Inhibiting EZH2 rescued bupivacaine-induced neuronal apoptosis in spinal cord dorsal root ganglia in mice

Zheng, Jinwei; Chen, Junping; Wu, Guorong; Wu, Chaoshuang; Wang, Ruichun; Wang, Wei

doi:10.1007/s00540-018-2506-8

Cited by 10 publications

(5 citation statements)

References 20 publications

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“…These results indicated that the epigenetic histone posttranscriptional modification plays a significant role in the apoptosis of brain cells in stroke or ischemia/reperfusion injury. This was in conformity with previous studies indicating that the inhibition of EZH2 counteracts neuronal apoptosis in the spinal cord dorsal root ganglia in vivo 45 …”

Section: Discussionsupporting

confidence: 93%

“…This was in conformity with previous studies indicating that the inhibition of EZH2 counteracts neuronal apoptosis in the spinal cord dorsal root ganglia in vivo. 45 In the present study, we provide evidence that EZH2-mediated H3K27me3 is involved in the epigenetic upregulation of PI3K/AKT/ mTOR signaling pathway during ischemic development. Studies reporting the implication of EZH2 in ischemic brain injury are scarce.…”

Section: Discussionsupporting

confidence: 55%

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Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

Chen

Fan

Wu³

et al. 2023

Environmental Toxicology

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BackgroundEpigenetic histone methylation plays a crucial role in cerebral ischemic injury, particularly in the context of ischemic stroke. However, the complete understanding of regulators involved in histone methylation, such as Enhancer of Zeste Homolog 2 (EZH2), along with their functional effects and underlying mechanisms, remains incomplete.MethodsHere, we employed a rat model of MCAO (Middle cerebral artery occlusion) and an OGD (Oxygen‐Glucose Deprivation) model of primary cortical neurons to study the role of EZH2 and H3K27me3 in cerebral ischemia‐reperfusion injury. The infarct volume was measured through TTC staining, while cell apoptosis was detected using TUNEL staining. The mRNA expression levels were quantified through quantitative real‐time polymerase chain reaction (qPCR), whereas protein expressions were evaluated via western blotting and immunofluorescence experiments.ResultsThe expression levels of EZH2 and H3K27me3 were upregulated in OGD; these expression levels were further enhanced by GSK‐J4 but reduced by EPZ‐6438 and AKT inhibitor (LY294002) under OGD conditions. Similar trends were observed for mTOR, AKT, and PI3K while contrasting results were noted for UTX and JMJD3. The phosphorylation levels of mTOR, AKT, and PI3K were activated by OGD, further stimulated by GSK‐J4, but inhibited by EPZ‐6438 and AKT inhibitor. Inhibition of EZH2 or AKT effectively counteracted OGD‐/MCAO‐induced cell apoptosis. Additionally, inhibition of EZH2 or AKT mitigated MCAO‐induced infarct size and neurological deficit in vivo.ConclusionsCollectively, our results demonstrate that EZH2 inhibition exerts a protective effect against ischemic brain injury by modulating the H3K27me3/PI3K/AKT/mTOR signaling pathway. The results provide novel insights into potential therapeutic mechanisms for stroke treatment.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 55%

Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

Chen

Fan

Wu³

et al. 2023

Environmental Toxicology

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“…Both bupivacaine and ropivacaine are long-acting amide LAs. Administration of bupivacaine has been shown to induce neurological damage in a preclinical experimental rodent study [9,10]. Ropivacaine was developed after bupivacaine was noted to be associated with cardiac toxicity [11].…”

Section: Introductionmentioning

confidence: 99%

The role of DRP1 in ropivacaine-induced mitochondrial dysfunction and neurotoxicity

