Molecular Medicine最新文献

{"title":"TET1 mitigates prenatal fluoride-induced cognition impairment by modulating Bcl2 DNA hydroxymethylation level.","authors":"Yongle Cai, Xingdong Zeng, Mengyan Wu, Haonan Chen, Miao Sun, Hao Yang","doi":"10.1186/s10020-025-01174-w","DOIUrl":"10.1186/s10020-025-01174-w","url":null,"abstract":"<p><p>Fluoride exposure during pregnancy commonly compromises fetal neurodevelopment and largely results in a broad spectrum of cognitive deficiencies in the adult offspring. However, the precise mechanisms underlying these effects remain to be fully elucidated. Herein, we investigate the impacts of fluoride on neural excitability and apoptosis, synaptic plasticity, and cognitive function, as well as possible underlying mechanisms. Our results indicated that exposure to a high sodium fluoride (100 mg/L) during pregnancy in the mouse can cause the cognitive deficits of their offspring, accompanied by a decrease in the expression of Tet-eleven translocation protein 1 (TET1), an enzyme responsible for DNA hydroxymethylation. Additionally, there is a reduction in the dendritic spine density and the expression of postsynaptic density protein-95 (PSD95) in the hippocampal regions of male offspring. Furthermore, in vitro fluoride treatment significantly exacerbates neuronal apoptosis and reduces the frequency of spikes in spontaneous action potential. More significantly, we also found that TET1 could directly bind to the promotor region of Bcl2, altering its DNA hydroxymethylation and Bcl2 expression. Intriguingly, Tet1 knock-out mice exhibited cognitive deficits similar to those observed in male animals exposed to high levels of fluoride. Furthermore, the down-regulation of TET1 protein, along with the consequent alteration in Bcl2 hydroxymethylation and increased neuronal apoptosis, are likely mechanisms underlying the impact of prenatal fluoride exposure on the neurodevelopment of male offspring. These findings provide novel insights into the molecular mechanisms by which fluoride exposure induces neurodevelopmental impairment of the male offspring.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"117"},"PeriodicalIF":6.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3 regulated by histone lactylation promotes ossification of the ligamentum flavum by enhancing the m6A methylation of BMP2.","authors":"Jiaming Zhou, Rui Wang, Zequn Zhang, Yuan Xue","doi":"10.1186/s10020-025-01173-x","DOIUrl":"10.1186/s10020-025-01173-x","url":null,"abstract":"<p><p>Ossification of the ligamentum flavum (OLF) is characterized by ligamentum flavum thickening and subsequent thoracic canal stenosis. Emerging evidence has demonstrated the involvement of N6-methyladenosine (m6A) methylation in OLF pathogenesis. This study investigates the regulatory role of METTL3-mediated m6A methylation of BMP2 in OLF progression. Clinical ligamentum flavum tissues were analyzed for m6A levels using dot blot analysis. Osteogenic differentiation was assessed through quantitative real-time PCR (qPCR), alkaline phosphatase staining, alizarin red S staining, and western blot analysis. Mechanistic insights were obtained through methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays. The regulatory role of histone lactylation on METTL3 expression was examined using LDHA knockdown, sodium lactate (Nala) treatment, and 2-deoxy-D-glucose (2-DG) administration in OLF cells. Our findings revealed significant upregulation of METTL3 expression and m6A levels in OLF patients. METTL3 was shown to enhance osteogenic differentiation and m6A methylation of BMP2, which was specifically recognized by IGF2BP1. Furthermore, increased histone lactylation was observed in OLF patients, with enrichment in the METTL3 promoter region facilitating its transcriptional activation. LDHA knockdown-mediated inhibition of endogenous lactylation suppressed osteogenic differentiation, a phenotype that was rescued by METTL3 overexpression. In conclusion, this study elucidates that histone lactylation-mediated upregulation of METTL3 promotes OLF progression through IGF2BP1-dependent m6A methylation of BMP2, providing novel insights into potential therapeutic strategies for OLF management.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"118"},"PeriodicalIF":6.