Yu Zhengtao,Xia Ying,Li Jiameng,Jiang Junwen,Li You,Li Youjun,Wang Liu
Background Ischemia/reperfusion (I/R) injury is a severe brain disorder with currently limited effective treatments. This study aims to explore the role of N6-methyladenosine (m6A) modification and associated regulatory factors in I/R to identify potential therapeutic targets. Methods We utilized a middle cerebral artery occlusion (MCAO) rat model and SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to assess m6A levels and investigate the impact of METTL3 overexpression on long non-coding RNA (lncRNA) CRNDE expression. The effects of silencing lncRNA CRNDE on the interaction between YTHDC1 and ATG10 mRNA, as well as the stability of ATG10 mRNA, were evaluated. Additionally, apoptosis rates, pro-inflammatory and anti-inflammatory factor levels, ATG10 expression, and autophagic activity were analyzed to determine the effects of METTL3 . The reverse effects of YTHDC1 overexpression were also examined. Results MCAO rats and OGD/R-treated SH-SY5Y cells exhibited reduced m6A levels. METTL3 overexpression significantly inhibited lncRNA CRNDE expression. Silencing lncRNA CRNDE mitigated OGD/R-induced apoptosis and inflammation in SH-SY5Y cells, while enhancing autophagy and stabilizing ATG10 mRNA. METTL3 overexpression decreased cell apoptosis, reduced the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and increased IL-10 secretion. Furthermore, METTL3 overexpression upregulated ATG10 expression and promoted autophagy. Conversely, lncRNA CRNDE overexpression negated these effects. Conclusion The inhibition of lncRNA CRNDE affects the interaction between YTHDC1 and ATG10 mRNA and stabilizes ATG10 mRNA, mediated by METTL3 overexpression. These findings suggest that targeting lncRNA CRNDE to reduce apoptosis, inhibit inflammation, increase ATG10 expression, and enhance autophagy could offer new therapeutic strategies for I/R injury.
Hydrogen sulfide (H 2 S) is a colorless, toxic, asphyxiant gas. In recent years, industrial accidents involving H 2 S exposure have frequently resulted in fatalities and disabilities. Acute respiratory distress syndrome (ARDS) poses a substantial burden on healthcare systems worldwide. The syndrome's heterogeneity and multifaceted pathogenesis, combined with a paucity of effective treatments, contribute to a persistently high mortality rate, which currently stands at 30–35%. The present study utilized metabolomics, transcriptomics, and CUT&Tag sequencing to explore ARDS pathogenesis, providing insights into its mechanisms and therapeutic targets for its treatment. Serum metabolomics for individuals with H 2 S-induced ARDS identified lactate accumulation as a pivotal metabolic event that mediates changes in H 2 S-induced ARDS biomarkers. Lactate, a potential biomarker of H 2 S-induced ARDS, is associated with a poor prognosis. However, whether elevated lactate directly promotes H 2 S-induced ARDS and the mechanisms underlying this effect remain unclear. Here, we demonstrate that lactate disrupts the alveolar epithelial barrier, thereby facilitating the development of ARDS. Mechanistically, lactate promotes histone H3K18 lactylation at the promoter for ATG10, a gene involved in the process of autophagy, driving its transcription and upregulating autophagy in alveolar epithelial cells, which results in disruption of the epithelial barrier. For rats, the reduction of lactate generation by a glycolytic inhibitor mitigates H 2 S-induced ARDS, as evidenced by attenuated pulmonary edema. Our results show that the lactate-autophagy axis mediates H 2 S-induced ARDS. Therefore, targeting the regulation of lactate production and/or autophagy is a therapeutic strategy for patients with H 2 S-induced ARDS.
危险品化学品经营许可证（带存储）