Effects of DNA methylation and its application in inflammatory bowel disease (Review).

Inflammatory bowel disease (IBD) is marked by persistent inflammation, and its development and progression are linked to environmental, genetic, immune system and gut microbial factors. DNA methylation (DNAm), as one of the protein modifications, is a crucial epigenetic process used by cells to control gene transcription. DNAm is one of the most common areas that has drawn increasing attention recently, with studies revealing that the interleukin (IL)­23/IL­12, wingless­related integration site, IL­6­associated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3 and apoptosis signaling pathways are involved in DNAm and in the pathogenesis of IBD. It has emerged that DNAm­associated genes are involved in perpetuating the persistent inflammation that characterizes a number of diseases, including IBD, providing a novel therapeutic strategy for exploring their treatment. The present review discusses DNAm­associated genes in the pathogenesis of IBD and summarizes their application as possible diagnostic, prognostic and therapeutic biomarkers in IBD. This may provide a reference for the particular form of IBD and its related methylation genes, aiding in clinical decision­making and encouraging therapeutic alternatives.

Protective Effect of CD137 Deficiency against Post-infarction Cardiac Fibrosis and Adverse Cardiac Remodeling via ERK1/2 Signaling Pathways.

Myocardial fibrosis, a common complication of myocardial infarction (MI), is characterized by excessive collagen deposition and can result in impaired cardiac function. The specific role of CD137 in the development of post-MI myocardial fibrosis remains unclear. Thus, this study aimed to elucidate the effects of CD137 signaling using CD137 knockout mice and in vitro experiments. CD137 expression levels progressively increased in the heart following MI, particularly in myofibroblast, which play a key role in fibrosis. Remarkably, CD137 knockout mice exhibited improved cardiac function and reduced fibrosis compared to wild-type mice at day 28 post-MI. The use of Masson's trichrome and picrosirius red staining demonstrated a reduction in the infarct area and collagen volume fraction in CD137 knockout mice. Furthermore, the expression of alpha-smooth muscle actin (α-SMA) and collagen I, key markers of fibrosis, was decreased in heart tissues lacking CD137. In vitro experiments supported these findings, as CD137 depletion attenuated cardiac fibroblast differentiation, and migration, and collagen I synthesis. Additionally, the administration of CD137L recombinant protein further promoted α-SMA expression and collagen I synthesis, suggesting a pro-fibrotic effect. Notably, the application of an inhibitor targeting the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway attenuated the pro-fibrotic effects of CD137L. To conclude, this study provides evidence that CD137 plays a significant role in promoting myocardial fibrosis after MI. Inhibition of CD137 signaling pathways may hold therapeutic potential for mitigating pathological cardiac remodeling and improving post-MI cardiac function.

Exosomes derived from human umbilical cord mesenchymal stem cells regulate lymphangiogenesis via the miR-302d-3p/VEGFR3/AKT axis to ameliorate inflammatory bowel disease.

BACKGROUND: Exosomes released from human umbilical cord mesenchymal stem cell (hucMSC-Ex) have been revealed to hold great potential for the development of new treatment approaches for various diseases, including inflammatory bowel disease (IBD). Lymphatic vessels are vital for IBD development and progression to colorectal cancer (CRC), as an occluded conduit for lymphatic fluid to return to the blood. OBJECTIVE: The mechanism involved remains largely unexplored. Here, we investigate the therapeutic effect of hucMSC-Ex in a mouse model of IBD during the modulation of lymphangiogenesis. METHODS: We established a dextran sulfate sodium (DSS)-induced IBD model in BALB/c mice and observed the influence of hucMSC-Ex on tissue repair, intestinal lymphatic function, changes in lymphangiogenesis, and infiltration of macrophages. We also evaluated the functional changes of human lymphatic endothelial cells (hLECs) in vitro to determine the mechanism by which hucMSC-Ex regulate lymphangiogenesis. Finally, we identified key molecules in hucMSC-Ex by sequencing, database comparison, and cell validation. RESULTS: Results showed that hucMSC-Ex alleviates IBD in mice by improving intestinal lymphatic drainage, inhibiting lymphangiogenesis, and infiltration of macrophages. Mechanistically, the miRNA sequencing results showed that miR-302d-3p was highly expressed in hucMSC-Ex and played an important role in inhibiting lymphangiogenesis by targeting Fms-related receptor tyrosine kinase 4 (FLT4). At the same time, the phosphorylation of AKT was inhibited and vascular endothelial growth factor receptor 3 (VEGFR3) was reduced. CONCLUSION: Collectively, our study suggests that hucMSC-Ex can regulate lymphangiogenesis via the miR-302d-3p/VEGFR3/AKT axis to ameliorate IBD. Our findings identify VEGFR3 as a potential therapeutic target in IBD, where tightly regulated lymphangiogenesis is crucial in its pathogenesis and progression.