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin inhibits ferroptosis-mediated vascular occlusion by regulating the CXCL10/CXCR3 axis in retinopathy of prematurity.","authors":"Rui Niu, Jing Wang, Xiaolin Pan, Min Ran, Peng Hao, Wei Zhang, Yatu Guo, Wei Zhang","doi":"10.1186/s10020-025-01161-1","DOIUrl":"10.1186/s10020-025-01161-1","url":null,"abstract":"<p><p>Retinopathy of prematurity (ROP) is a disorder that causes blindness in children at a high incidence. Retinal endothelial cells are damaged by variations in oxygen partial pressure, which leads to vascular obstruction and, eventually, ischemia and hypoxia, which cause the formation of new blood vessels. However, little is known about the molecular mechanism of hyperoxic vascular occlusion. High oxygen levels are thought to cause ferroptosis. In this study, experiments with both animal and in vitro models demonstrated that elevated expression of C-X-C motif chemokine ligand 10 (CXCL10)/C-X-C motif chemokine receptor 3 (CXCR3) in retinal vascular endothelial cells induced ferroptosis. Curcumin decreased ferroptosis by inhibiting the production of CXCL10/CXCR3. Curcumin also preserved distal sprouts and filopodia, increasing tip cell and astrocyte counts. As a result, we hypothesize that curcumin reduces ferroptosis and preserves retinal blood vessels under hyperoxic conditions by suppressing the CXCL10/CXCR3 axis. Coimmunoprecipitation (COIP) data were used to determine which proteins interact with CXCR3 during ferroptosis. For the first time, our study applied curcumin to treat eye diseases in oxygen-induced retinopathy (OIR) mice and explored the underlying mechanism in cell experiments, laying the foundation for clinical patients to use this drug. Exploring the interaction between CXCL10/CXCR3 and ferroptosis provides an experimental basis for using the CXCL10/CXCR3 axis as a therapeutic target for the treatment of ROP ophthalmopathy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"113"},"PeriodicalIF":6.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-caryophyllene reduces inflammation to protect against ischemic stroke by suppressing HMGB1 signaling.","authors":"Yuchun Wang, Yang Yang, Tuo Meng, Shengwei Liu, Jingdong Liu, Daohang Liu, Bharati Laxman, Sha Chen, Zhi Dong","doi":"10.1186/s10020-025-01171-z","DOIUrl":"10.1186/s10020-025-01171-z","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke is characterized by high mortality and high disability rates and accounts for the vast majority of current stroke cases. Reperfusion after surgical treatment can cause serious secondary damage to ischemic stroke patients, but there are still no specific drugs for the clinical treatment of ischemic stroke. Inflammation plays a critical role in ischemia and reperfusion injury, highlighting the urgent need for new anti-inflammatory targets and therapeutic agents. High-mobility group box-1 (HMGB1) is highly expressed in both neuronal cell bodies and axons and has been found to have late proinflammatory effects; thus, the role of HMGB1 in stroke has recently become a hot research topic in critical care medicine. An increase in HMGB1 expression leads to the aggravation of inflammatory reactions after ischemic stroke. B-caryophyllene (BCP) is a natural drug with anti-inflammatory effects. However, whether HMGB1 is involved in the anti-inflammatory mechanism of BCP is still unknown. We aimed to investigate the relationship between HMGB1 and BCP in in vivo and in vitro ischemic stroke models.</p><p><strong>Methods: </strong>A middle cerebral artery embolism model was established in mice by thread thrombus, and primary neurons were subjected to oxygen‒glucose deprivation and reoxygenation (OGD/R) in vitro. In vitro, the HMGB1 DNA overexpression virus(GV-HMGB1)or the HMGB1 DNA silencing virus(RNAi-HMGB1)was injected into the lateral ventricles of mice..</p><p><strong>Results: </strong>HMGB1 expression increases after ischemic stroke and further affects the expression of TLR4, RAGE and other related inflammatory factors, thus reducing the inflammatory response and ultimately protecting against injury. These results confirmed the effect of HMGB1 on TLR4/RAGE signaling and the subsequent regulation of inflammation, oxidative stress and apoptosis. Furthermore, BCP potentially alleviates ischemic brain damage by suppressing HMGB1/TLR4/RAGE signaling, reducing the expression of IL-1β/IL-6/TNF-α, and inhibiting neuronal death and the inflammatory response.