Journal of Translational Medicine最新文献

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.

Background: Peripheral nerve injury (PNI) is a public health problem that can lead to sensory and motor deficits as well as neuropathic pain and secondary lesions. We explored the effects of the combination of MaR1 and NGF on sciatic nerve regeneration, reduction of neuropathic pain, and anti-inflammation, and further elucidated the associated molecular mechanisms.

Methods: After treatment of PC12 (adrenal pheochromocytoma cells) cells with NGF, MaR1 and H₂O₂, changes in proliferation were detected by CCK8; cell migration ability was detected by Transwell; reactive oxygen species (ROS) and apoptosis were detected by flow cytometry; and the mRNA expression of the inflammatory factors IL-1β, IL-6, and TNF-α was detected by qRT-PCR. Western blot detected the protein expression of β-catenin, P62, GSK-3β, LC3B, NF200, S100, MBP; Immunofluorescence analysis of LC3B expression; During recovery experiments, observe changes following treatment with GSK-3β activators and the autophagy agonist rapamycin. PNI model was constructed using 6-week-old male SD rats, NGF, MaR1 or saline was injected locally, and the drug was administered 3 times on alternate days after surgery, sciatic nerve function index analysis and muscle atrophy test were performed after surgery; the gastrocnemius muscle wet weight ratio and HE staining were observed after the samples were taken after surgery, and NF200, S100, MBP, β-catenin, and P62 were detected by Western blot, GSK-3β, LC3B levels; the expression of NF200, β-catenin, P62, GSK-3β, LC3B was detected by immunohistochemistry.

Results: NGF and MaR1 were non-toxic and the combination of NGF and MaR1 increased the proliferation and migration of PC12 cells, reduced H₂O₂ induced ROS production, inhibited apoptosis, and had a significant anti-inflammatory effect. In vivo studies showed that MaR1 and NGF combined could more effectively promote nerve repair and recovery of sensory and motor functions in SD rats, and reduce gastrocnemius muscle atrophy.The combination of MaR1 and NGF inhibited autophagy through GSK-3β/β-catenin signaling pathway to regulate the growth and repair of sciatic nerve. And the GSK-3β agonist DIF-3 and the autophagy activator rapamycin antagonize this effect.

Conclusion: The combination of MaR1 and NGF promotes sciatic nerve repair and motor function recovery and reduces local inflammation by inhibiting autophagy through the GSK-3β/β-catenin pathway.