Molecular Medicine最新文献

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.

Rare diseases refer to a group of neglected diseases with low prevalence that face challenges in diagnostics as well as therapeutics due to phenotypic heterogeneity and ineffective clinical trials. In this study, we evaluated two novel analogs of hydroxyethylamine & phthalimide (LTC-181 and LTC-1717) for their potential effect on the epimerase activity of mutant GNE proteins associated with GNE myopathy. GNE gene encodes a key bifunctional sialic acid biosynthetic enzyme, UDP-N-acetyl Glucosamine 2-epimerase/N-acetyl Mannosamine Kinase; GNE). The compounds have significantly increased the epimerase activity of r-F307C-GNE and r-A555V-GNE mutant proteins in vitro. Reduced GNE epimerase activity and sialic acid content in muscle cell-based model for GNE function (SKM-GNEHz) was increased by 2-fold after addition of these compounds. The proteomic study showed that the compounds affected cytoskeletal organization, autophagy and muscle atrophy. Also, treatment with analogs enhanced the cell viability of SKM-GNEHz cells with increased F-actin polymerization and cell migration, thereby, restoring GNE deficient function. Additionally, effect of these compounds was observed with enhanced autophagy and reduced muscle atrophy function in GNE deficient muscle cell. Docking and interaction studies showed that LTC-1717 stabilize GNE better than LTC-181, indicating better therapeutic potential. Overall, this study indicates that HEA-phthalimide analog could be promising leads for treating GNE myopathy.

Throughout a person's lifetime, thyroid hormones (THs) have an outsized impact on cardiovascular health from prenatal heart development to adult cardiac contractile function and blood pressure regulation. Maintaining a healthy functioning hypothalamic-thyroid axis is crucial for preventing cardiac-related and all-cause mortality. Patients with moderate to severe heart failure (HF) often manifest with low or borderline-low TH function. In this review article, we examine the potential of TH therapy in HF management by highlighting outcomes from recent clinical studies. We also address the need for a serum-based biomarker such as brain natriuretic peptide (BNP) that indicates disease stage of HF and that also correlates with cardiac tissue TH status. Recent and newer therapeutic strategies (including the combination of Triiodothyronine and Thyroxine) to advance the management of patients living with HF are proposed including a reassessment of what is normal thyroid status in these patients and the potential of TH treatment.