Ac-FLTD-CMK inhibits pyroptosis and exerts neuroprotective effect in a mice model of traumatic brain injury

Wang, Pengfei; Pan, Baogen; Tian, Jie; Yang, Lei; Chen, Zeshang; Yang, Lijun; Fan, Zhimin

doi:10.1097/wnr.0000000000001580

Cited by 13 publications

(6 citation statements)

References 36 publications

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“…administered with STING inhibitor C-176 (5 mg/kg, Med Chem Express). For pyroptosis intervention, pyroptosis inhibitor Ac-FLTD-CMK (10 mg/kg) was administered as described previously 44 . In some experiments, septic mice model was established in neutrophil-specific NAT10 over-expression (MRP8Cre/Rosa26-loxP-stop-loxP-NAT10) or control mice (Rosa26-loxP-stop-loxP-NAT10).…”

Section: Methodsmentioning

confidence: 99%

NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway

et al. 2022

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Emerging evidence suggests that pyroptosis is involved in sepsis. However, the role of neutrophil pyroptosis in sepsis and the mechanisms remains elusive. We find that N-acetyltransferase 10 (NAT10), an acetyltransferase responsible for the N4-acetylation of Cytidine (ac4C) in mRNA, is significantly downregulated in neutrophils from septic mice. Neutrophil-specific over-expression of NAT10 improves the survival and ameliorates lung injury in septic mice by inhibiting neutrophil pyroptosis. Notably, UNC-52-like kinase 1 (ULK1) is identified as the target of NAT10 in neutrophils. The decreased expression of NAT10 resultes in the decay of ULK1 transcripts and therefore the reduced expression of ULK1. As a regulator of STING phosphorylation, the loss of ULK1 enhances the activation of STING-IRF3 signaling and subsequently the elevated pyroptosis-inducing NLRP3 inflammasome in neutrophils. While over-expression of NAT10 restrains pyroptosis in neutrophils as well as septic lethality in mice by reversing the ULK1-STING-NLRP3 axis. The decreased expression of NAT10 are also observed in sepsis patients and its correlation with clinical severity is found. Collectively, our findings disclose that NAT10 is a negative regulator of neutrophil pyroptosis and its downregulation contributes to the progress of sepsis by exacerbating pyroptosis via the ULK1-STING-NLRP3 axis, therefore revealing a potential therapeutic target for sepsis.

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Section: Methodsmentioning

confidence: 99%

NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway

et al. 2022

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“…The cleavage of GSDMD after combining with Caspase-1 is a key step in pyroptosis [15]. It has been shown that directly inhibiting or blocking the cleavage of GSDMD can significantly inhibit cell pyroptosis and improve neurobehavioral function, which can help preserve brain function [62][63][64]. As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells protect against TBI-induced pyroptosis in vivo and in vitro through TSG-6

Feng

Hua

et al. 2022

Cell Commun Signal

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Background Pyroptosis, especially microglial pyroptosis, may play an important role in central nervous system pathologies, including traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs), such as human umbilical cord MSCs (hUMSCs), has been a focus of brain injury treatment. Recently, MSCs have been found to play a role in many diseases by regulating the pyroptosis pathway. However, the effect of MSC transplantation on pyroptosis following TBI remains unknown. Tumor necrosis factor α stimulated gene 6/protein (TSG-6), a potent anti-inflammatory factor expressed in many cell types including MSCs, plays an anti-inflammatory role in many diseases; however, the effect of TSG-6 secreted by MSCs on pyroptosis remains unclear. Methods Mice were subjected to controlled cortical impact injury in vivo. To assess the time course of pyroptosis after TBI, brains of TBI mice were collected at different time points. To study the effect of TSG-6 secreted by hUMSCs in regulating pyroptosis, normal hUMSCs, sh-TSG-6 hUMSCs, or different concentrations of rmTSG-6 were injected intracerebroventricularly into mice 4 h after TBI. Neurological deficits, double immunofluorescence staining, presence of inflammatory factors, cell apoptosis, and pyroptosis were assessed. In vitro, we investigated the anti-pyroptosis effects of hUMSCs and TSG-6 in a lipopolysaccharide/ATP-induced BV2 microglial pyroptosis model. Results In TBI mice, the co-localization of Iba-1 (marking microglia/macrophages) with NLRP3/Caspase-1 p20/GSDMD was distinctly observed at 48 h. In vivo, hUMSC transplantation or treatment with rmTSG-6 in TBI mice significantly improved neurological deficits, reduced inflammatory cytokine expression, and inhibited both NLRP3/Caspase-1 p20/GSDMD expression and microglial pyroptosis in the cerebral cortices of TBI mice. However, the therapeutic effect of hUMSCs on TBI mice was reduced by the inhibition of TSG-6 expression in hUMSCs. In vitro, lipopolysaccharide/ATP-induced BV2 microglial pyroptosis was inhibited by co-culture with hUMSCs or with rmTSG-6. However, the inhibitory effect of hUMSCs on BV2 microglial pyroptosis was significantly reduced by TSG-6-shRNA transfection. Conclusion In TBI mice, microglial pyroptosis was observed. Both in vivo and in vitro, hUMSCs inhibited pyroptosis, particularly microglial pyroptosis, by regulating the NLRP3/Caspase-1/GSDMD signaling pathway via TSG-6.

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“…It has con rmed that downregulated. CASP3 expression could reduce LDH release and attenuate brain edema and blood-brain barrier damage (Wang et al 2021). IL1B played a myriad of effects such as neuronal proliferation, differentiation, apoptosis, and long-term potentiation in the brain (Tsai et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology-based and molecular docking prediction of the active ingredients and mechanism of the herb pair of Huangqi and Taoren for application in ischemic brain injury

Tian

Liang

et al. 2022

Preprint

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The traditional Chinese herb pair of Huangqi (HQ) and Taoren (TR) for the treatment of ischemic brain injury (IBI). However, the mechanism of action of HQ and TR for treating IBI still remains unclear. Network pharmacology was adopted to detect the active components of DL and TR. The key targets and signaling pathways in the treatment of IBI were predicted, and the key ingredients and targets were screened for molecular docking. In this study, we identified 27 active components from the herb pair of DL and TR, predicted to act on IBI-associated targets by network pharmacology. PPI network demonstrated that 36 proteins might serve as the key targets of DL and HQ for the treatment of IBI. GO and KEGG pathway enrichment analyzes indicated that the effects of DL and HQ are mediated by genes related to inflammation and apoptosis as well as the HIF-1α, lipid and atherosclerosis pathways. We also had transcription factors and miRNAs analysis of hub genes. Molecular docking revealed good binding ability between the active compounds and screened targets. We comprehensively illustrated the active ingredients, potential targets, and molecular mechanism of the herb pair of HQ and TR treat IBI.

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Ac-FLTD-CMK inhibits pyroptosis and exerts neuroprotective effect in a mice model of traumatic brain injury

Cited by 13 publications

References 36 publications

NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway

NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway

Mesenchymal stem cells protect against TBI-induced pyroptosis in vivo and in vitro through TSG-6

Network pharmacology-based and molecular docking prediction of the active ingredients and mechanism of the herb pair of Huangqi and Taoren for application in ischemic brain injury

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