Molecular Medicine最新文献

{"title":"Neuroprotective effect of riboflavin kinase on cerebral ischemia injury in rats.","authors":"Yingxin Zou, Minghua Ruan, Xu Feng, Fei Liu, Weihong Liu, Song Chen, Zhiyong Chu","doi":"10.1186/s10020-025-01170-0","DOIUrl":"10.1186/s10020-025-01170-0","url":null,"abstract":"<p><strong>Background: </strong>Riboflavin kinase (RFK, also called flavokinase) is a catalytic enzyme that converts riboflavin to its active form in vivo. Dysfunction of the RFK gene has been associated with susceptibility to ischemic stroke. However, the protective role and mechanisms of RFK in ischemic stroke have not been elucidated.</p><p><strong>Methods: </strong>Lentivirus-mediated RFK knock-up (RFK( +)) and knock-down (RFK(-)) were used to investigate the protective effect and mechanism of RFK in the rat middle cerebral artery occlusion (MCAO) model in vivo and in the oxygen and glucose deprivation (OGD) model of neurons in vitro; and the dependence of the protective effect of RFK on flavins was also investigated.</p><p><strong>Results: </strong>We demonstrated that RFK was an endogenous protein against ischemia brain injury both in vivo and in vitro experiments. RFK inhibited cerebral infarction, cerebral edema and neuronal apoptosis after cerebral ischemia. Its mechanisms include inhibition of the protein expression of Caspase 12 and Caspase 3 induced by cerebral ischemia, and thus inhibiting endoplasmic reticulum stress (ERS) and neuronal apoptosis; the protective effect of RFK depends on the presence of the flavoprotein Ero1; exogenous riboflavin supplementation protected cortical neurons from ischemic injury and prolonged the lifespan in stroke-prone spontaneously hypertensive rats with low RFK gene function, but this protective effect is limited and cannot completely reverse the decreasing trend of neuronal tolerance to ischemic injury caused by RFK gene dysfunction; the protective effect of RFK against ischemic injury is independent of the presence of flavins and their concentrations.</p><p><strong>Conclusions: </strong>The present study demonstrates that RFK is an important regulatory molecule against ischemia brain injury and its mechanism involves inhibition of ERS. The protective effect of RFK is independent of the presence of flavins and their concentrations. RFK deserves further investigation as a promising target gene for the detection of stroke susceptibility. Flavins may be used as a preventive or adjunctive treatments for ischemic brain injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"125"},"PeriodicalIF":6.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Layer-specific molecular signatures of colon anastomotic healing and leakage in mice.","authors":"Hilal Sengul, Vasiliki Bantavi, Laura Gloeck, Andrew Y F Li Yim, Patrick Leven, Patrik Efferz, Bianca Schneiker, Mariola Lysson, Wouter J De Jonge, Sven Wehner","doi":"10.1186/s10020-025-01167-9","DOIUrl":"10.1186/s10020-025-01167-9","url":null,"abstract":"<p><strong>Background: </strong>Colon anastomotic leakage (CAL) is a postoperative complication originating from disturbed colon anastomotic healing (CAH). Wound healing involves several well-coordinated stages, which have not been comprehensively studied for CAH or CAL. This study aims to provide transcriptional profiles of different intestinal layers of anastomotic tissues throughout distinct healing stages and to identify CAL-related genes.</p><p><strong>Methods: </strong>Proximal colon anastomosis was constructed with 8 interrupted sutures in mice. Six hours, 24 h and 72 h after surgery, anastomotic complications were assessed. Transcriptional profiles of inner (mucosa and submucosa) and outer (muscularis externa) layer of the anastomotic and naive control tissues were analyzed with 3' bulk mRNA sequencing to identify the layer-specific healing and leakage pathways. Selective target genes differing between CAL and CAH were measured for their protein expression.