Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis

Bu, Xueshan; Gong, Ping; Zhang, Lei; Song, Wenqin; Hou, Jiabao; Li, Qingwen; Wang, Wei; Xia, Zhongyuan

doi:10.1016/j.neuint.2024.105788

Neurochemistry International

2024

DOI: 10.1016/j.neuint.2024.105788

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Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis

Xueshan Bu,

Ping Gong,

Lei Zhang

et al.

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Cited by 4 publications

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Neuroprotection of celastrol against postoperative cognitive dysfunction through dampening cGAS-STING signaling

Bu,

Guo,

Gao

et al. 2024

Experimental Neurology

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Neuroprotection of celastrol against postoperative cognitive dysfunction through dampening cGAS-STING signaling

Bu,

Guo,

Gao

et al. 2024

Experimental Neurology

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Raptinal: a powerful tool for rapid induction of apoptotic cell death

Smith,

Hergenrother

2024

Cell Death Discov.

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Chemical inducers of apoptosis have been utilized for decades as tools to uncover steps of the apoptotic cascade and to treat various diseases, most notably cancer. While there are several useful compounds available, limitations in potency, universality, or speed of cell death of these pro-apoptotic agents have meant that no single compound is suitable for all (or most) purposes. Raptinal is a recently described small molecule that induces intrinsic pathway apoptosis rapidly and reliably, and consequently, has been utilized in cell culture and whole organisms for a wide range of biological studies. Its distinct mechanism of action complements the current arsenal of cytotoxic compounds, making it useful as a probe for the apoptosis pathway and other cellular processes. The rapid induction of cell death by Raptinal and its widespread commercial availability make it the pro-apoptotic agent of choice for many applications.

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MEF2C Alleviates Postoperative Cognitive Dysfunction by Repressing Ferroptosis

Wang,

Wu,

et al. 2024

CNS Neurosci Ther

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BackgroundFerroptosis, a form of programmed cell death featured by lipid peroxidation, has been proposed as a potential etiology for postoperative cognitive dysfunction (POCD). Myocyte‐specific enhancer factor 2C (MEF2C), a transcription factor expressed in various brain cell types, has been implicated in cognitive disorders. This study sought to ascertain whether MEF2C governs postoperative cognitive capacity by affecting ferroptosis.MethodsTranscriptomic analysis of public data was used to identify MEF2C as a candidate differentially expressed gene in the hippocampus of POCD mice. The POCD mouse model was established via aseptic laparotomy under isoflurane anesthesia after treatment with recombinant adeno‐associated virus 9 (AAV9)‐mediated overexpression of MEF2C and/or the glutathione peroxidase 4 (GPX4) inhibitor RSL3. Cognitive performance, Nissl staining, and ferroptosis‐related parameters were assessed. Dual‐luciferase reporter gene assays and chromatin immunoprecipitation assays were implemented to elucidate the mechanism by which MEF2C transcriptionally activates GPX4.ResultsMEF2C mRNA and protein levels decreased in the mouse hippocampus following anesthesia and surgery. MEF2C overexpression ameliorated postoperative memory decline, hindered lipid peroxidation and iron accumulation, and enhanced antioxidant capacity, which were reversed by RSL3. Additionally, MEF2C was found to directly bind to the Gpx4 promoter and activate its transcription.ConclusionsOur findings suggest that MEF2C may be a promising therapeutic target for POCD through its negative modulation of ferroptosis.

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Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis

Cited by 4 publications

References 54 publications

Neuroprotection of celastrol against postoperative cognitive dysfunction through dampening cGAS-STING signaling

Neuroprotection of celastrol against postoperative cognitive dysfunction through dampening cGAS-STING signaling

Raptinal: a powerful tool for rapid induction of apoptotic cell death

MEF2C Alleviates Postoperative Cognitive Dysfunction by Repressing Ferroptosis

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