Aberrant epigenetic regulation of microRNAs and their targets contributes to colorectal cancer (CRC) progression. This study examined the methylation-dependent regulation of the miR-124-KITENIN axis and its clinical significance in CRC. Site‑specific hypermethylation within the KITENIN (VANGL1) locus, particularly at cg00819310, was associated with poorer patient survival. miR-124, a direct negative regulator of KITENIN, was frequently hypermethylated and transcriptionally silenced, leading to KITENIN upregulation. Treatment with 5-aza-2'-deoxycytidine restored miR-124 expression and reduced KITENIN levels in CRC cells. These results demonstrate that miR-124 silencing enhances KITENIN activation and CRC progression, supporting miR-124 methylation as a potential prognostic and therapeutic target.
Exosomes are nano-sized extracellular vesicles loaded with bioactive cargo that mediate intercellular communication. Their emerging role in tissue regeneration has garnered increasing attention, especially in the context of peripheral nerve injury (PNI), which poses a significant therapeutic challenge. Although many studies have explored exosome-based therapies for PNI, the findings are often fragmented and lack a comprehensive synthesis. This systematic review aims to synthesize the current evidence and elucidate the molecular mechanisms through which exosomes contribute to neural regeneration. This systematic review, conducted in accordance with PRISMA 2020 guidelines, included 33 eligible studies identified through Scopus, ScienceDirect, PubMed, and Google Scholar. Exosomes derived from diverse cellular sources were assessed for their capacity to enhance repair outcomes. Reported cargo, including miRNAs and neurotrophic factors, has been shown to activate key signaling pathways that promote neurite outgrowth, modulate Schwann cell and immune responses, stimulate angiogenesis, and activate perineurial cells. By orchestrating these processes, exosomes emerge as a promising therapeutic strategy to enhance nerve regeneration and functional recovery.
Cardiac fibrosis is a major driver of heart failure and a key therapeutic target. Here, we demonstrated the role of atonal homologue 8 (ATOH8) in the modulation of cardiac fibrosis in heart failure. The expression of ATOH8 was significantly reduced in patients with heart failure and in the left ventricular tissues of model mice. ATOH8 silencing resulted in the worsening of fibrosis, and adenovirus- induced overexpression of ATOH8 attenuated the progression of cardiac fibrosis under in vitro conditions. RNA sequencing analysis demonstrated that ATOH8 potentially influences cardiac fibrosis by modulating the TGF-/Smad signaling pathway. This was verified through ATOH8 silencing experiments, which showed a marked reduction in the expression of Smad7-a known inhibitor of fibrosis. Further investigation into the molecular mechanisms via immunoprecipitation mass spectrometry indicated that ATOH8 can directly bind to the transcription factor RUNX2, which was found to directly interact with the promoter region of Smad7 to suppress its expression. Accordingly, ATOH8 silencing was found to enhance RUNX2-mediated transcriptional repression of Smad7. The findings collectively imply that ATOH8 attenuates cardiac fibrosis through the RUNX2/Smad7 axis, although interactions with other fibrotic proteins need to be explored further. Through in vivo experiments in model mice of heart failure, we were able to demonstrate that the targeted overexpression of ATOH8 in fibroblasts via adeno-associated virus-9 carrying periostin significantly alleviated cardiac fibrosis and dysfunction induced by transverse aortic constriction surgery. Thus, the findings presented here indicate that ATOH8 potentially represents a novel biomarker and therapeutic target for the attenuation of cardiac fibrosis.
Peripheral nerve injury (PNI) causes rapid disruption of neuromuscular connectivity, leading to sarcopenia characterized by muscle wasting, mitochondrial dysfunction, and metabolic imbalance. Although calcium dysregulation and aberrant AMPK/mTOR signaling are known contributors, the molecular cascade linking nerve injury to muscle degeneration remains incompletely understood. This review explores pharmacological and molecular strategies to restore neuromuscular integrity after PNI. We focus on agents such as 4-aminopyridine (4-AP), a potassium channel blocker that enhances nerve conduction, and clemastine, an antihistamine that promotes Schwann cell-mediated remyelination. These compounds represent a potential dual approach to accelerating nerve repair while maintaining muscle viability. We also explore muscle-centered molecular strategies, focusing on pathways such as Forkhead box protein O (FOXO), Glycogen synthase kinase 3 beta (GSK-3β), signal transducer and activator of transcription 3 (STAT3), and TGF-β/Smad, which govern the balance between protein synthesis and degradation. Of note, most current studies suggest that phytochemicals derived from marine sources, including seaweed, may attenuate denervation-induced catabolism by modulating FOXO signaling and suppressing E3 ubiquitin ligase activity. Additionally, we highlight the critical crosstalk between motor neurons and skeletal muscle, mediated by neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Neurotrophin-3 (NT-3), which support both neuromuscular junction stability and axonal regrowth. By integrating insights from nerve biology and muscle physiology, this review outlines a therapeutic framework that targets both nerve regeneration and muscle preservation, an approach that effectively addresses nerve injury-induced sarcopenia effectively.