</p><p><strong>Conclusion: </strong>These data indicate that BCP exerts a protective effect against ischemic stroke-induced inflammatory injury by regulating the HMGB1/TLR4/RAGE signaling pathway, which provides new insights into the mechanisms of this therapeutic candidate for the treatment of ischemic stroke.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"112"},"PeriodicalIF":6.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease pathogenicity in Hutchinson-Gilford progeria syndrome mice: insights from lung-associated alterations.","authors":"Jingjing Wang, Yuelin Guan, Yue Wang, Junyi Tan, Zhongkai Cao, Yuhan Ding, Langping Gao, Haidong Fu, Xiangjun Chen, Jianyu Lin, Ning Shen, Xudong Fu, Fangqin Wang, Jianhua Mao, Lidan Hu","doi":"10.1186/s10020-025-01165-x","DOIUrl":"10.1186/s10020-025-01165-x","url":null,"abstract":"<p><strong>Background: </strong>Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by accelerated aging, impaired growth, disrupted lipid metabolism, and reduced lifespan.</p><p><strong>Methods: </strong>Prior research has primarily focused on cardiovascular manifestations, our research sheds light on multiple organs that underwent significant age-related changes validated by tissue cross-sections H&E, Masson's trichrome, and β-galactosidase staining.</p><p><strong>Results: </strong>Among these pathologies tissues, the lung was severely affected and substantiated by clinical data of pulmonary anomalies from our HGPS patients. Biochemical and histological analyses of lung tissue from the HGPS mouse model revealed elevated Progerin expression, abnormal NAD metabolism, cellular senescence markers (higher level of p16 and p27, lower level of ki67), and various age-related morphology changes, including fibrosis, inflammation, and thickening of alveolar walls. Transcriptomic analyses of lung tissue indicated that down-regulated genes (Thy1, Tnc, Cspg4, Ccr1) were associated with extracellular space, immune response, calcium signaling pathway, osteoclast differentiation, and lipid binding pathway.</p><p><strong>Conclusions: </strong>This study unveiled the previously overlooked organs involved in HGPS pathogenesis and suggested a specific emphasis on the lung. Our findings suggest that pulmonary abnormalities may contribute to disease progression, warranting further investigation into their role in HGPS monitoring and management.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"114"},"PeriodicalIF":6.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel genetic determinants contribute to hearing loss in a central European cohort with enlarged vestibular aqueduct.","authors":"Emanuele Bernardinelli, Raffaella Liuni, Rapolas Jamontas, Paola Tesolin, Anna Morgan, Giorgia Girotto, Sebastian Roesch, Silvia Dossena","doi":"10.1186/s10020-025-01159-9","DOIUrl":"10.1186/s10020-025-01159-9","url":null,"abstract":"<p><strong>Background: </strong>The enlarged vestibular aqueduct (EVA) is the most commonly detected inner ear malformation. Biallelic pathogenic variants in the SLC26A4 gene, coding for the anion exchanger pendrin, are frequently involved in determining Pendred syndrome and nonsyndromic autosomal recessive hearing loss DFNB4 in EVA patients. In Caucasian cohorts, the genetic determinants of EVA remain unknown in approximately 50% of cases. We have recruited a cohort of 32 Austrian patients with hearing loss and EVA to define the prevalence and type of pathogenic sequence alterations in SLC26A4 and discover novel EVA-associated genes.</p><p><strong>Methods: </strong>Sanger sequencing, single nucleotide polymorphism (SNP) assays, copy number variation (CNV) testing, and Exome Sequencing (ES) were employed for gene analysis. Cell-based functional and molecular assays were used to discriminate between gene variants with and without impact on protein function.