XQ-1H protects against ischemic stroke by regulating microglia polarization through PPARγ pathway in mice

Liu, Rui; Diao, Junjian; He, Shucheng; Li, Binbin; Fei, Yuxiang; Li, Yunman; Fang, Weirong

doi:10.1016/j.intimp.2018.02.014

Cited by 42 publications

(29 citation statements)

References 33 publications

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“…Activation and differentiation of microglia involves multiple signaling pathways, such as the Notch signaling pathway, NF-κB, tyrosine protein kinase (JAK) signal transduction/transcriptional activator (STAT), peroxisome proliferator-activator receptor-γ (PPAR-γ) and cAMP response element binding protein (CREB) (Grandbarbe et al, 2007; Xu et al, 2015; Ghosh et al, 2016; Chen J. et al, 2017; Qin et al, 2017; Wei et al, 2017; Liu et al, 2018). The Notch signaling pathway is highly conserved and participates in almost all physiological and pathological processes such as differentiation, proliferation and apoptosis of all cellular types.…”

Section: Discussionmentioning

confidence: 99%

Lipoxin A4 Regulates Lipopolysaccharide-Induced BV2 Microglial Activation and Differentiation via the Notch Signaling Pathway

Ding

et al. 2019

Front. Cell. Neurosci.

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Inflammatory responses contribute to the pathogenesis of various neurological diseases, and microglia plays an important role in the process. Activated microglia can differentiate into the pro-inflammatory, tissue-damaging M1 phenotype or the anti-inflammatory, tissue-repairing M2 phenotype. Regulating microglia differentiation, hence limiting a harmful response, might help improve the prognosis of inflammation-related nervous system diseases. The present study aimed 1. to observe the anti-inflammatory effect of lipoxin A4 (LXA4) on the inflammatory response associated to lipopolysaccharide (LPS)-induced microglia activation, 2. to clarify that LXA4 modulates the activation and differentiation of microglia induced by LPS stimulation, 3. to determine whether LXA4 regulates the activation and differentiation of microglia through the Notch signaling pathway, 4. to provide a foundation for the use of LXA4 for the treatment of inflammatory related neurological diseases. To construct a model of cellular inflammation, immortalized murine BV2 microglia cells were provided 200 ng/ml LPS. To measure the mRNA and protein levels of inflammatory factors (interleukin [IL]-1β, IL-10, and tumor necrosis factor [TNF]-α) and M1 and M2 microglia markers (inducible nitric oxide synthase [iNOS], cluster of differentiation [CD]32, arginase [Arg]1, and CD206), we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), immunofluorescence, or flow cytometry. To determine the mRNA and protein levels of Notch signaling components (Notch1, Hes1, and Hes5), we performed qRT-PCR and western blot. LXA4 inhibits the expression of Notch1 and Hes1 associated with M1 type microglial differentiation and decreases the M1 type microglia marker iNOS and related inflammatory factors IL-1β and TNF-α. Moreover, LXA4 upregulates the expression of the M2-associated Hes5, as well as the expression of the M2 microglia marker Arg1 and the associated inflammatory factor IL-10. These effects are blocked by the administration of the γ-secretase inhibitor DAPT, a specific blocker of the Notch signaling pathway. LXA4 inhibits the microglia activation induced by LPS and the differentiation into M1 type with pro-inflammatory effect, while promoting the differentiation to M2 type with anti-inflammatory effect. LXA4 downregulates the inflammatory mediators IL-1β, TNF-α, and iNOS, while upregulating the anti-inflammatory mediator IL-10, which acts through the Notch signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Lipoxin A4 Regulates Lipopolysaccharide-Induced BV2 Microglial Activation and Differentiation via the Notch Signaling Pathway

Ding

et al. 2019

Front. Cell. Neurosci.

