static muscle contraction and exhibit diminished mMg²⁺ uptake, disrupted ATP synthesis, and impaired mitochondrial respiration. <em>In vitro</em>, caffeine-stimulated KO myotubes showed preserved Ca²⁺ oscillations but lacked lactate production and mMg²⁺ uptake. Restoration of lactate levels <em>via</em> glucose supplementation rescued mMg²⁺ transport and improved metabolic output. These findings underscore the significance of lactate as a crucial regulator of mMg²⁺ homeostasis and provide valuable mechanistic insights into the metabolic dysfunction observed in McArdle disease.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168130"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752420","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}