Journal of Translational Medicine最新文献

Background: Neuroblastoma, originating from the sympathetic neural crest, is the most prevalent extracranial solid tumor in children. Amplification of MYCN is a widely recognized indicator of poor prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have impeded the development of direct inhibitors with favorable drug-like properties. This study aimed to investigate the upstream regulatory mechanisms of N-Myc stabilization in neuroblastoma and explore potential therapeutic strategies targeting these mechanisms.

Methods: The regulatory role of NeuroD1 in neuroblastoma was evaluated through in vitro and in vivo experiments. Mechanistic studies were performed to examine the effects of NeuroD1 knockdown on N-Myc ubiquitination and degradation. Transcriptional target screening through RNAseq and ChIPseq was conducted to identify downstream effectors of NeuroD1, and the interaction between USP1 and N-Myc was assessed by co-IP and western blot. The therapeutic efficacy of Pimozide was investigated in neuroblastoma cells in vitro.

Results: NeuroD1 was identified as a critical regulator associated with MYCN amplification. NeuroD1 promoted the proliferation of neuroblastoma cells in vitro and in vivo. Mechanistically, NeuroD1 knockdown increased K48-linked polyubiquitination of N-Myc, leading to its proteasomal degradation. USP1 was identified as a key downstream effector of NeuroD1 and was shown to interact with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Pimozide effectively suppressed USP1 expression, reduced N-Myc levels, and inhibited neuroblastoma cell proliferation.

Conclusion: This study uncovered a novel oncogenic axis in neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, promoting N-Myc stabilization and tumor progression. Furthermore, the findings highlight the therapeutic potential of repurposing Pimozide as a promising treatment strategy for this aggressive tumor subtype.

Introduction: The third most prevalent form of cancer, colorectal cancer (CRC), is associated with a high mortality rate due to colorectal liver metastases (CRLM). However, the molecular mechanisms underlying CRLM remain poorly understood.

Methods: ScRNA-seq data and Bulk RNA-seq data were collected from GEO database. First, we screened genes that showed differentially expression in three groups of colorectal tissues (normal vs. primary tumor vs. metastases). We then performed machine learning to identify signature genes involved in colorectal cancer. We further investigated the expression patterns of these core genes at the single-cell level. Through the integration of single-cell and bulk RNA-seq data, we have identified pivotal genes linked to CRC liver metastasis. Furthermore, we revealed that TCF21 is overexpressed in colorectal tumor tissues with metastases using clinical samples and HCT116 cells.

Results: We have identified 12 pivotal genes linked to CRC liver metastasis, which aims to dissect the molecular underpinnings of colorectal cancer and pave the way for novel therapeutic targets in clinical practice. Using scRNA-seq analysis, our findings revealed unique cellular communication features in CRC metastasis. Besides, TCF21^high stromal cells were mainly enriched in metastatic tissues and TCF21 RNA level is associated with CRC metastasis, indicating vital role of TCF21 in CRC. Mechanistically, TCF21 regulates the expression of WNT5A and overexpression of WNT5A could reverse the effect of TCF21 deficiency in CRC.

Conclusions: We identified 12 signature hub genes associated with CRLM by using both scRNA-seq and bulk RNA-seq analysis. Further, we revealed the vital role of TCF21, which promotes CRLM by regulating WNT5A in CRC metastasis. The revelations have illuminated the pivotal function of the TCF21-WNT5A pathway in the development of colorectal cancer, indicating possible avenues for therapeutic intervention aimed at preventing and managing the spread of CRC.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID share clinical features including persistent fatigue, post-exertional malaise (PEM), and gastrointestinal (GI) dysfunction. Growing evidence implicates brain-gut axis dysregulation, characterized by dysbiosis, neuroinflammation within the central nervous system (CNS), increased intestinal permeability, and microbial translocation in their pathophysiology. However, therapeutic strategies targeting these pathways remain poorly defined.

Methods: We report a case of post-COVID ME/CFS successfully treated with electroacupuncture (EA)-based deep peroneal nerve stimulation which was employed to potentiate the vagal reflex. Fatigue trajectories were assessed using the Multidimensional Fatigue Inventory over 12 weeks. Based on the case, a systematic review of randomized controlled trials (RCTs) evaluating brain-gut axis-modulating interventions in ME/CFS or Long COVID was conducted.

Results: The patient exhibited a significant reduction in total fatigue, with early improvements in motivation and mental fatigue, and delayed improvement in physical fatigue following transient systemic symptom flares. Across included RCTs (n = 8, 790 participants), four investigated gut microbiome-modulating therapies and four employed nerve stimulation. Synbiotic and herbal interventions demonstrated benefits for fatigue or PEM, accompanied by alterations in specific bacterial populations or CNS metabolisms. Regarding nerve stimulation, transcranial direct current stimulation (tDCS) combined with exercise program improved fatigue, whereas standalone tDCS, auricular or peripheral TENS showed limited efficacy.

Conclusion: Brain-gut axis-based interventions may alleviate fatigue in ME/CFS and Long COVID by potentially modulating neuroinflammation, restoring microbiome balance, and improving epithelial barrier function. EA-based vagal stimulation represents a feasible option for patients with severe or treatment-resistant symptoms. Larger mechanistic studies and rigorously designed RCTs are needed to establish therapeutic targets and optimize intervention strategies.