</p><p><strong>Results: </strong>Our data indicate that the mucosa/submucosa and muscularis externa enter inflammation stage at 6 h, proliferation stage at 24 h and tissue remodeling stage at 72 h during CAH. We observed that transcription profiles of the mucosa/submucosa, but not the muscularis externa, differ between CAH and CAL. Particularly, genes related to extracellular remodeling (including Col18a1 and Col16a1) and wound healing (Pdpn and Timp1) showed lower expression in the mucosa/submucosa of CAL tissue compared to CAH. Conformingly, protein levels for collagens as well IL-34 were decreased in CAL, while the TGF-β-pseudo-receptor BAMBI was increased in CAL compared to CAH tissues.</p><p><strong>Conclusions: </strong>Mucosa/submucosa and muscularis externa are mostly in synchronization during the inflammation, proliferation, and extracellular remodeling stages during CAH. Transcriptional profiles within the anastomotic mucosa/submucosa differ between CAH and CAL in genes related to extracellular modelling and wound healing, indicating that genes of these pathways may contribute to CAL.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"124"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764507","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":"Extrachromosomal circular DNA as a novel biomarker for the progression of colorectal cancer.","authors":"Quanpeng Qiu, Yi Ding, Xiaolong Guo, Jing Han, Jiaqi Zhang, Yaping Liu, Junjun She, Yinnan Chen","doi":"10.1186/s10020-025-01164-y","DOIUrl":"10.1186/s10020-025-01164-y","url":null,"abstract":"<p><strong>Background: </strong>Extrachromosomal circular DNA (eccDNA) has potential in tumor diagnosis, particularly for improving diagnostic accuracy and early cancer detection; however, many challenges remain in its application to clinical practice.</p><p><strong>Methods: </strong>We conducted a Circle-Seq analysis on clinical samples at different stages of colorectal cancer progression to examine the dynamic changes of eccDNA during the progression of colorectal cancer. We used breakpoint-specific PCR to verify candidate eccDNAs identified by Circle-Seq. The results were further validated using the AOM/DSS-induced colorectal cancer model.</p><p><strong>Results: </strong>There was an increase in the abundance of eccDNA with the progression of colorectal cancer. The genes associated with these eccDNA molecules were primarily related to signaling pathways involved in tumor development and metastasis. Our analysis also revealed that eccDNA abundance positively correlates with gene expression, and eccDNA derived from specific genes has potential value for the early diagnosis of tumors.</p><p><strong>Conclusions: </strong>This study revealed a connection between eccDNA and colorectal cancer progression and highlights the clinical potential of eccDNA for the early diagnosis of colorectal cancer.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"123"},"PeriodicalIF":6.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753542","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":"Metformin ameliorates osteoporosis by enhancing bone angiogenesis via the YAP1/TAZ-HIF1α axis.","authors":"Hao Yin, Zhe Ruan, Teng-Fei Wan, Zhi-Rou Lin, Chun-Yuan Chen, Zhen-Xing Wang, Jia Cao, Yi-Yi Wang, Ling Jin, Yi-Wei Liu, Guo-Qiang Zhu, Jiang-Shan Gong, Jing-Tao Zou, Yi Luo, Yin Hu, Zhao-Hui Li, Hao Luo, Yu-Qi Liu, Cheng Long, Shu-Shan Zhao, Yong Zhu, Hui Xie","doi":"10.1186/s10020-025-01169-7","DOIUrl":"10.1186/s10020-025-01169-7","url":null,"abstract":"<p><strong>Background: </strong>Osteoporosis, resulting from an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation, affects millions globally. Recent studies have identified type H vessels (CD31^hiEMCN^hi) as a specialized subset of bone blood vessels that positively regulate bone formation. This study aims to investigate the effects of metformin on bone mass, strength, and angiogenesis in osteoporotic mice, and to elucidate the underlying molecular mechanisms, particularly focusing on the YAP1/TAZ-HIF1α axis.</p><p><strong>Methods: </strong>Osteoporotic mice were administered metformin, and bone mass and strength were measured. In vivo and in vitro angiogenesis assays were performed under hypoxic conditions. Expression levels of YAP1/TAZ and HIF1α were assessed in femoral metaphysis and hypoxia-cultured human microvascular endothelial cells (HMECs). Small interfering RNA was used to interfere with HIF1α or YAP1/TAZ expression in hypoxia-cultured HMECs. Additionally, we employed AAV-mediated overexpression of YAP1/TAZ in vivo to determine whether elevated YAP1/TAZ levels alter metformin's effects on bone mass and angiogenesis.