Molecular Medicine最新文献

Background: This study explored the impact of vaginal microbes, metabolites, and METTL1-mediated m7G modification of BRCA1 mRNA on High-Grade Serous Ovarian Cancer (HGSOC).

Methods: METTL1 and BRCA1 expression levels were assessed via bioinformatics, Western blotting, and RT-qPCR. Their interaction was studied using RNA co-immunoprecipitation and RNA pull-down assays. The functions and mechanisms of METTL1 and BRCA1 in HGSOC were investigated through CCK-8 assays, flow cytometry, transwell migration assays, and nude mouse xenograft models. We analyzed vaginal microbial and metabolite differences in HGSOC patients with varying BRCA1 expression using 16 S rRNA sequencing and liquid chromatography. Associations were evaluated with Spearman correlation and heat maps, while molecular docking assessed key metabolite binding to METTL1. The roles and interactions of selected metabolites with METTL1/BRCA1 in HGSOC were validated through in vivo and in vitro experiments.

Results: In HGSOC, both METTL1 and BRCA1 were up-regulated. METTL1 enhanced BRCA1 expression via m7G modification, boosting cell proliferation and tumor growth. Elevated BRCA1 levels were associated with changes in vaginal microbiota, particularly increased Lactobacillus, and alterations in metabolic pathways. Correlation analysis indicated that Lactobacillus was significantly negatively correlated with 5-formamidoimidazole-4-carboxamide ribotide, inosine, cobalt-precorrin-7, and uridine, but positively correlated with L-lysine. The strongest correlation was with 5-formamidoimidazole-4-carboxamide ribotide. Molecular docking showed that this compound binds strongly to METTL1. Functional tests demonstrated that it inhibits HGSOC cell proliferation and tumor growth by disrupting METTL1-mediated m7G modification of BRCA1. Overexpression of METTL1 or BRCA1 negated its anti-tumor effects.

Conclusion: The vaginal microbial metabolite 5-formamidoimidazole-4-carboxamide ribotide reduces BRCA1 expression and slows HGSOC progression by modifying BRCA1 m7G through METTL1, suggesting its potential as an HGSOC treatment.

Background: The pathogenesis of osteoarthritis (OA) is not yet fully elucidated. FABP4 plays a role in the occurrence of metabolic OA, however, the mechanism remains unclear. The purpose of this study was to further explore the mechanism by which FABP4 mediates the occurrence of metabolic OA.

Methods: In vivo, FABP4 knockout mice (KO) and wild-type littermates (WT) were fed with high-fat diet (HFD) for 3 and 6 months. WT mice were fed with HFD and treated with FABP4 inhibitor BMS309403 (30 mg/kg/d) or vehicle for 6 months. Knee cartilage degenerative changes and subchondral bone changes were assessed. In vitro, FABP4 was used to stimulate mouse bone marrow mesenchymal stem cells (mMSCs) and endothelial progenitor cells (EPCs). Osteogenesis and angiogenesis were assessed.

Results: In vivo, knocking out of FABP4 and pharmaceutical inhibition of FABP4 significantly alleviated subchondral bone sclerosis and type H vessel formation in mice fed with HFD, and was significantly associated with osteogenesis and angiogenesis. In vitro, FABP4 promotes the differentiation of MSCs into osteoblasts through activation of the PI3K/Akt signaling pathway, and promotes the expression of osteogenesis-related proteins. FABP4 also promotes endothelial cell migration, tube formation, and wound healing through activating the PI3K/Akt pathway.

Conclusions: This study suggests that FABP4 induced subchondral bone osteogenesis and angiogenesis. The PI3K-Akt signaling pathway plays a critical role in both processes. Inhibition of FABP4 may serve as a potential therapeutic approach for metabolic OA.

