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  • Title: The Role of the SIRT1-mTOR Signaling Pathway in Regulating Autophagy in Sevoflurane-Induced Apoptosis of Fetal Rat Brain Neurons.
    Author: Li Y, Xiao C, Tan Y, Jing S.
    Journal: Front Biosci (Landmark Ed); 2024 Sep 20; 29(9):324. PubMed ID: 39344320.
    Abstract:
    BACKGROUND: Isoflurane is a commonly used general anesthetic widely employed in clinical surgeries. Recent studies have indicated that isoflurane might induce negative impacts on the nervous system, notably by triggering neuronal apoptosis. This process is pivotal to the development and emergence of neurological disorders; its misregulation could result in functional deficits and the initiation of diseases within nervous system. However, the potential molecular mechanism of isoflurane on the neuronal apoptosis remains fully unexplored. This study aims to investigate the regulatory role of the sirtuin 1-mechanistic target of rapamycin (SIRT1-mTOR) signaling pathway in autophagy during isoflurane-induced apoptosis of fetal rat brain neuronal cells. METHODS: Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, real-time quantitative polymerase chain reaction (qPCR), and Western blot were utilized to evaluate the apoptotic status of hippocampal tissue cells in fetal mice after sevoflurane exposure. Our further investigation was commenced with flow cytometry, immunofluorescence, qPCR, and Western blot to determine the impact of autophagy on sevoflurane-induced apoptosis in these neurons. On the other hand, we conducted an additional set of analyses, including flow cytometric analysis, qPCR, and Western blot, to further elucidate the neuroprotective potential of autophagy in neural cells of fetal mice subjected to sevoflurane-induced apoptosis. RESULTS: Our findings indicated that a 3% sevoflurane treatment led to a significant rise in apoptosis among fetal rat hippocampal tissue cells and neurons. Levels of apoptosis-associated proteins, cleaved-caspase-3 and Bcl-2 associated X protein (Bax), were found to be markedly higher, coinciding with an enhancement in autophagy as evidenced by increased microtubule-associated proteins 1A/1B-light chain 3 (LC3) and decreased p62 expression. Concurrently, there was a notable up-regulation of sirtuin 1 (SIRT1) and a down-regulation of mechanistic target of rapamycin (mTOR) expression. In conclusion, our research elucidated the pivotal function of cellular autophagy in an apoptosis induced by sevoflurane in fetal rat nerve cells. Through experimental manipulation, we observed that interference with SIRT1 resulted in a reduction of both cleaved-caspase-3 and Bax levels. This intervention also beget a diminished expression of the autophagy-associated factor LC3 and an up-regulation of p62. Furthermore, inhibition against mTOR reversed the effects induced by SIRT1 interference, suggesting a complex interplay amid these regulatory pathways. CONCLUSIONS: SIRT1 possesses a capacity to modulate apoptosis in the hippocampal neurons of fetal rats triggered by sevoflurane, with mTOR functioning as an inhibitory factor within this signaling pathway.
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