</p><p><strong>Results: </strong>Metformin significantly enhanced bone mass and strength in osteoporotic mice. It also promoted angiogenesis under hypoxia conditions both in vivo and in vitro. Metformin reduced YAP1/TAZ expression while increasing HIF1α expression in both the femoral metaphysis of osteoporotic mice and hypoxia-cultured HMECs. Interference with HIF1α or YAP1/TAZ confirmed that metformin enhances HIF1α and its target genes primarily by inhibiting YAP1/TAZ. Furthermore, overexpression of YAP1/TAZ partially reversed the bone-protective effect of metformin, leading to reduced HIF1α levels and diminished type H vessel formation.</p><p><strong>Conclusion: </strong>Our findings suggest that metformin holds promise as a therapeutic agent for osteoporosis by enhancing type H vessel formation through the inhibition of the YAP1/TAZ-HIF1α axis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"122"},"PeriodicalIF":6.0,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753544","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":"Rescue of a panel of Hemophilia A-causing 5'ss splicing mutations by unique Exon-specific U1snRNA variants.","authors":"Laura Peretto, Claudia D'angiolillo, Paolo Ferraresi, Dario Balestra, Mirko Pinotti","doi":"10.1186/s10020-025-01176-8","DOIUrl":"10.1186/s10020-025-01176-8","url":null,"abstract":"<p><strong>Background: </strong>Aberrant mRNA splicing is a well-established pathogenic mechanism for human disease, but its real impact is hardly predictable and underestimated. Splicing can be therefore modulated for therapeutic purposes, and splicing-switching molecules are in clinics for some diseases. Here, conscious that over 10% of all pathogenic mutations occurs at 5'ss, we aimed at characterizing and rescuing nine 5'ss mutations in three models of defective F8 exons whose skipping would lead to factor VIII (FVIII) deficiency (Hemophilia A), the most frequent coagulation factor disorder.</p><p><strong>Methods: </strong>HEK293T cells were transfected with F8 minigene variants, alone or with engineered U1 small nuclear RNAs (U1snRNAs), and splicing patterns analysed via RT-PCR.</p><p><strong>Results: </strong>All 5'ss mutations induced exon skipping, and the proportion of correct transcripts, not predictable by computational analysis, was consistent with residual FVIII levels in patients. For each exon we identified a unique engineered U1snRNAs, either compensatory or Exon Specific (ExSpeU1), able to rescue all mutations. Overall, ExSpeU1s were more effective than compensatory U1snRNAs, particularly in the defective exons 6 and 22.</p><p><strong>Conclusions: </strong>Data highlight the importance of splicing assays to elucidate genotype-phenotype relationships and proved the correction efficacy of ExSpeU1s for each targeted defective F8 exon, thus expanding their translational potential for HA.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"121"},"PeriodicalIF":6.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730549","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":"Identifying nexilin as a central gene in neutrophil-driven abdominal aortic aneurysm pathogenesis.","authors":"Bohan Yang, Yiyan Xu, Fengfei Yan, Cheng Peng, Ye Song, Song Han, Haiyang Wang","doi":"10.1186/s10020-025-01157-x","DOIUrl":"10.1186/s10020-025-01157-x","url":null,"abstract":"<p><strong>Objectives: </strong>Abdominal aortic aneurysm (AAA) is an inflammation-driven disease in which neutrophil infiltration is critical to its progression. This study aims to explore the molecular mechanisms behind neutrophil infiltration in AAA and identify key regulatory genes.</p><p><strong>Methods: </strong>We utilized weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis to compare AAA and healthy abdominal aortic tissues. Functional enrichment analysis and a protein-protein interaction (PPI) network were constructed to understand gene functions. Machine learning algorithms were applied to identify key hub genes, followed by in vivo validation using an ApoE-/- mouse model.