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GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.

ABSTRACT: This study aimed to investigate the effects of PPAR-?/? receptor agonist GW0742 on neuroinflammation in a rat model of hypoxia-ischaemia (HI) and in PC12 cells in OGD model. HI was induced by ligating the common carotid artery and inducing hypoxia for 150 minutes. Immunofluorescence was used for quantification of microglia activation and for determining cellular localization of PPAR-?/?. Expression of proteins was measured by Western blot. Activation of miR-17-5p by GW0742 was assessed in PC12 cells by Dual-Luciferase Reporter Gene Assay. The endogenous expression of TXNIP, NLRP3, cleaved caspase-1 and IL-1? was increased after HI. GW0742 treatment significantly reduced the number of activated pro-inflammatory microglia in ipsilateral hemisphere after HI. Mechanistically, GW0742 significantly decreased the expression of TXNIP, NLRP3, IL-6 and TNF-?. Either PPAR-?/? antagonist GSK3787, miR-17-5p inhibitor, or TXNIP CRISPR activation abolished the anti-inflammatory effects of GW0742. Activation of PPAR-?/? by GW0742 activated miR-17-5p expression in PC12 cells and increased cell viability after OGD, which was accompanied by decreased expression of TXNIP and reduced secretion of IL-1? and TNF-?. In conclusion, GW0742 may be a promising neurotherapeutic for the management of HI patients.

SUBMITTER: Gamdzyk M

PROVIDER: S-EPMC7686982 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.

Gamdzyk Marcin M Doycheva Desislava Met DM Kang Ruiqing R Tang Hong H Travis Zackary D ZD Tang Jiping J Zhang John H JH

Journal of cellular and molecular medicine 20201009 21

This study aimed to investigate the effects of PPAR-β/δ receptor agonist GW0742 on neuroinflammation in a rat model of hypoxia-ischaemia (HI) and in PC12 cells in OGD model. HI was induced by ligating the common carotid artery and inducing hypoxia for 150 minutes. Immunofluorescence was used for quantification of microglia activation and for determining cellular localization of PPAR-β/δ. Expression of proteins was measured by Western blot. Activation of miR-17-5p by GW0742 was assessed in PC12 c ...[more]

PMID: 33034416

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Project description:BackgroundAtherosclerosis (AS) is chronic inflammatory arterial disorder. Artesunate could exhibit anti-inflammatory activity in AS, but its role in AS is still in its incipient stage. In this study, we explored the anti-inflammatory effect of artesunate in AS and its underlying mechanism.MethodsWe isolated CD14+ monocytes from peripheral blood (PB) of 115 coronary heart disease (CHD) patients and 33 non-CHD patients confirmed by coronary angiography. Phorbol myristate acetate (PMA) was used to induce the differentiation of THP-1 monocytes to macrophages. Cells were treated with artesunate at a final concentration of 2.5, 5 or 10 µmol/L. The activation of NLRP3 inflammasome was assessed by immunoblotting of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The expression of pro-caspase-1/pro-interleukin (IL)-1β/pro-IL-18 and their mature forms was measured using immunoblotting. A rat model of AS was induced by vitamin D3 (VD3) and a 21-day high-fat diet.ResultsDownregulated miR-16-5p and upregulated thioredoxin-interacting protein (TXNIP) was determined in CD14+ monocytes from CHD patients and associated with disease severity. Artesunate abrogated the activation of NLRP3 inflammasome in the presence of inflammasome activators in cultured macrophages. Artesunate reduced TXNIP expression and impaired the interaction between TXNIP and NLRP3, thereby inhibiting release of inflammatory cytokines and ASC production in cultured macrophages. In addition, miR-16-5p negatively regulated the messenger RNA (mRNA) of TXNIP. Artesunate increased the expression of miR-16-5p in a dose-dependent manner, and inhibition of miR-16-5p enhanced the secretion of inflammatory cytokines. Our in vivo experiments also demonstrated that artesunate reduced lipid accumulation, atherosclerotic plaque formation, and antagonized inflammation in a dose-dependent manner by upregulating miR-16-5p.ConclusionsIn summary, the present study unveiled a mechanism underlying the anti-inflammatory role of artesunate in AS.

Dataset Information

GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.

Publications

GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.

Similar Datasets

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