mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity

Wang, Wenyuan; Wan-Qing, Yi; Qi-Yun, Hu; Yu-Si, Liu; Qian, Shaojie; Liu, Jintao; Mao, Hui; Cai, Fang; Hui-Ling, Yang

doi:10.1007/s12035-022-03070-4

Cited by 10 publications

(8 citation statements)

References 58 publications

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“…In addition, because endotoxemia is also promoted by pyroptosis, which is characterized by the activation of inflammasomes and caspases as well as the creation of cell membrane pores (1,3), we validated the role of RPTOR in pyroptosis of LPS-treated HUVECs. RPTOR is one of the genes involved in mTOR pathways (34), and it has been found that dysregulation of mTOR activity is involved in pyroptotic cell death (35), suggesting that RPTOR can affect pyroptosis. As our experimental results revealed, the knockdown of RPTOR reduced levels of TNF-α, IL-1β, and IL-6, indicating that overexpressed RPTOR promoted inflammation.…”

Section: Discussionmentioning

confidence: 99%

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

Wu,

Yu,

Wang

et al. 2023

Shock

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Objective Autophagy elevation in endotoxemia plays a protective role by negatively regulating the pyroptosis of vascular endothelial cells, but the molecular mechanisms are still poorly understood. The present study aimed to identify the mechanism underlying autophagy and pyroptosis in endotoxemia. Methods Bioinformatics analysis and whole-gene transcriptome sequencing prediction were used to identify the endotoxemia-related lncRNA-miRNA-mRNA axis of interest. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) to mimic the inflammatory environment encountered in endotoxemia. Autophagy and pyroptosis of LPS-treated HUVECs were assessed in response to the knockdown of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) /miR-433-3p (miRNA-433-3p) / RPTOR (regulatory associated protein of mTOR). The binding affinity of MALAT1, miR-433-3p, and RPTOR was detected by RNA pull-down and luciferase activity assays. The endothelial cell-specific RPTOR knockout mice were developed and rendered septic using LPS induction to verify the role of RPTOR in autophagy, pyroptosis, and inflammatory response in vivo. Results The in vitro experiments indicated that LPS could stimulate HUVECs to highly express RPTOR, and its knockdown enhanced cellular autophagy and restricted pyroptosis to curb inflammatory responses. Mechanically, MALAT1 is competitively bound to miR-433-3p to release RPTOR expression, thereby promoting pyroptosis and aggravating endotoxemia. In vivo experiments further confirmed that the knockdown of RPTOR activated autophagy and curtailed pyroptosis in septic mice. Conclusion MALAT1 is highly expressed in endotoxemia. MALAT1 promotes RPTOR expression by competitively absorbing miR-433-3p, inhibits LPS-activated HUVEC cell autophagy, promotes cell death, enhances LPS-induced inflammatory activation of vascular endothelial cells, and ultimately promotes the progression of endotoxemia.

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Section: Discussionmentioning

confidence: 99%

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

Wu,

Yu,

Wang

et al. 2023

Shock

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“…DMF plays a role in inhibiting pyroptosis by succinate GSDMD, which prevents the interaction of GSDMD and caspase (Humphries et al, 2020). Rats treated with DSF or NFA exhibited attenuated cognitive impairment caused by sevoflurane neurotoxicity (Wen-Yuan et al, 2022). Inhibition of cytokines also prevents PNDs.…”

Section: Drug Functional Mechanism or Site Function And Effectmentioning

confidence: 99%

“…Once the GSDMD-N-terminal is released, it oligomerizes in the membrane to form pores that permit the release of cytokines, such as IL-1β, and lead to ion flux, such as calcium and potassium, which may further prompt activation of the NLRP3 inflammasome ( Liu et al, 2016 ; Fischer et al, 2021 ). GSDMD-induced pyroptosis contributes to cognitive disorders caused by sevoflurane neurotoxicity ( Wen-Yuan et al, 2022 ). An increasing number of studies have shown that other members of the gasdermin family (GSDMA3, GSDMB ( Zhou et al, 2020 ), GSDMC ( Hou et al, 2020 ), and GSDME ( Rogers et al, 2017 ; Wang Y. et al, 2017 ) contribute to pyroptosis via other caspases or molecules ( Huang et al, 2021 ).…”

Section: Components Of Nlrp3 and Its Mechanismmentioning

confidence: 99%

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

et al. 2023

Front. Aging Neurosci.

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Perioperative neurocognitive disorders (PNDs) are frequent complications associated with cognitive impairment during the perioperative period, including acute postoperative delirium and long-lasting postoperative cognitive dysfunction. There are some risk factors for PNDs, such as age, surgical trauma, anesthetics, and the health of the patient, but the underlying mechanism has not been fully elucidated. Pyroptosis is a form of programmed cell death that is mediated by the gasdermin protein and is involved in cognitive dysfunction disorders. The canonical pathway induced by nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasomes contributes to PNDs, which suggests that targeting NLRP3 inflammasomes may be an effective strategy for the treatment of PNDs. Therefore, inhibiting upstream activators and blocking the assembly of the NLRP3 inflammasome may attenuate PNDs. The present review summarizes recent studies and systematically describes the pathogenesis of NLRP3 activation and regulation and potential therapeutics targeting NLRP3 inflammasomes in PNDs patients.

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“…In addition, NSA and DSF treatment also attenuated the release of DAMPs and subsequent plasma membrane disruption induced by sevoflurane challenge, thereby attenuating the neurotoxicity of sevoflurane in vitro. 328 …”

Section: Pyroptosis and Ndsmentioning

confidence: 99%

Role of pyroptosis in the pathogenesis and treatment of diseases

Jin

Liu

et al. 2023

MedComm

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Programmed cell death (PCD) is regarded as a pathological form of cell death with an intracellular program mediated, which plays a pivotal role in maintaining homeostasis and embryonic development. Pyroptosis is a new paradigm of PCD, which has received increasing attention due to its close association with immunity and disease. Pyroptosis is a form of inflammatory cell death mediated by gasdermin that promotes the release of proinflammatory cytokines and contents induced by inflammasome activation. Recently, increasing evidence in studies shows that pyroptosis has a crucial role in inflammatory conditions like cardiovascular diseases (CVDs), cancer, neurological diseases (NDs), and metabolic diseases (MDs), suggesting that targeting cell death is a potential intervention for the treatment of these inflammatory diseases. Based on this, the review aims to identify the molecular mechanisms and signaling pathways related to pyroptosis activation and summarizes the current insights into the complicated relationship between pyroptosis and multiple human inflammatory diseases (CVDs, cancer, NDs, and MDs). We also discuss a promising novel strategy and method for treating these inflammatory diseases by targeting pyroptosis and focus on the pyroptosis pathway application in clinics.

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mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity

Cited by 10 publications

References 58 publications

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders

Role of pyroptosis in the pathogenesis and treatment of diseases

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