</p><p><strong>Results: </strong>Neutrophils, NK cells, and pDCs were significantly increased in AAA tissues. WGCNA identified 234 genes associated with neutrophil infiltration, of which 39 were significantly differentially expressed. Functional enrichment analysis highlighted roles in actin-related processes and pathways. Nexilin (NEXN) was consistently identified as a key hub gene negatively correlated with immune cell infiltration. In vivo validation confirmed that NEXN inhibits AAA progression in ApoE-/- mice by regulating immune cell infiltration.</p><p><strong>Conclusion: </strong>NEXN plays a crucial role in modulating neutrophil infiltration in AAA. These findings provide new molecular insights into AAA pathogenesis and suggest NEXN as a potential target for AAA therapy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"120"},"PeriodicalIF":6.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720628","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 transcriptional repressor Ctbp2 as a metabolite sensor regulating cardiomyocytes proliferation and heart regeneration.","authors":"Yanting Meng, Jianwen Ding, Yanping Wang, Jing Wang, Wei Huang, Wenkang Jiang, Jiayi Li, Xiujuan Lang, Sifan Zhang, Yumei Liu, Xijun Liu, Hulun Li, Bo Sun","doi":"10.1186/s10020-025-01168-8","DOIUrl":"10.1186/s10020-025-01168-8","url":null,"abstract":"<p><strong>Background: </strong>C-terminal binding protein-2 (Ctbp2) is an evolutionarily conserved transcriptional repressor that regulates fundamental processes such as cell proliferation and apoptosis. However, the potential role of Ctbp2 in cardiomyocyte proliferation and heart regeneration remains unclear. In this study, we aim to explore the important role of Ctbp2 in cardiomyocyte proliferation and the regeneration of injured adult hearts.</p><p><strong>Methods and results: </strong>In this study, we found that the expression of Ctbp2 in cardiomyocytes is downregulated after adulthood. Silencing Ctbp2 in cardiomyocytes on the post-natal day 1 (P1) reduced the proliferation ability of cardiomyocytes, whereas overexpressing Ctbp2 enhanced the proliferation ability of cardiomyocytes. Additionally, overexpressing Ctbp2 via adeno-associated virus-9 (AAV9) had no effect on the hearts of normal adult mice, but in the case of heart injury, overexpression of Ctbp2 in adult mice cardiomyocytes promoted cardiomyocyte proliferation. Mechanistically, the transcriptional repressor Ctbp2 acts as a metabolite sensor, and its regulation of cardiomyocyte proliferation is influenced by the metabolites NADH/NAD+ and fatty acyl-CoAs. Ctbp2 is activated by the intracellular accumulation of NADH during cardiomyocyte ischemia and hypoxia, inhibiting the transcriptional activity of the transcription factor FoxO1, thereby repressing the expression of the target genes and cell cycle negative regulators p21 and p27, allowing cardiomyocytes to re-enter the cell cycle. In contrast, normal adult cardiomyocytes mainly use fatty acid oxidation metabolism as their primary energy source, and the intracellular production of fatty acyl-CoAs inactivates Ctbp2, thus preventing it from inhibiting FoxO1 mediated cell cycle arrest.</p><p><strong>Conclusion: </strong>In conclusion, this study demonstrates that the Ctbp2-FoxO1-p21/p27 axis can promote cardiomyocyte proliferation and heart regeneration. As a metabolite sensor, Ctbp2 is activated during cardiomyocyte ischemia and hypoxia, while it is inactivated under normal conditions. This controllable and transient regulation of cardiomyocyte proliferation can avoid the detrimental effects on cardiac function caused by long-term regulation of cardiomyocyte proliferation, such as hypertrophic cardiomyopathy or heart failure. This provides new targets and new ideas for addressing the issues of cardiomyocyte proliferation and heart regeneration.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"119"},"PeriodicalIF":6.