</p><p><strong>Results: </strong>SLC26A4 biallelic variants were detected in 5/32 patients (16%) and monoallelic variants in 5/32 patients (16%). The pathogenicity of the uncharacterized SLC26A4 protein variants was assigned or excluded based on their ion transport function and cellular abundance. The monoallelic or biallelic Caucasian EVA haplotype was detected in 7/32 (22%) patients, but its pathogenicity could not be confirmed. X-linked pathogenic variants in POU3F4 (2/32, 6%) and biallelic pathogenic variants in GJB2 (2/32, 6%) were also found. No CNV of SLC26A4 and STRC genes was detected. ES of eleven undiagnosed patients with bilateral EVA detected rare sequence variants in six EVA-unrelated genes (monoallelic variants in SCD5, REST, EDNRB, TJP2, TMC1, and two variants in CDH23) in five patients (5/11, 45%). Cell-based assays showed that the TJP2 variant leads to a mislocalized protein product forming dimers with the wild-type, supporting autosomal dominant pathogenicity. The genetic causes of hearing loss and EVA remained unidentified in (14/32) 44% of patients.</p><p><strong>Conclusions: </strong>The present investigation confirms the role of SLC26A4 in determining hearing loss with EVA, identifies novel genes in this pathophysiological context, highlights the importance of functional testing to exclude or assign pathogenicity of a given gene variant, proposes a possible diagnostic workflow, suggests a novel pathomechanism of disease for TJP2, and highlights voids of knowledge that deserve further investigation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"111"},"PeriodicalIF":6.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Runx2 drives Schwann cells repair phenotype switch through chromatin remodeling and Sox2 activation after nerve injury.","authors":"Bo He, Shouwen Su, Zeyu Zhang, Zhongpei Lin, Qinglin Qiu, Yan Yang, Xiaoyue Wen, Zhaowei Zhu","doi":"10.1186/s10020-025-01142-4","DOIUrl":"10.1186/s10020-025-01142-4","url":null,"abstract":"<p><strong>Background: </strong>The states of Schwann cells undergo significant shifts during nerve regeneration. Previous studies have shown the expression of Runx2 is locally upregulated within the affected areas. However, the regulatory mechanisms underlying its epigenetic control remain unclear.</p><p><strong>Methods: </strong>To investigate the epigenetic mechanisms through which Runx2 influences the phenotypic transition of repair Schwann cells. Runx2 siRNA fragments and Runx2 overexpression plasmids were constructed. Healthy adult Sprague-Dawley (SD) rats weighted 100-150 g, regardless of sex, were randomly selected. Following the establishment of a sciatic nerve crush injury model, samples were collected for qPCR analysis at 4 and 7 days post-injury. In vitro, the alterations in cell morphology, proliferation, apoptosis, and the ability to promote neural regeneration following the downregulation or upregulation of Runx2 in Schwann cells were assessed. A comprehensive analysis of transcriptome data, ATAC sequencing, and CUT&Tag sequencing of histones and transcription factors in SCs after Runx2 overexpression, along with single-cell RNA sequencing data from GSE216665 and Sox2 overexpression data from RSC96 in GSE94590, was conducted to elucidate the mechanism of action of Runx2, which was subsequently validated using dual luciferase assays.</p><p><strong>Results: </strong>Runx2 expression increased locally during the early stages of injury, primarily localized within Zhu Schwann cells (Zhu SCs). Runx2-overexpressing Schwann cells, when cultured in vitro, underwent a transformation from long, spindle-shaped He Schwann cells (He SCs) to flat, rounded Zhu SCs. Multi-omics analysis indicated that Runx2-OE may positively feedback-regulate its expression by opening transcriptional regulatory regions and binding to its own gene regulatory domains. Furthermore, it could also activate transcription factors such as Sox2, transitioning them from a transcriptionally silent to an active state, thereby enhancing Sox2 expression and synergistically regulating the phenotypic transition of Schwann cells.</p><p><strong>Conclusions: </strong>Runx2 can activate and recruit downstream stemness factors, such as Sox2, by modulating chromatin accessibility and histone modification status within Schwann cells, thereby promoting and maintaining the timely phenotypic transformation of Schwann cells following injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"110"},"PeriodicalIF":6.