Molecular Medicine最新文献

{"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}

{"title":"The clinical potential of PDL-1 pathway and some related micro-RNAs as promising diagnostic markers for breast cancer.","authors":"Eman A Al-Sharabass, Motawa E El-Houseini, Heba Effat, Sherif Abdelaziz Ibrahim, Mona S Abdellateif","doi":"10.1186/s10020-025-01137-1","DOIUrl":"10.1186/s10020-025-01137-1","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint pathways play important roles in breast cancer (BC) pathogenesis and therapy.</p><p><strong>Methods: </strong>Expression levels of programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-ligand 1 (PD-L1), Forkhead box P3 (FOXP3), miR-155, and miR-195 were assessed in the peripheral blood of 90 BC patients compared to 30 healthy controls using quantitative real-time PCR (qRt-PCR). The plasma level of soluble MHC class I chain related-protein B (MIC-B) protein was assessed using the enzyme linked immunosorbent assay (ELISA) technique. The data were correlated to the clinico-pathological characteristics of the patients.</p><p><strong>Results: </strong>There was a significant increase in the expression levels of PDL-1 [17.59 (3.24-123), p < 0.001], CTLA-4 [23.34 (1.3-1267), p = 0.006], PD-1 [10.25 (1-280), p < 0.001], FOXP3 [11.5 (1-234.8), p = 0.001], miR-155 [87.3 (1.5-910), p < 0.001] in BC patients compared to normal controls. The miR-195 was significantly downregulated in BC patients [0.23 (0-0.98, p < 0.001]. The plasma level of MIC-B was significantly increased in the BC patients [0.941 (0.204-6.38) ng/ml], compared to the control group [0.351 (0.211-0.884) ng/mL, p < 0.00]. PDL-1, CTLA-4, PD-1, and FOXP3 achieved a specificity of 100% for distinguishing BC patients, at a sensitivity of 93.3%, 82.2%, 62.2%, and 71.1% respectively. The combined expression of PDL-1 and CTLA-4 scored a 100% sensitivity and 100% specificity for diagnosing BC (p < 0.001). The sensitivity, specificity, and AUC of miR-155 were 88.9%, 96.7%, and 0.934; respectively (p < 0.001). While those of miR-195 were 73.3%, 60%, and 0.716; respectively (p = 0.001). MIC-B expression showed a 77.8% sensitivity, 80% specificity, and 0.811 AUC at a cutoff of 1.17 ng/ml (p < 0.001). Combined expression of miR-155 and miR-195 achieved a sensitivity of 91.1%, a specificity of 96.7%, and AUC of 0.926 (p < 0.001). Multivariate analysis showed that PDL-1 (OR:13.825, p = 0.004), CTLA-4 (OR: 20.958, p = 0.010), PD-1(OR:10.550, p = 0.044), MIC-B (OR: 17.89, p = 0.003), miR-155 (OR: 211.356, P < 0.001), and miR-195(OR:0.006, P < 0.001) were considered as independent risk factors for BC.</p><p><strong>Conclusions: </strong>The PB levels of PDL-1, CTLA-4, PD-1, FOXP3, MIC-B, miR-155, and miR-195 could be used as promising diagnostic markers for BC patients.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"106"},"PeriodicalIF":6.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663788","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":"Role of the oral-gut microbiota axis in pancreatic cancer: a new perspective on tumor pathophysiology, diagnosis, and treatment.","authors":"Xuanchi Guo, Yuhan Shao","doi":"10.1186/s10020-025-01166-w","DOIUrl":"10.1186/s10020-025-01166-w","url":null,"abstract":"<p><p>Pancreatic cancer, one of the most lethal malignancies, remains challenging due to late diagnosis, aggressive progression, and therapeutic resistance. Recent advances have revealed the presence of intratumoral microbiota, predominantly originating from the oral and gut microbiomes, which play pivotal roles in pancreatic cancer pathogenesis. The dynamic interplay between oral and gut microbial communities, termed the \"oral-gut microbiota axis,\" contributes multifacetedly to pancreatic ductal adenocarcinoma (PDAC). Microbial translocation via anatomical or circulatory routes establishes tumor-resident microbiota, driving oncogenesis through metabolic reprogramming, immune regulation, inhibition of apoptosis, chronic inflammation, and dysregulation of the cell cycle. Additionally, intratumoral microbiota promote chemoresistance and immune evasion, further complicating treatment outcomes. Emerging evidence highlights microbial signatures in saliva and fecal samples as promising non-invasive diagnostic biomarkers, while microbial diversity correlates with prognosis. Therapeutic strategies targeting this axis-such as antibiotics, probiotics, and engineered bacteria-demonstrate potential to enhance treatment efficacy. By integrating mechanisms of microbial influence on tumor biology, drug resistance, and therapeutic applications, the oral-gut microbiota axis emerges as a critical regulator of PDAC, offering novel perspectives for early detection, prognostic assessment, and microbiome-based therapeutic interventions.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"103"},"PeriodicalIF":6.