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“…In addition, PPAR-γ suppresses the ischemic neuronal death through inhibiting p22phox and the subsequent NOX activation [15]. Meanwhile, PPAR-γ pathway has the protective role for human ischemic stroke [19]. Recent evidence has suggested Sirt3 prevents the trans-differentiation of cardiac fibroblasts by upregulating PPAR-γ [20].…”

Section: Introductionmentioning

confidence: 99%

PPAR-γ promotes p38 MAP kinase-mediated endothelial cell permeability through activating Sirt3

et al. 2019

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BackgroundIschemia-reperfusion (I/R)-induced vascular dysfunction is the main factor to acute ischemic stroke. Sirt3 is one of the sirtuin family members, which plays an important role in the development of neurological diseases.MethodsIn this study, we constructed I/R injury model on HBMEC cells and induced the overexpression of Sirt3 in model cells. Meanwhile, the p38 activator U-46619 was used to examine the connection between Sirt3 and p38. We also examined the level of endothelial associated proteins, including occluding, ZO-1 and claudin-4 by using qRT-PCR and western blot.ResultsOur findings indicated that overexpression of Sirt3 decreased the permeability of model cells and promoted in the growth of endothelial cells. However, the activation of p38 could antagonize the function of Sirt3 in HBMEC cells. Moreover, Our results indicated a positive correlation between Sirt3 and inter-endothelial junction proteins. Importantly, PPAR-γ agonist and inhibitor were utilized to investigate the role of PPAR-γ in Sirt3 mediated cell function. Sirt3 was targeted by PPAR-γ in model cells.ConclusionsTaken together, this research not only demonstrated PPAR-γ might benefit to the growth of endothelial cell though activating Sirt3 but also indicated its potential value in the treatment for ischemic stroke.

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“…All these effects could be inhibited by administration of the PPARγ inhibitor GW9662. The results proved that XQ-1H regulated the polarization of microglia by promoting the anti-inflammatory phenotype and inhibiting the pro-inflammatory phenotype (21). White matter is composed mainly of axonal fibers, oligodendrocytes, and other glial cells, and is highly vulnerable to ischemic injury.…”

Section: The Role Of Pparγ In Inhibiting Microglial Activation and Rementioning

confidence: 81%

“…And their data provided the evidence of pioglitazone for secondary prevention of ischemic stroke in Asian T2DM patients, which provides a theoretical basis for the development of new cardiovascular and cerebrovascular disease drugs (9). The research progress of PPARγ agonists in the treatment of CI/RI in the last 5 years is summarized in the Table 1 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

The Protective Effects of Peroxisome Proliferator-Activated Receptor Gamma in Cerebral Ischemia-Reperfusion Injury

et al. 2020

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Cerebral ischemia-reperfusion injury (CI/RI) is a complex pathological process that often occurs secondary to trauma, surgery, and shock. Peroxisome proliferator activated receptor gamma (PPARγ) is a subunit of the PPAR and is a ligand-activated nuclear transcription factor. After being activated by its ligand, PPARγ can combine with specific DNA response elements to regulate the transcription and expression of genes. It has a wide range of biological functions, such as regulating lipid metabolism, improving insulin sensitivity, modulating anti-tumor mechanisms, and inhibiting inflammation. In recent years, some studies have shown that PPARγ exerts a protective effect during CI/RI. This article aims to summarize the research progress of studies that have investigated the protective effects of PPARγ in CI/RI and the cellular and molecular mechanisms through which these effects are modulated, including inhibition of excitatory amino acid toxicity, reduced Ca 2+ overload, anti-oxidative stress, anti-inflammation, inhibition of microglial activation, maintain the BBB, promotion of angiogenesis, and neurogenesis and anti-apoptotic processes.

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XQ-1H protects against ischemic stroke by regulating microglia polarization through PPARγ pathway in mice

Cited by 42 publications

References 33 publications

Lipoxin A4 Regulates Lipopolysaccharide-Induced BV2 Microglial Activation and Differentiation via the Notch Signaling Pathway

Lipoxin A4 Regulates Lipopolysaccharide-Induced BV2 Microglial Activation and Differentiation via the Notch Signaling Pathway

PPAR-γ promotes p38 MAP kinase-mediated endothelial cell permeability through activating Sirt3

The Protective Effects of Peroxisome Proliferator-Activated Receptor Gamma in Cerebral Ischemia-Reperfusion Injury

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