vx-765 has been researched along with Stroke* in 2 studies
2 other study(ies) available for vx-765 and Stroke
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VX-765 enhances autophagy of human umbilical cord mesenchymal stem cells against stroke-induced apoptosis and inflammatory responses via AMPK/mTOR signaling pathway.
To investigate the protective effect of VX-765 on human umbilical mesenchymal stem cells (HUMSCs) in stroke and its mechanism.. Mouse models of ischemic stroke were established using the distal middle cerebral artery occlusion (dMCAO) method. The dMCAO mice were accordingly transplanted with HUMSCs, VX-765-treated HUMSCs, or VX-765 + MHY185-treated HUMSCs. The HUMSCs were inserted with green fluorescent protein (GFP) for measurement of transplantation efficiency which was determined by immunofluorescence assay. Oxygen-glucose deprivation (OGD) was applied to mimic ischemic environment in vitro experiments, and the HUMSCs herein were transfected with AMPK inhibitor Compound C or autophagy inhibitor 3-MA. MTT assay was used to test the toxicity of VX-765. TUNEL staining and ELISA were applied to measure the levels of apoptosis and inflammatory cytokines (IL-1β, IL-6, and IL-10), respectively. The expressions of autophagy-associated proteins, AMPK, and mTOR were detected by Western blotting. TTC staining was applied to reveal the infarct lesions in the brain of dMCAO mice.. The pro-inflammatory cytokines, TUNEL-positive cells, and p-mTOR were decreased while the anti-inflammatory cytokine, autophagy-related proteins, and p-AMPK were increased in HUMSCs treated with VX-765 under OGD condition. Different expression patterns were found with the above factors after transfection of 3-MA or Compound C. The pro-inflammatory cytokines, TUNEL-positive cells, and infarct sections were decreased while the anti-inflammatory cytokine and autophagy-related proteins were increased in dMCAO mice transplanted with VX-765-treated HUMSCs compared to those transplanted with HUMSCs only. The autophagy was inhibited while p-mTOR was up-regulated after transfection of MHY.. VX-765 protects HUMSCs against stroke-induced apoptosis and inflammatory responses by activating autophagy via the AMPK/mTOR signaling pathway in vivo and in vitro. Topics: AMP-Activated Protein Kinase Kinases; Animals; Apoptosis; Autophagy; Dipeptides; Humans; Inflammation Mediators; Mesenchymal Stem Cells; para-Aminobenzoates; Protein Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; Stroke; TOR Serine-Threonine Kinases; Umbilical Cord | 2020 |
Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-κB activation.
Stroke is a life-threatening neurological disease with limited therapeutic options. Inflammation is believed to be involved in the pathogenesis of ischemic stroke and contribute to the degree of brain injury. Vx-765 is a potent, selective, small-molecule caspase-1 inhibitor. Current studies have shown the anti-inflammatory properties of vx-765 in various disease; however, the impact of vx-765 on the ischemic stroke is still unclear. In the present study, we determine the neuroprotective effect of vx-765 in mice subjected to transient middle cerebral artery occlusion (MCAO). We found that caspase-1 inhibition by administration of vx-765 ameliorated cerebral injury in mice after ischemic stroke by reducing infarct volume and ameliorating the neurological deficits. Mechanistically, we showed that the contribution of vx-765 to ischemic injuries may be associated with reducing microglial activation, and downregulating the production of associated pro inflammatory cytokines including IL-1β, TNF-α, and iNOS, as well as upregulating anti-inflammatory cytokines such as TGF-β and YM-1. Additionally, vx-765 altered the phenotype of microglia via switching the microglia polarization toward M2 phenotype, as demonstrably related to inhibition of the NF-κB activation. Our findings indicate that vx-765 protects against MCAO injury and attenuated microglia mediated neuroinflammation primarily by shifting microglia polarization from M1 phenotype toward M2 phenotype. Vx-765 might be a potential therapeutic drug for ameliorating ischemic stroke. Topics: Animals; Caspase 1; Caspase Inhibitors; Dipeptides; Disease Models, Animal; Infarction, Middle Cerebral Artery; Macrophage Activation; Macrophages; Male; Mice, Inbred C57BL; Microglia; Neuroprotection; Neuroprotective Agents; NF-kappa B; para-Aminobenzoates; Stroke | 2019 |