Chen

Yan

Zhang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Ropivacaine is a commonly used local anaesthetic, but its side effects remain largely unknown. In the present study, we investigated the side effects of ropivacaine in human neuronal SH-5Y5Y cells. We show that 0.5% and 1% ropivacaine could cause fission-like mitochondrial morphological changes. Ropivacaine exclusively induces mitochondrial fission protein DRP1, generation of ROS and causes mitochondrial dysfunction including decreasing mitochondrial membrane potential, the activity of cytochrome C oxidase and ATP production. The side effects of ropivacaine appear to be dependent on DRP1 expression as silencing of DRP1 in neuronal cells abolishes ropivacaine-induced morphological changes and mitochondrial dysfunction. Silencing of DRP1 prevents ropivacaine-induced cellular LDH release and cell death. Moreover, DRP1-deficient neuronal cells are resistant to ropivacaine-induced apoptosis and silencing of DRP1 rescues the activity of cytochrome C oxidase and cellular ATP production. Collectively, our data indicate that imbalances in mitochondrial dynamics, mitochondrial dysfunction and cell death resulting from ropivacaine are all dependent on DRP1 expression. Our study provides valuable data to assess the safety of ropivacaine.

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“…The CNC Networks predicted the interaction of numerous differentially expressed lncRNAs with three functional genes, including EZH2, Plod3, and SUV39H1. The inhibition of EZH2 activity was shown to suppress bupivacaine-induced neuronal apoptosis in spinal cord dorsal root ganglia [ 32 ]. Overexpression of the PLOD3 gene, which encodes a lysyl hydroxylase, significantly promotes the progression of gliomas and is associated with a poor prognosis in glioma patients [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Alteration of long non-coding RNAs and mRNAs expression profiles by compound heterozygous ASXL3 mutations in the mouse brain

Zhang

et al. 2021

Bioengineered

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Compound mutations in the additional sex combs-like 3 (ASXL3) gene greatly impact the expression of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in mouse myocardial tissues. Little is known about ASXL3 mutation effects on lncRNAs and mRNAs expression in the cerebrum and cerebellum. This study aims to clarify this point using quantitative real-time polymerase chain reaction and Western blotting. Transcriptome analysis based on RNA-seq followed by bioinformatics analysis were used to compare lncRNA and mRNA expression profiles. Cell proliferation, cell cycle progression, and apoptosis were evaluated after silencing of ASXL3 expression using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium method and flow cytometry. Results showed that ASXL3 gene expression was decreased in the cerebrum and cerebellum of mice with ASXL3 P723R*P1817A mutations. We identified 319 lncRNAs and 252 mRNAs differentially expressed in the cerebrum of ASXL3 P723R*P1817A mutant mice. In the cerebellum of ASXL3 P723R*P1817A mutant mice, 5330 lncRNAs and 2204 mRNAs were differentially expressed. Differentially expressed lncRNAs and mRNAs were widely distributed across the mouse genome and were associated with various biological processes and pathways. ASXL3 silencing by siRNA transfection affected the proliferation, cell cycle progression, and apoptosis of neural cells. Therefore, the ASXL3 P723R*P1817A mutations greatly modify the lncRNA and mRNA expression profiles in the mouse cerebrum and cerebellum.

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Inhibiting EZH2 rescued bupivacaine-induced neuronal apoptosis in spinal cord dorsal root ganglia in mice

Abstract: EZH2 is upregulated, whereas inhibiting EZH2 exerted rescuing effect in anesthetics (bupivacaine)-induced spinal cord DRG. The possible downstream target of EZH2 inhibition may interact with caspase and TrkC signaling pathways.

Cited by 10 publications

References 20 publications

Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

Histone methyltransferase enzyme enhancer of zeste homolog 2 counteracts ischemic brain injury via H3K27me3‐mediated regulation of PI3K/AKT/mTOR signaling pathway

The role of DRP1 in ropivacaine-induced mitochondrial dysfunction and neurotoxicity

Alteration of long non-coding RNAs and mRNAs expression profiles by compound heterozygous ASXL3 mutations in the mouse brain

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