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perinatal hypoxia-mediated neurodevelopment abnormalities in congenital heart disease mouse model.","authors":"Renwei Chen, Haifan Wang, Liqin Zeng, Jiafei He, Xiaohan Liu, Xinting Ji, Paul Yao, Shuo Gu","doi":"10.1186/s10020-025-01158-w","DOIUrl":"10.1186/s10020-025-01158-w","url":null,"abstract":"<p><strong>Background: </strong>Cyanotic congenital heart disease (CHD) in children has been associated with neurodevelopmental abnormalities, although the underlying mechanisms remain largely unknown. Multiple factors are likely involved in this process. This research aims to explore the potential effects of hypoxia and vascular system-derived factors in neurodevelopmental outcomes in offspring.</p><p><strong>Methods: </strong>Mouse aorta endothelial cells (MEC) and amygdala neurons were isolated to investigate the effects of hypoxia on pro-inflammatory cytokine release, gene expression, redox balance, mitochondrial function, and epigenetic modifications. A CHD mouse model was established to evaluate the impact of perinatal hypoxia on fetal brain development. Estrogen receptor β (ERβ) expression in endothelial cells was modulated using Tie2-driven lentivirus both in vitro and in vivo study to assess the vascular system's contribution to hypoxia-mediated neurodevelopmental abnormalities.</p><p><strong>Results: </strong>Hypoxia exposure, along with factors released from MEC, led to altered gene expression, oxidative stress, mitochondrial dysfunction, and epigenetic modifications in amygdala neurons. In the CHD mouse model, perinatal hypoxia resulted in compromised vascular function, altered gene expression, disrupted redox balance in brain tissues, and impaired behavioral outcomes in offspring. Prenatal expression of ERβ in endothelial cells partially ameliorated these neurodevelopmental abnormalities, while prenatal knockdown of ERβ mimicked the effects of perinatal hypoxia.</p><p><strong>Conclusions: </strong>Hypoxia, combined with endothelial cell-derived factors, induces epigenetic changes in neurons. In the CHD mouse model, perinatal hypoxia causes vascular dysfunction, altered gene expression, and redox imbalance in brain tissues, leading to behavioral impairments in offspring. Prenatal expression of ERβ in endothelial cells mitigates these effects, suggesting that modulating gene expression in the vascular system during pregnancy could play a protective role against hypoxia-induced neurodevelopmental abnormalities in CHD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"109"},"PeriodicalIF":6.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal diversity in molecular and functional abnormalities in the mdx dystrophic brain.","authors":"Joanna Pomeroy, Malgorzata Borczyk, Maria Kawalec, Jacek Hajto, Emma Carlson, Samuel Svärd, Suraj Verma, Eric Bareke, Anna Boratyńska-Jasińska, Dorota Dymkowska, Alvaro Mellado-Ibáñez, David Laight, Krzysztof Zabłocki, Annalisa Occhipinti, Loydie Majewska, Claudio Angione, Jacek Majewski, Gennady G Yegutkin, Michal Korostynski, Barbara Zabłocka, Dariusz C Górecki","doi":"10.1186/s10020-025-01109-5","DOIUrl":"10.1186/s10020-025-01109-5","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration and neuropsychiatric abnormalities. Loss of full-length dystrophins is both necessary and sufficient to initiate DMD. These isoforms are expressed in the hippocampus, cerebral cortex (Dp427c), and cerebellar Purkinje cells (Dp427p). However, our understanding of the consequences of their absence, which is crucial for developing targeted interventions, remains inadequate. We combined RNA sequencing with genome-scale metabolic modelling (GSMM), immunodetection, and mitochondrial assays to investigate dystrophic alterations in the brains of the mdx mouse model of DMD. The cerebra and cerebella were analysed separately to discern the roles of Dp427c and Dp427p, respectively. Investigating these regions at 10 days (10d) and 10 weeks (10w) followed the evolution of abnormalities from development to early adulthood. These time points also encompass periods before onset and during muscle inflammation, enabling assessment of the potential damage caused by inflammatory