Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation

Sun, Meiyan; Deng, Bin; Zhao, Xiaoyong; Gao, Changjun; Yang, Lu; Zhao, Hui; Yu, De‐Quan; Zhang, Feng; Xu, Li; Chen, Lei; Sun, Xude

doi:10.1038/srep11445

Cited by 85 publications

(64 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The production of pro‐inflammatory mediators leads to the neuronal cell damage of inflammatory surroundings. In recent years, abundant studies provide strong evidence that activated macroglia play a crucial role in the pathogenesis of ischemic stroke . Our data suggested that RMST overexpression in OGD‐stimulated BV2 cells induced neuronal apoptosis, while RMST‐knockdown rescued neuronal apoptosis.…”

Section: Discussionmentioning

confidence: 56%

LncRNA RMST activates TAK1‐mediated NF‐κB signaling and promotes activation of microglial cells via competitively binding with hnRNPK

Sun

Wang

et al. 2019

IUBMB Life

View full text Add to dashboard Cite

This study aimed to explore the biological role and molecular mechanism of long noncoding RNA (lncRNA) rhabdomyosarcoma 2-associated transcript (RMST) in regulating microglial activation. Mouse microglial BV2 cells were cultured to establish the cell model of cerebral ischemic stroke by oxygen-glucose deprivation (OGD). We observed highly expressed RMST, increased expression of M1, and decreased expression of M2 markers in BV2 microglial cells stimulated with OGD. These alterations were reversed by RMST knockdown. Activation of transforming growth factor-betaactivated kinase 1 (TAK1)-mediated nuclear factor-κB (NF-κB) pathway was observed upon OGD stimulation, which was promoted by RMST through competitively binding with heterogeneous nuclear ribonucleoprotein K (hnRNPK), confirmed by RNA pull down and RNA immunoprecipitation (RIP) assays. Furthermore, RMST overexpressing-BV2 cells effectively enhanced neuronal apoptosis. In conclusion, RMST promoted OGD-induced microglial M1 polarization by competitively interacting with hnRNPK via TAK1-mediated NF-κB pathway, which will provide a basis for understanding the pathogenesis of cerebrovascular diseases. K E Y W O R D Sischemic stroke, long noncoding RNA, microglial polarization, oxygen-glucose deprivation, RMST

show abstract

Section: Discussionmentioning

confidence: 56%

LncRNA RMST activates TAK1‐mediated NF‐κB signaling and promotes activation of microglial cells via competitively binding with hnRNPK

Sun

Wang

et al. 2019

IUBMB Life

View full text Add to dashboard Cite

show abstract

“…TLR4 is involved in the immune response to exogenous microbial infection. The first line of defense is the key upstream factor that activates the inflammatory response (Sun et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Clemastine Fumarate Protects Against Myocardial Ischemia Reperfusion Injury by Activating the TLR4/PI3K/Akt Signaling Pathway

