ACSL4 contributes to sevoflurane-induced ferroptotic neuronal death in SH-SY5Y cells via the 5' AMP-activated protein kinase/ mammalian target of rapamycin pathway

Cheng, Lei; Zhu, Xiaodan; Liu, Yang; Zhu, Kai; Kuang, Lin; Li, Fujun

doi:10.21037/atm-21-4249

Cited by 23 publications

(14 citation statements)

References 36 publications

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“…Ferroptosis in neuronal cells was associated with many diseases in CNS, such as Alzheimer's disease [5,6], epilepsy [7], and neonatal brain injury [8]. Recently, several studies focused on sevoflurane anesthesia-induced cognitive impairment also found the involvement of ferroptosis in neuronal cells [9][10][11][12]. In 2020, Wu et al reported that sevoflurane anesthesia contributed iron overload and ferroptosis in hippocampal neurons, which may be activated by NMDAR-RASD1 signaling via DMT1 action [9].…”

Section: Introductionmentioning

confidence: 99%

“…In 2020, Wu et al reported that sevoflurane anesthesia contributed iron overload and ferroptosis in hippocampal neurons, which may be activated by NMDAR-RASD1 signaling via DMT1 action [ 9 ]. Cheng et al found sevoflurane-induced ferroptotic neuronal death in SH-SY5Y cells, which was associated with the involvement of ACSL4 [ 10 ]. In addition, ferroptosis modulated sevoflurane-induced cognitive impairment through interaction between Mind bomb-2 (Mib2) and glutathione peroxidase 4 (Gpx4) [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods. In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results. A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion. Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…In addition, the degenerative neurological changes associated with aging make the elderly more susceptible to multifactorial stimulation of cognitive decline in the perioperative period, which can also be considered degenerative neurotoxicity. New insights suggest that ferroptosis is involved in the pathology of postoperative cognitive dysfunction [ 101 , 102 ]. The evidence from experimental studies to date is summarized in Table 1 .…”

Section: Evidence For Attenuation Of Developmental and Degenerative N...mentioning

confidence: 99%

“…Furthermore, it was proposed that silencing of ACSL4 attenuated sevoflurane-induced ferroptosis by activating the AMPK/mTOR signaling pathway. Transfection of si-ACSL4 eliminated the inhibition of SH-SY5Y cell viability by sevoflurane [ 102 ]. In recent years, it was suggested that the E3 ubiquitin-protein ligase Mind bomb-2 (MIB2) could be involved in regulating neuronal function.…”

Section: Evidence For Attenuation Of Developmental and Degenerative N...mentioning

confidence: 99%

Ferroptosis is involved in regulating perioperative neurocognitive disorders: emerging perspectives

Song

Xue

et al. 2022

J Neuroinflammation

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Since the twenty-first century, the development of technological advances in anesthesia and surgery has brought benefits to human health. However, the adverse neurological effects of perioperative-related factors (e.g., surgical trauma, anesthesia, etc.) as stressors cannot be ignored as well. The nervous system appears to be more “fragile” and vulnerable to damage in developing and aging individuals. Ferroptosis is a novel form of programmed cell death proposed in 2012. In recent years, the regulation of ferroptosis to treat cancer, immune system disorders, and neurodegenerative diseases have seen an unprecedented surge of interest. The association of ferroptosis with perioperative neurocognitive disorders has also received much attention. Cognitive impairment can not only affect the individual’s quality of life, but also impose a burden on the family and society. Therefore, the search for effective preventive and therapeutic methods to alleviate cognitive impairment caused by perioperative-related factors is a challenge that needs to be urgently addressed. In our review, we first briefly describe the connection between iron accumulation in neurons and impairment of brain function during development and aging. It is followed by a review of the pathways of ferroptosis, mainly including iron metabolism, amino acid metabolism, and lipid metabolism pathway. Furthermore, we analyze the connection between ferroptosis and perioperative-related factors. The surgery itself, general anesthetic drugs, and many other relevant factors in the perioperative period may affect neuronal iron homeostasis. Finally, we summarize the experimental evidence for ameliorating developmental and degenerative neurotoxicity by modulating ferroptosis. The suppression of ferroptosis seems to provide the possibility to prevent and improve perioperative neurocognitive impairment.

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“…ACSL4 is also involved in Sev-induced neuronal ferroptosis. Sev-induced ferroptosis is inhibited by ACSL4 downregulation through the 5′ AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signalling pathway ( Cheng et al, 2021 ). Therefore, targeting ACSL4 may be a potential therapeutic strategy to alleviate Sev-induced POCD.…”

Section: The Effect Of Anaesthetics On Ferroptosismentioning

confidence: 99%

The effect of narcotics on ferroptosis-related molecular mechanisms and signalling pathways

Zeng

Yang

et al. 2022

Front. Pharmacol.

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Ferroptosis is a novel programmed cell death form characterized by iron-mediated reactive oxygen species-induced lipid peroxidation and subsequent cell damage that is distinct from apoptosis, necroptosis, pyroptosis, and autophagy. Most studies on ferroptosis are based on its function and mechanism, but there have been relatively few studies on the effects of drugs, especially anaesthetics, on ferroptosis. Therefore, we summarized the recent literature on the effects of anaesthetics on ferroptosis to understand the underlying mechanism. In particular, we focused on the targets of various anaesthetics in different mechanisms of ferroptosis and the effects of ferroptosis induction or inhibition by narcotics on various diseases. The aims of this review are to provide a relatively reasonable drug regimen for clinicians, to explore potential ferroptosis protection drugs and targets, to reduce perioperative complications and to improve the postoperative performance of patients, especially those who are critically ill.

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ACSL4 contributes to sevoflurane-induced ferroptotic neuronal death in SH-SY5Y cells via the 5' AMP-activated protein kinase/ mammalian target of rapamycin pathway

Cited by 23 publications

References 36 publications

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Ferroptosis is involved in regulating perioperative neurocognitive disorders: emerging perspectives

The effect of narcotics on ferroptosis-related molecular mechanisms and signalling pathways

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