Mild hypothermia alleviates diabetes aggravated cerebral ischemic injury via activating autophagy and inhibiting pyroptosis

Tu, Yanling; Guo, Cen; Song, Feifei; Huo, Yajing; Yang, Geng; Guo, Mingwei; Bao, Haifeng; Wu, Xuqing; Fan, Wei

doi:10.1016/j.brainresbull.2019.05.003

Cited by 51 publications

(33 citation statements)

References 34 publications

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“…Thereafter, these pores dissipate cellular ionic gradients, which then cause water influx, cell swelling, eventual osmotic lysis, and release of inflammatory intracellular contents [12]. Pyroptosis has been demonstrated to occupy a crucial place in nerve cell death after cerebral ischemic injury [7,10,46]. Analogously, our study observed an upregulated expression of full-length GSDMD and its N-terminus cleavage product via NF-κB signal-primed inflammasome cascades in the acute phase of cerebral ischemia.…”

Section: Discussionsupporting

confidence: 71%

Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

Sun

Peng

et al. 2020

J Neuroinflammation

115

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Background Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemic stroke. NLRP3 inflammasome, involved in the regulation of inflammatory cascade, can simultaneously lead to GSDMD-executed pyroptosis in cerebral ischemia. Low-density lipoprotein receptor (LDLR), responsible for cholesterol uptake, was noted to exert potential anti-inflammatory bioactivities. Nevertheless, the role of LDLR in neuroinflammation mobilized by cerebral ischemia/reperfusion (I/R) has not been investigated. Methods Ischemic stroke mice model was accomplished by middle cerebral artery occlusion. Oxygen-glucose deprivation was employed after primary cortical neuron was extracted and cultured. A pharmacological inhibitor of NLRP3 (CY-09) was administered to suppress NLPR3 activation. Histological and biochemical analysis were performed to assess the neuronal death both in vitro and in vivo. In addition, neurological deficits and behavioral deterioration were evaluated in mice. Results The expression of LDLR was downregulated following cerebral I/R injury. Genetic knockout of Ldlr enhanced caspase-1-dependent cleavage of GSDMD and resulted in severe neuronal pyroptosis. LDLR deficiency contributed to excessive NLRP3-mediated maturation and release of IL-1β and IL-18 under in vitro and in vivo ischemic conditions. These influences ultimately led to aggravated neurological deficits and long-term cognitive dysfunction. Blockade of NLRP3 substantially retarded neuronal pyroptosis in Ldlr−/− mice and cultured Ldlr−/− neuron after experimental stroke. Conclusions These results demonstrated that LDLR modulates NLRP3-mediated neuronal pyroptosis and neuroinflammation following ischemic stroke. Our findings characterize a novel role for LDLR as a potential therapeutic target in neuroinflammatory responses to acute cerebral ischemic injury.

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Section: Discussionsupporting

confidence: 71%

Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

Sun

Peng

et al. 2020

J Neuroinflammation

115

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“…Mild hypothermia (MH) exerts neuroprotective effects against cerebral ischemia. It was previously reported that MH reduces brain hemorrhage and blood-brain barrier disruption after stroke (7), and that it may alleviate cerebral ischemic injury in diabetic patients through promoting autophagy and inhibiting pyroptosis (8). Researchers also demonstrated that inhibition of Notch3 and Notch4 signaling is involved in the protective effect of MH against cerebral ischemic injury (9).…”

Section: Introductionmentioning

confidence: 96%

Protective effects of combined treatment with mild hypothermia and edaravone against cerebral ischemia/reperfusion injury via oxidative stress and Nrf2 pathway regulation