et al. 2020

View full text Add to dashboard Cite

Our pilot studies have shown that clemastine fumarate (CLE) can protect against myocardial ischemia-reperfusion injury (MIRI) through regulation of toll like receptor 4 (TLR4). However, the protective mechanism of CLE and related signaling pathways for MIRI remains unclear. The objective of this study is to determine the mechanism by which CLE relieves MIRI in cardiomyocytes and its relationship with the TLR4/PI3K/Akt signaling pathway. CCK8 analysis was used to test the optimal concentration of TLR4 inhibitor CLI-095 and TLR4 agonist lipopolysaccharide (LPS) on MIRI. The expression of inflammatory factors, oxidative stress response, cell damage, and intracellular calcium redistribution of cardiomyocytes were examined using the ELISA kits, Total Superoxide Dismutase Assay Kit with WST-8 and Lipid Peroxidation MDA Assay Kit, LDH Cytotoxicity Assay Kit, and laser scanning confocal microscope. The expression of TLR4/PI3K/Akt and cleaved caspase-3 were determined by Western blotting and immunofluorescent staining. Our results showed that MIRI aggravated the inflammatory response, oxidative stress, cellular damage of cardiomyocytes, and caused redistribution of intracellular calcium, upregulated the expression of TLR4 protein, cleaved caspase-3 protein, and down-regulated the expression of PI3K/Akt protein. After treatment with CLE, the inflammatory response, oxidative stress, and cellular damage of cardiomyocytes were alleviated, and intracellular calcium ion accumulation decreased. The expression of TLR4 protein, cleaved caspase-3 protein declined, but PI3K/Akt protein expression increased in cardiomyocytes treated with CLE. In addition, after treatment with the TLR4 inhibitor CLI-095, the results were similar to those of CLE treatment. The TLR4 agonist LPS aggravated the reactions caused by MIRI. The role of LPS was reversed after CLE treatment. These results suggested that CLE can attenuate MIRI by activating the TLR4/PI3K/Akt signaling pathway.

show abstract

“…Although we utilized our best efforts to control for the confounders, monitored systemic physiological parameters, and included proper sham and control groups for appropriate comparisons, we cannot completely exclude any effect of anesthesia or acute effects of surgical trauma on our observations. Isoflurane, for instance, is a neuroprotectant and has profound effects on cerebral blood flow (94)(95)(96)(97)(98). The acute surgical procedures that involved craniotomy may have aggravated inflammatory changes in the tissue, increasing leukocyte adhesion (71).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-mediated dynamic capillary stalls in ischemic penumbra: persistent traffic jams after reperfusion contribute to injury

Erdener

Tang

Kılıç

et al. 2019

Preprint

View full text Add to dashboard Cite

the study objectives, designed and performed the experiments, acquired, processed and analyzed the data, wrote the manuscript. J.T. set up and optimized the OCT equipment, wrote acquisition codes and processing algorithms. K.K. designed surgical procedures and performed experiments. D.P set up and optimized the laser speckle imaging equipment, S.K wrote data analysis codes, analyzed data. A.C and J.G. set up and optimized two-photon microscope, prepared data analysis codes and performed the experiments. T.V. performed experiments, acquired and analyzed data. S.S. and C.B.S. contributed to study objectives and experimental design and critically evaluated the manuscript. D.A.B. supervised the project in overall, contributed to study objectives and experimental design, and critically evaluated the manuscript. AbstractEver since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in the salvageable penumbra after recanalization. These stalls, which are distinct from permanent cellular plugs that can lead to no-flow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments, within 3 hours after stroke onset. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. By decreasing the number and duration of stalls, we were able to improve the blood flow in the penumbra within 2-24 hours after reperfusion, increase capillary oxygenation, decrease cellular damage and improve functional outcome. Thereby the dynamic microcirculatory stall phenomenon contributes to the ongoing penumbral injury and is a potential hyperacute stage mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke. SignificanceThis work provides in vivo evidence that, even in perfused capillaries, abnormal capillary flow patterns in the form of dynamic stalls can contribute to ongoing tissue injury in the salvageable penumbra in very early hours of cerebral ischemia. These events resembling micro traffic jams in a complex road network, are mediated by passage of neutrophils through the microcirculation and persist despite recanalization of the occluded artery.

show abstract

Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation

Cited by 85 publications

References 58 publications

LncRNA RMST activates TAK1‐mediated NF‐κB signaling and promotes activation of microglial cells via competitively binding with hnRNPK

LncRNA RMST activates TAK1‐mediated NF‐κB signaling and promotes activation of microglial cells via competitively binding with hnRNPK

Clemastine Fumarate Protects Against Myocardial Ischemia Reperfusion Injury by Activating the TLR4/PI3K/Akt Signaling Pathway

Neutrophil-mediated dynamic capillary stalls in ischemic penumbra: persistent traffic jams after reperfusion contribute to injury

Contact Info

Product

Resources

About