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720655","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":"Involvement of microRNAs-449/FASN axis in response to trastuzumab therapy in HER2-positive breast cancer.","authors":"Ana Lameirinhas, Sandra Torres-Ruiz, Iris Garrido-Cano, Cristina Hernando, María Teresa Martínez, Ana Rovira, Joan Albanell, Sandra Zazo, Federico Rojo, Begoña Bermejo, Ana Lluch, Juan Miguel Cejalvo, Eduardo Tormo, Pilar Eroles","doi":"10.1186/s10020-025-01163-z","DOIUrl":"10.1186/s10020-025-01163-z","url":null,"abstract":"<p><p>The anti-HER2 monoclonal antibody trastuzumab and new derivative formulations are the standard treatment for HER2-positive breast cancer. However, after 1 to 5 years of treatment, some patients acquire resistance to therapy, leading to relapse. The microRNA-449 family members were downregulated in HER2-positive breast cancer cell lines and low levels were associated with patients' worse prognosis. Moreover, trastuzumab-resistant HER2-positive breast cancer cell lines showed lower microRNAs-449 and higher Fatty Acid Synthase (FASN) expression, compared to sensitive cell lines. The direct regulation of FASN by microRNA-449a and microRNA-449b-5p was demonstrated. Moreover, microRNAs-449 overexpression and FASN inhibition decreased cell proliferation and sensitized cells to trastuzumab treatment by inhibiting the PI3K/AKT signaling pathway. Together, these results suggest the microRNAs-449/FASN axis as a potential therapeutic target in combination with anti-HER2 agents to overcome trastuzumab resistance and to improve treatment response in HER2-positive breast cancer patients.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"116"},"PeriodicalIF":6.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710739","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":"Knockdown of SLC7A5 inhibits malignant progression and attenuates oxaliplatin resistance in gastric cancer by suppressing glycolysis.","authors":"Yan Zhang, Jian Cao, Zheng Yuan, Jiahui Zhou, Hao Zuo, Xinsheng Miao, Xinhua Gu","doi":"10.1186/s10020-025-01175-9","DOIUrl":"10.1186/s10020-025-01175-9","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy resistance is a major challenge in the treatment of intermediate and advanced gastric cancer (GC). This study aimed to recognize oxaliplatin resistance-related genes (OXARGs) in GC and to explore their role and mechanism in oxaliplatin resistance of GC.</p><p><strong>Methods: </strong>OXARGs with prognostic value in GC were analyzed using GC oxaliplatin resistance data from the GEO and TCGA databases. RT-qPCR and WB assay were applied to verify the expression of MT2A, NOTCH1 and SLC7A5 in oxaliplatin-resistant GC cells (HGC27R and MKN45R). The effect of SLC7A5 on the malignant phenotype of oxaliplatin-resistant GC cells was verified by CCK-8, EDU, TUNEL, colony formation, wound healing, transwell assay, tumor bearing experiments and WB assay.</p><p><strong>Results: </strong>Bioinformatics analysis and experimental validation indicate that SLC7A5 was a target for oxaliplatin-resistance in GC. Knockdown of SLC7A5 obviously decreased the viability, migration, and invasion of oxaliplatin-resistant GC cells in vitro and tumor growth in vivo. It also increased the apoptosis levels and BAX expression, and reduced the expression of BCL2, MMP 2 and MMP9. Additionally, the knockdown of SLC7A5 enhanced the sensitivity of oxaliplatin-resistant GC cells to oxaliplatin both in vitro and in vivo. Furthermore, knockdown of SLC7A5 downregulated the expression of HK2, LDHA, Glut1, and PDK1 both in vivo and in vitro, leading to increased extracellular glucose levels and decreased lactate levels. However, glutathione significantly attenuated the regulatory effect of SLC7A5 knockdown on the malignant phenotype of oxaliplatin-resistant GC cells.</p><p><strong>Trial registration: </strong>Not Applicable.</p><p><strong>Conclusion: </strong>Knockdown of SLC7A5 inhibits malignant progression and attenuates oxaliplatin resistance in GC by suppressing glycolysis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"115"},"PeriodicalIF":6.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710741","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":"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}