The COVID-19 pandemic has precipitated a surge in neurocognitive dysfunction, with long-term implications for global health systems and socioeconomic stability. Despite growing clinical recognition of post-COVID cognitive deficits ("brain fog"), the molecular mechanisms driving these impairments remain poorly understood. Our study addresses this critical gap by identifying SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 N protein), a core structural component of the virus, as a novel etiological factor in senescence-mediated cognitive decline. We observed that SARS-CoV-2 N protein caused microglial senescence both in vivo and in vitro. Mechanistically, SARS-CoV-2 N protein-induced metabolic shifting toward glycolysis initiated a cascade of microglial senescence, which propagated cognitive impairment. We found that glycolysis inhibition reduced SARS-CoV-2 N protein-triggered microglial senescence and attenuated cognitive impairment in mice. Disrupted mitochondrial dynamics impaired oxidative phosphorylation capacity, forcing glycolytic reprogramming that ultimately triggered cellular senescence activation. We found that the SARS-CoV-2 N protein promoted excessive mitochondrial dysfunction in microglia, resulting in mitochondrial fragmentation. Inhibition of mitochondrial fission effectively rescued SARS-CoV-2 N protein-induced microglial senescence. In conclusion, our study suggests that the SARS-CoV-2 N protein induces senescence-mediated cognitive impairment by promoting glycolysis in microglia. Therapeutic targeting of glycolysis in SARS-CoV-2 N protein-triggered microglial senescence could be beneficial for treating or preventing cognitive impairment.

Background: Immunotherapy is a promising treatment for drug-resistant cancers. However, its effectiveness against head and neck squamous cell carcinoma (HNSCC) is limited. This indicates the need to explore additional factors that can predict tumor response to new therapies and improve or supplement their effects. Therefore, we aimed to investigate whether the post-radiation usage of anti-TIGIT and/or anti-CD96 could enhance the antitumor response in HNSCC.

Methods: HNSCC tissues, as well as human and mouse cell lines, were examined to evaluate the effects of radiation on immune checkpoint receptors (TIGIT, CD96, and CD226) and tumor ligands (CD155, CD112, CD113, and CD111). Overall and disease-free survival, along with factors related to these immune checkpoint receptors and ligands, were detected. Moreover, we investigated the effects of radiation dose and exposure time on the expression of these receptors and ligands in vitro and in vivo. Tumor growth and survival rates were then evaluated using TIGIT and/or CD96 inhibitors injected intraperitoneally after exposure to radiation. Finally, various proliferative and immunological parameters of the tumor microenvironment were determined using immunohistochemistry and flow cytometry. Statistical analyses were performed using Student's t-test, one-way analysis of variance, or two-way analysis of variance.

Results: Elevated levels of TIGIT, CD96, CD155, CD112, CD113, and CD111 were observed in both HNSCC tissues and the cell lines. Radiation increased the expression of these inhibitory receptors and ligands. Thus, anti-TIGIT and anti-CD96 were used to target the upregulated expression of the receptors TIGIT and CD96, respectively. This treatment combination inhibited tumor growth by boosting apoptosis, reducing tumor cell proliferation, and restoring the cytotoxic functions of CD4⁺ and CD8⁺ T cells after radiation therapy.

Conclusion: Our findings suggest that TIGIT and CD96 could be markers of the clinical stage and treatment response of HNSCC. Therefore, administering anti-TIGIT and anti-CD96 after radiotherapy may provide a novel approach for incorporating immunoradiotherapy into HNSCC treatment.

Tumor necrosis factor receptor-associated factors (TRAFs) are a family of 7 signaling proteins that have regulatory roles in multiple fundamental cellular processes, including immunity, inflammation, apoptosis, permeability, and cell proliferation. TRAF7 is the most recently described with unique features distinguishing it from other TRAFs. It is an E3 ubiquitin ligase that activates MEKK3 and KLF2/4 signaling, inhibits MEK1/2 and c-Myb along with an NF-κβ-modulator, and stabilizes VE-cadherins in cell junctions. Germline mutations in TRAF7 lead to developmental delays and the dysmorphic features associated with TRAF7 syndrome. Somatic TRAF7 mutations are associated with subsets of meningiomas, mesotheliomas, and perineuriomas. Additionally, TRAF7 altered expression is associated with poorer prognoses in hepatocellular carcinoma, breast cancer, and prostate cancer. This review comprehensively describes the physiological roles of TRAF7 and the pathophysiology of clinical conditions with TRAF7 alterations. We highlight important directions for future work to improve our understanding of the mechanisms underlying TRAF7 related disease, identify prognostic biomarkers that help guide clinical decision making, and potentially identify novel therapeutic targets to expand our treatment options for these patients.