mediators crossing the dystrophic blood-brain barrier. For the first time, we demonstrated that transcriptomic and functional dystrophic alterations are unique to the cerebra and cerebella and vary substantially between 10d and 10w. The common anomalies involved altered numbers of retained introns and spliced exons across mdx transcripts, corresponding with alterations in the mRNA processing pathways. Abnormalities in the cerebra were significantly more pronounced in younger mice. The top enriched pathways included those related to metabolism, mRNA processing, and neuronal development. GSMM indicated dysregulation of glucose metabolism, which corresponded with GLUT1 protein downregulation. The cerebellar dystrophic transcriptome, while significantly altered, showed an opposite trajectory to that of the cerebra, with few changes identified at 10 days. These late defects are specific and indicate an impact on the functional maturation of the cerebella that occurs postnatally. Although no classical neuroinflammation markers or microglial activation were detected at 10 weeks, specific differences indicate that inflammation impacts DMD brains. Importantly, some dystrophic alterations occur late and may therefore be amenable to therapeutic intervention, offering potential avenues for mitigating DMD-related neuropsychiatric defects.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"108"},"PeriodicalIF":6.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen via GPER downregulated HIF-1a and MIF expression, attenuated cardiac arrhythmias, and myocardial inflammation during hypobaric hypoxia.","authors":"Prosperl Ivette Wowui, Richard Mprah, Marie Louise Ndzie Noah, Joseph Adu-Amankwaah, Anastasia Wemaaatu Lamawura Kanoseh, Li Tao, Diana Chulu, Simon Kumah Yalley, Saffia Shaheen, Hong Sun","doi":"10.1186/s10020-025-01144-2","DOIUrl":"10.1186/s10020-025-01144-2","url":null,"abstract":"<p><strong>Background: </strong>The human body is highly dependent on adequate oxygenation of the cellular space for physiologic homeostasis mediation. The insufficient oxygenation of the cellular space leads to hypoxia. Hypobaric hypoxia (HH) is the reduction in oxygen partial pressure and atmospheric pressure during ascent to high altitudes. This state induces a maladaptive response. Women and how hormones like estrogen influence hypoxia have not been explored with most research being conducted on males. In this study, we investigated the effects of estrogen and GPER on HIF-1a and MIF expression, cardiac arrhythmias, and inflammation during hypobaric hypoxia.</p><p><strong>Methods: </strong>Ovariectomy and SHAM operations were done on FVB wild-type (WT) female mice. 2 weeks after the operation, the mice were treated with estrogen (40 mg/kg) as a therapeutic intervention and placed in a hypoxic chamber at an altitude of 6000 m for 7 days. Cardiac electrical activity was assessed using electrocardiography. Alterations in protein expression, inflammatory, and GPER pathways were investigated using western blotting, ELISA, and immunofluorescence. Histological assessment was performed using Masson's trichrome staining. Peritoneal macrophages were isolated for in vitro study.</p><p><strong>Results: </strong>Under hypobaric hypoxia (HH), the ovariectomized (OVX) group showed increased macrophage migration inhibitory factor (MIF) and hypoxia-inducible factor-1 alpha (HIF-1α) expression. In contrast, these factors were downregulated in the estrogen-treated and control groups. HH also caused cardiac inflammation and fibrosis, especially in the OVX + HH group, which had elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) and decreased anti-inflammatory cytokines (TGF-β, IL-10). Inhibition with G15 (a GPER antagonist) increased MIF and HIF-1α, whereas activation with G1 (a GPER agonist) decreased their expression, highlighting GPER's crucial role in regulating MIF during HH.</p><p><strong>Conclusion: </strong>Estrogen regulates HIF-1α and MIF expression through the GPER during hypobaric hypoxia, suggesting a potential therapeutic pathway to mitigate maladaptive responses during high-altitude ascent.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"107"},"PeriodicalIF":6.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}