Wang

et al. 2020

Int J Oncol

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Mild hypothermia (MH) and edaravone (EDA) exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. However, whether MH and EDA exert synergistic effects against cerebral I/R injury remains unknown. The aim of the present study was to investigate the effects and mechanism of action of MH in combination with EDA in cerebral I/R injury. A rat cerebral I/R injury model was constructed by middle cerebral artery occlusion (MCAO) followed by reperfusion, and the mice were treated by MH, EDA or the inhibitor of the Nrf2 signaling pathway brusatol (Bru). It was observed that mice treated by MCAO had higher neurological deficit scores and oxidative stress levels, and low spatial learning and memory capacity; moreover, the CA1 region of the hippocampi of the mice exhibited reduced neuronal density and viability, and reduced mitochondrial dysfunction. However, MH in combination with EDA reversed the effects of MCAO, which were blocked by Bru injection. The levels of glutathione (GSH), GSH peroxidase, catalase and superoxide dismutase in rat ischemic hemisphere tissues were reduced by Bru. Western blotting demonstrated that the combined treatment with MH and EDA promoted the nuclear localization of Nrf2, and increased the levels of NAD(P)H quinone oxidoreductase and heme oxygenase (HO)-1. In conclusion, MH combined with EDA exerted synergistic neuroprotective effects against cerebral I/R injury involving changes in the Nrf2/HO-1 pathway.

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“…Pyroptosis is a form of lytic programmed cell death, which detects cell swelling, resulting in the release of proin ammatory cytokines (IL-1β and IL-18) 21 . Tu et al revealed that mild hypothermia alleviates ischemic injury via inhibiting pyroptosis 22 . Zi et al showed that sirtuin (SIRT)6 attenuated triggering receptor expressed on myeloid cells-1 (TREM)-1-mediated pyroptosis and EC in ammation in acute myocardial infarction 23 .…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor EB Alleviates Endothelial Cell Inflammation Through NLRP3 Inflammasome-Mediated Cell Pyroptosis in Atherosclerosis

Guo¹,

Hu²,

Sha³

et al. 2020

Preprint

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BackgroundIncreasing evidence suggests that transcription factor EB (TFEB) inhibits inflammation in endothelial cell (ECs) and reduces development of atherosclerosis. However, little is known about the mechanism of action of TFEB on inflammation in atherosclerosis (AS).MethodsThe levels of TFEB, NLRP3, VCAM-1, ICAM-1, E-selectin, MCP-1, cleaved caspase-1, IL-1β and IL-18 in ECs were examined by immunoblotting, quantitative real time-polymerase chain reaction (qRT-PCR) , Enzyme-linked immunosorbent assay. The LDH activity were examined by LDH assay. TUNEL-positive cell were examined by TUNEL assay. The relationship between TFEB and NLRP3 were examined by immunofluorescence and coimmunoprecipitation. The effects of TFEB on atherosclerotic lesions by hematoxylin and eosin, TUNEL and collagen staining in the aortic valve of ApoE-/- mice fed a high fat diet (HFD).ResultsHere, we report that H2O2-induced cell pyroptosis and inflammatory response were mainly due to nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation. The nuclear protein TFEB was significantly increased by H2O2, and knockdown of TFEB aggravated cell pyroptosis and inflammatory response. TFEB directly bound to NLRP3 and blocked NLRP3-mediated cell pyroptosis and inflammatory response. The effect of H2O2 on TFEB might be associated with AMP-activated protein kinase/mechanistic target of rapamycin-dependent signaling pathways.ConclusionsOur findings indicated that a novel TFEB–NLRP3 axis was a critical regulator in EC pyroptosis and inflammation, which could be potential therapeutic targets in AS and related cardiovascular diseases.

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Mild hypothermia alleviates diabetes aggravated cerebral ischemic injury via activating autophagy and inhibiting pyroptosis

Cited by 51 publications

References 34 publications

Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

Protective effects of combined treatment with mild hypothermia and edaravone against cerebral ischemia/reperfusion injury via oxidative stress and Nrf2 pathway regulation

Transcription Factor EB Alleviates Endothelial Cell Inflammation Through NLRP3 Inflammasome-Mediated Cell Pyroptosis in Atherosclerosis

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