High-dose Vitamin C injection ameliorates against sepsis-induced myocardial injury by anti-apoptosis, anti-inflammatory and pro-autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR signaling pathways in rats.

AIMS: This study aimed to evaluate the effects of VC on SIMI in rats. METHODS: In this study, the survival rate of high dose VC for SIMI was evaluated within 7 days. Rats were randomly assigned to three groups: Sham group, CLP group, and high dose VC (500 mg/kg i.v.) group. The animals in each group were treated with drugs for 1 day, 3 days or 5 days, respectively. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6, IL-10 and TNF-α) in serum were measured using ELISA kits. Western blot was used to detect proteins related to apoptosis, inflammation, autophagy, MAPK, NF-κB and PI3K/Akt/mTOR signaling pathways. RESULTS: High dose VC improved the survival rate of SIMI within 7 days. Echocardiography, HE staining and myocardial enzymes showed that high-dose VC relieved SIMI in rats in a time-dependent manner. And compared with CLP group, high-dose VC decreased the expressions of pro-apoptotic proteins, while increased the expression of anti-apoptotic protein. And compared with CLP group, high dose VC decreased phosphorylation levels of Erk1/2, P38, JNK, NF-κB and IKK α/ß in SIMI rats. High dose VC increased the expression of the protein Beclin-1 and LC3-II/LC3-I ratio, whereas decreased the expression of P62 in SIMI rats. Finally, high dose VC attenuated phosphorylation of PI3K, AKT and mTOR compared with the CLP group. SIGNIFICANCE: Our results showed that high dose VC has a good protective effect on SIMI after continuous treatment, which may be mediated by inhibiting apoptosis and inflammatory, and promoting autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR pathway.

Novel insights into the regulatory role of N6-methyladenosine methylation modified autophagy in sepsis.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is characterized by high morbidity and mortality and one of the major diseases that seriously hang over global human health. Autophagy is a crucial regulator in the complicated pathophysiological processes of sepsis. The activation of autophagy is known to be of great significance for protecting sepsis induced organ dysfunction. Recent research has demonstrated that N6-methyladenosine (m6A) methylation is a well-known post-transcriptional RNA modification that controls epigenetic and gene expression as well as a number of biological processes in sepsis. In addition, m6A affects the stability, export, splicing and translation of transcripts involved in the autophagic process. Although it has been suggested that m6A methylation regulates the biological metabolic processes of autophagy and is more frequently seen in the progression of sepsis pathogenesis, the underlying molecular mechanisms of m6A-modified autophagy in sepsis have not been thoroughly elucidated. The present article fills this gap by providing an epigenetic review of the processes of m6A-modified autophagy in sepsis and its potential role in the development of novel therapeutics.