Background: Certain environmental factors have been known to compromise the suppressive capacity of thymus-derived regulatory T cells (tTregs) while leaving transforming growth factor-beta (TGF-β)-induced Tregs (iTregs) unaffected. The objective of this study is to ascertain whether both Treg subsets exhibit comparable efficacy in regulating brain inflammation through the inhibition of immunogenic dendritic cells (DCs) and instead induce tolerogenic DCs.

Objectives: We aimed to delineate the different therapeutic potential roles of both Treg subsets in promoting the tolerogenic capacity of DCs and elucidate the mechanistic crosstalk between Tregs and DCs.

Methods: The clinical scores of experimental autoimmune encephalomyelitis (EAE) mice were continuously monitored, brain inflammation was assessed through hematoxylin and eosin (H&E) staining, and the presence of brain-infiltrating Th1/Th17 cells as well as splenic CD11c⁺ DCs was analyzed using flow cytometry. Additionally, a DC-T coculture assay was conducted, and the underlying mechanisms were determined by western blotting and flow cytometry.

Results: iTregs exhibit greater efficacy than tTregs in mitigating brain inflammation in both EAE and EAE provoked by a high-salt diet. iTregs suppress the pro-inflammatory activity of DCs while promoting the generation of a tolerance-inducing DC phenotype. This effect is primarily mediated by membrane-bound TGF-β signaling, rather than through IL-10R signaling, and involves the inhibition of the AKT/mTOR pathway.

Conclusion: iTreg cells play a pivotal role in orchestrating the formation of a robust immunoregulatory circuit involving tolerogenic DCs, which holds significant promise as a target for the development of innovative immunotherapeutic strategies for autoimmune disorders.

Background: Breast cancer (BC) exhibits significant heterogeneity in incidence and mortality worldwide. Neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced BC; however, its efficacy varies by subtype. This study examined the gene expression profiles associated with NAC response in Colombian women with invasive BC.

Methods: RNA sequencing of pre-treatment tissues from 58 patients (29 responders and 29 non-responders) identified differentially expressed genes (DEGs) for each molecular subtype, and prognostic performance was evaluated using risk scores.

Results: Functional enrichment analysis highlighted the immune system pathways in non-responders. Changes in cytokine target activity and immune cell populations were analyzed to understand the role of the tumor microenvironment (TME) in response to treatment. APOD, GPR132, FGF10, and HBB emerged as independent predictors of NAC response, with APOD showing a protective effect in LuminalB/HER2- patients. These results were corroborated by immunohistochemistry and public databases. Drug sensitivity analysis revealed varied responses to potential therapeutics among the non-responders.

Conclusions: This study underscores the need to identify specific gene expression profiles and immune cell population changes to predict NAC responses, paving the way for personalized and effective treatments for the Colombian BC population.

Retinal ganglion cells (RGCs) are neurons that transmit visual information from the retina to the brain. Their degeneration, as seen in glaucoma and other optic neuropathies, leads to irreversible vision loss. As mature human RGCs are difficult to access, most of their studies rely on rodent models, which do not fully recapitulate human retinal biology. Human pluripotent stem cells (hPSCs) provide a promising source for generating RGCs in vitro, supporting disease modelling, drug screening, and future cell replacement therapies. This review outlines key markers that define RGC identity, maturation stages, and subtype diversity. We summarise recent advances in the differentiation of hPSCs towards RGCs, their functional characterisation, and their applications in disease modelling, drug screening, and transplantation.