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657043","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":"Integrated bioinformatics and validation reveal TMEM45A in systemic lupus erythematosus regulating atrial fibrosis in atrial fibrillation.","authors":"Hongjie Xu, Sufan Ding, Xiaoping Ning, Ye Ma, Qi Yu, Yi Shen, Lin Han, Zhiyun Xu","doi":"10.1186/s10020-025-01162-0","DOIUrl":"10.1186/s10020-025-01162-0","url":null,"abstract":"<p><strong>Background: </strong>Accumulative evidence has shown that systemic lupus erythematosus (SLE) increases the risk of various cardiovascular diseases including atrial fibrillation (AF). The study aimed to screen potential key genes underlying co-pathogenesis between SLE and AF, and to discover therapeutic targets for AF.</p><p><strong>Methods: </strong>Differentially expressed genes (DEGs) were identified, and co-expressed gene modules were obtained through weighted gene co-expression network analysis (WGCNA) based on the AF and SLE expression profiles from the GEO database. Subsequently, machine learning algorithms including LASSO regression and support vector machine (SVM) method were employed to identify the candidate therapeutic target for SLE-related AF. Furthermore, the therapeutic role of TMEM45A was validated both in vivo and vitro.</p><p><strong>Results: </strong>Totally, 26 DEGs were identified in SLE and AF. The PPI network combined with WGCNA identified 51 key genes in SLE and AF. Ultimately, Machine learning-based methods screened three hub genes in SLE combined with AF, including TMEM45A, ITGB2 and NFKBIA. The cMAP analysis exposed KI-8751 and YM-155 as potential drugs for AF treatment. Regarding TMEM45A, the aberrant expression was validated in blood of SLE patients. Additionally, TMEM45A expression was up-regulated in the atrial tissue of patients with AF. Furthermore, TMEM45A knockdown alleviated AF occurrence and atrial fibrosis in vivo and Ang II-induced NRCFs fibrosis in vitro.</p><p><strong>Conclusion: </strong>The crosstalk genes underlying co-pathogenesis between SLE and AF were unraveled. Furthermore, the pro-fibrotic role of TMEM45A was validated in vivo and vitro, highlighting its potential as a therapeutic target for AF.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"104"},"PeriodicalIF":6.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656893","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":"Epitranscriptomic regulation of HIF-1: bidirectional regulatory pathways.","authors":"Daniel Benak, Petra Alanova, Kristyna Holzerova, Miloslava Chalupova, Barbora Opletalova, Frantisek Kolar, Gabriela Pavlinkova, Marketa Hlavackova","doi":"10.1186/s10020-025-01149-x","DOIUrl":"10.1186/s10020-025-01149-x","url":null,"abstract":"<p><strong>Background: </strong>Epitranscriptomics, the study of RNA modifications such as N⁶-methyladenosine (m⁶A), provides a novel layer of gene expression regulation with implications for numerous biological processes, including cellular adaptation to hypoxia. Hypoxia-inducible factor-1 (HIF-1), a master regulator of the cellular response to low oxygen, plays a critical role in adaptive and pathological processes, including cancer, ischemic heart disease, and metabolic disorders. Recent discoveries accent the dynamic interplay between m⁶A modifications and HIF-1 signaling, revealing a complex bidirectional regulatory network. While the roles of other RNA modifications in HIF-1 regulation remain largely unexplored, emerging evidence suggests their potential significance.</p><p><strong>Main body: </strong>This review examines the reciprocal regulation between HIF-1 and epitranscriptomic machinery, including m⁶A writers, readers, and erasers. HIF-1 modulates the expression of key m⁶A components, while its own mRNA is regulated by m⁶A modifications, positioning HIF-1 as both a regulator and a target in this system. This interaction enhances our understanding of cellular hypoxic responses and opens avenues for clinical applications in treating conditions like cancer and ischemic heart disease. Promising progress has been made in developing selective inhibitors targeting the m⁶A-HIF-1 regulatory axis. However, challenges such as off-target effects and the complexity of RNA modification dynamics remain significant barriers to clinical translation.</p><p><strong>Conclusion: </strong>The intricate interplay between m⁶A and HIF-1 highlights the critical role of epitranscriptomics in hypoxia-driven processes. Further research into these regulatory networks could drive therapeutic innovation in cancer, ischemic heart disease, and other hypoxia-related conditions. Overcoming challenges in specificity and off-target effects will be essential for realizing the potential of these emerging therapies.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"105"},"PeriodicalIF":6.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656852","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}