Clinical and Translational Medicine最新文献

Epigenetics plays a central role in neuropsychiatric disorders, contributing significantly to their complexity and manifestation. Major depressive disorder (MDD) and bipolar disorder (BD) have profound impact on mood, affect and cognition. Emerging evidence suggests that epigenetic modification of genes plays a pivotal role in the pathogenesis of both MDD and BD. Long non-coding RNAs (lncRNA) constitute a heterogeneous class of transcripts and have emerged as crucial regulators of epigenetic processes, offering promising insights into the pathophysiology of various diseases. Despite their limited coding potential, lncRNAs are known to play a critical role in achieving global transcriptomic regulation in a spatiotemporal fashion, especially in complex tissue like the brain. This review aims to discuss the specific dysregulation of lncRNAs so far observed in the brains of MDD and BD patients and understand their mechanistic contributions to the disease pathogenesis.

Key points

Interest in RNA posttranscriptional modifications, particularly 5-methylcytosine (m5C), has surged in recent years. Studies have shown that m5C plays a key role in cellular processes and is closely linked to tumourigenesis. This growing focus emphasises the importance of understanding the diverse impacts of m5C modifications in both normal cellular functions and cancer development. Moreover, strides in methodologies for discerning m5C have facilitated intricate transcriptome cartography of RNA methylation at the solitary nucleotide echelon. This technical progress has fueled a surge in m5C-centric investigations, facilitating further exploration of this RNA modification. This review provides a comprehensive analysis of the oncogenic potential of m5C RNA modification, elucidating the precise molecular mechanisms driving its role in cancer development. It consolidates current knowledge regarding the biological consequences of m5C RNA modification in tumour cells. Understanding the role of methylation-related processes in tumourigenesis shows promise for advancing cancer diagnosis and therapeutic strategies.

Highlights

Mesenchymal stem cell therapy involves the secretion of various factors to regulate the local microenvironment in various of diseases. This therapy offers hope for treating acute myocardial infarction (MI), which poses a serious threat to human health. However, challenges such as low paracrine efficiency and poor cell survival persist due to the harsh post-infarction conditions, such as hypoxia. Recently, enhanced cell therapy, in which vascular endothelial growth factor A (VEGFA) and basic fibroblast growth factor (bFGF) are used as therapeutic agents to limit myocardial injury and simultaneously induce neovascularisation, has been recognised as a promising new strategy to improve the efficacy of cell therapy. Chemically synthetic modified messenger RNA (modRNA), a novel protein expression technology, enables safe, rapid, efficient and pulsatile expression of target proteins in vivo and in vitro settings. It has been widely applied in the fields of vaccine research and tissue regeneration. In this study, human adipose-derived stem cells (hADSCs) were transfected with VEGFA and bFGF modRNA to transiently overexpress these proteins before transplantation. This modification enhanced the paracrine effect of transplanted hADSCs and promoted stability in the vascular network at the transplantation site. Overexpression of VEGFA and bFGF in hADSCs not only inhibited apoptosis but also reduced ventricular remodelling and improved cardiac function and left ventricular conduction. Overall, the additive effects of VEGFA modRNA, bFGF modRNA and hADSCs hold promise for comprehensive cardiac repair post-MI and show substantial potential for treating ischemic heart diseases.

Key points

Background

Contrast-induced acute kidney injury (CI-AKI) continues to pose a pressing clinical challenge during invasive cardiovascular procedures due to the limited availability of preventative strategies. We aimed to demonstrate that irisin, a myokine induced by exercise, protects against CI-AKI by inhibiting the cGAS-STING inflammatory pathway.

Methods and results

We explored the relationship between serum irisin levels and CI-AKI incidence in patients administered the contrast media iohexol. Notably, lower serum irisin levels were strongly associated with an increased incidence of CI-AKI following contrast media administration. To establish a causal link between serum irisin levels and CI-AKI, we utilised a mouse model that simulates exercise by overexpressing muscle-specific PGC-1α. This approach showed a significant reduction in tubular injury and mitochondrial dysfunction induced by iohexol via cGAS/STING suppression, thereby diminishing inflammation. Mechanistically, irisin was found to inhibit the activation of cGAS/STING, preventing double stranded DNA (dsDNA) leakage and reducing inflammation in tubular epithelial cells (TECs). Pharmacological inhibition of STING further corroborated these observations. Moreover, we identified integrin complex αV/β5 as the irisin receptor on TECs, which is essential for irisin-mediated suppression of cGAS-STING signalling and resolution of inflammation.

Conclusions

Our data position irisin as a crucial factor in muscle‒kidney crosstalk, inhibiting cGAS-STING signalling and preventing dsDNA leakage via integrin αV/β5 in TECs, thus mitigating tubular injury and inflammation. These data underscore the potential of irisin as both a predictive biomarker for CI-AKI and a promising candidate for preventative strategies against CI-AKI.

Highlights

Maternal immune activation (MIA) is recognised as a risk factor in the neurodevelopmental disorders. However, the precise molecular pathways through which MIA disrupts neurovascular function remain largely unexplored. Here, we identify a novel MIA-associated brain endothelial piRNA (MIABEPIR) involved in regulating BMEC function and BBB integrity. RNA microarray analysis of foetal brain tissue from MIA-exposed mice revealed significant changes in piRNA expression, including a marked upregulation of MIABEPIR upregulated piRNAs. Immunofluorescence and FISH confirmed that MIABEPIR is localised in the microvascular endothelial cells of the brain. MIABEPIR overexpression enhances BMEC proliferation and angiogenesis but disrupts BBB integrity. In vivo, intracranial administration of lentiviral MIABEPIR in foetal mice resulted in marked BBB disruption. Mechanistically, we identified DAPK2 as a downstream target of MIABEPIR, leading to its downregulation. This suppression of DAPK2 inhibits autophagy in BMECs, suggesting that MIABEPIR modulates endothelial cell autophagy through the DAPK2 pathway. Our findings reveal a novel piRNA-mediated regulatory mechanism in neurovascular function during MIA and highlight MIABEPIR's role in MIA-induced neurodevelopmental abnormalities. Targeting the MIABEPIR-DAPK2 axis represents a potential therapeutic strategy for addressing neurovascular dysfunction in neurodevelopmental disorders associated with maternal immune stress.