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Project description:Epigenetic regulators present novel opportunities for both ischemic stroke research and therapeutic interventions. While previous work has implicated that they may provide neuroprotection by potentially influencing coordinated sets of genes and pathways, most of them remains largely uncharacterized in ischemic conditions. In this study, we used the oxygen-glucose deprivation (OGD) model in the immortalized mouse hippocampal neuronal cell line HT-22 and carried out an RNAi screen on epigenetic regulators. We identified Prmt5 as a novel negative regulator of neuronal cell survival after OGD, which presented a phenotype of translocation from the cytosol to the nucleus upon oxygen and energy depletion both in vitro and in vivo. Prmt5 bound to the chromatin and a large number of promoter regions to repress downstream gene expression. Silencing Prmt5 significantly dampened the OGD-induced changes for a large-scale of genes, and gene ontology analysis showed that Prmt5-target genes were highly enriched for Hedgehog signaling. Encouraged by the above observation, we treated mice with middle cerebral artery occlusion (MCAO) with the Prmt5 inhibitor EPZ015666 and found that Prmt5 inhibition sustain protection against neuronal death in vivo. Together, our findings revealed a novel epigenetic mechanism of Prmt5 in cerebral ischemia and uncovered a potential target for neuroprotection.
2024-02-10 | GSE248392 | GEO
Project description:Epigenetic regulators present novel opportunities for both ischemic stroke research and therapeutic interventions. While previous work has implicated that they may provide neuroprotection by potentially influencing coordinated sets of genes and pathways, most of them remains largely uncharacterized in ischemic conditions. In this study, we used the oxygen-glucose deprivation (OGD) model in the immortalized mouse hippocampal neuronal cell line HT-22 and carried out an RNAi screen on epigenetic regulators. We identified Prmt5 as a novel negative regulator of neuronal cell survival after OGD, which presented a phenotype of translocation from the cytosol to the nucleus upon oxygen and energy depletion both in vitro and in vivo. Prmt5 bound to the chromatin and a large number of promoter regions to repress downstream gene expression. Silencing Prmt5 significantly dampened the OGD-induced changes for a large-scale of genes, and gene ontology analysis showed that Prmt5-target genes were highly enriched for Hedgehog signaling. Encouraged by the above observation, we treated mice with middle cerebral artery occlusion (MCAO) with the Prmt5 inhibitor EPZ015666 and found that Prmt5 inhibition sustain protection against neuronal death in vivo. Together, our findings revealed a novel epigenetic mechanism of Prmt5 in cerebral ischemia and uncovered a potential target for neuroprotection.
2024-02-10 | GSE248390 | GEO
Project description:Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia
| PRJNA1043661 | ENA
Project description:Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia [ChIP-seq]
| PRJNA1043663 | ENA
Project description:Genetic Screen Identified Prmt5 as a Neuroprotection Target against Cerebral Ischemia [RNA-seq]
| PRJNA1043664 | ENA
Project description:The aim of this study was to investigate the antioxidant and anti-inflammatory effects of skimmianine on cerebral ischemia-reperfusion (IR) injury. Twenty-four female Wistar albino rats were randomly divided into three groups: Sham, Ischemia-Reperfusion (IR), and IR + Skimmianine (40 mg/kg Skimmianine). Cerebral ischemia was induced using a monofilament nylon suture to occlude the middle cerebral artery for 60 min. Following 23 h of reperfusion, the animals were sacrificed 14 days later. The effects of skimmianine on brain tissue post-IR injury were examined through biochemical and immunochemical analyses. In silico analysis using the Enrichr platform explored skimmianine's potential biological processes involving IBA-1, IL-6, and NF-κB proteins. In the IR group, MDA levels increased, while SOD and CAT antioxidant enzyme activities decreased. In the IR + Skimmianine group, skimmianine treatment resulted in decreased MDA levels and increased SOD and CAT activities. Significant increases in IBA-1 expression were observed in the IR group, which skimmianine treatment significantly reduced, modulating microglial activation. High levels of IL-6 expression were noted in pyramidal neurons, vascular structures, and neuroglial cells in the IR group; skimmianine treatment reduced IL-6 expression, demonstrating anti-inflammatory effects. Increased NF-κB expression was observed in neurons and blood vessels in the gray and white matter in the IR group; skimmianine treatment reduced NF-κB expression. Gene Ontology results suggest skimmianine impacts immune and inflammatory responses via IBA-1 and IL-6, with potential effects on estrogen mechanisms mediated by NF-κB. Skimmianine may be a potential therapeutic strategy due to its antioxidant and anti-inflammatory effects on cerebral IR injury.
| S-EPMC11276333 | biostudies-literature
Project description:Androgens within physiological ranges protect castrated male mice from cerebral ischemic injury. Yet, underlying mechanisms are unclear. Here, we report that, after middle cerebral artery occlusion (MCAO), salt-induced kinase 1 (SIK1) was induced by a potent androgen-dihydrotestosterone (DHT) at protective doses. To investigate whether SIK1 contributes to DHT neuroprotection after cerebral ischemia, we constructed lentivirus-expressing small interference RNA (siRNA) against SIK1. The SIK1 knockdown by siRNA exacerbated oxygen-glucose deprivation (OGD)-induced cell death in primary cortical neurons, suggesting that SIK1 is an endogenous neuroprotective gene against cerebral ischemia. Furthermore, lentivirus-mediated SIK1 knockdown increased both cortical and striatal infarct sizes in castrated mice treated with a protective dose of DHT. Earlier studies show that SIK1 inhibits histone deacetylase (HDAC) activities by acting as a class IIa HDAC kinase. We observed that SIK1 knockdown decreased histone H3 acetylation in primary neurons. The SIK1 siRNA also exacerbated OGD-induced neuronal death in the presence of trichostatin A (TSA), an HDAC inhibitor, and decreased histone H3 acetylation at 4 hours reoxygenation in TSA-treated neurons. Finally, we showed that DHT at protective doses prevented ischemia-induced histone deacetylation after MCAO. Our finding suggests that SIK1 contributes to neuroprotection by androgens within physiological ranges by inhibiting histone deacetylation.
| S-EPMC3049497 | biostudies-literature
Project description:Orientin is a flavonoid monomer. In recent years, its importance as a source of pharmacological active substance is growing rapidly due to its properties such as anti-myocardial ischemia, anti-apoptosis, anti-radiation, anti-tumor, and anti-aging. However, the neuroprotective effects of Orientin on stroke injury have not been comprehensively evaluated. The aim of the present study was thus to investigate the neuroprotective capacity and the potential mechanisms of Cyperus esculentus L. orientin (CLO) from Cyperus esculentus L. leaves against ischemia/reperfusion (I/R) injury using standard orientin as control. For in vitro studies, we treated HT22 cells with CoCl2 as an in vitro ischemic injury model. HT22 cells in the control group were treated with CoCl2. For in vivo studies, we used rat models of middle cerebral artery occlusion, and animals that received sham surgery were used as controls. We found that CLO protected CoCl2-induced HT22 cells against ischemia/reperfusion injury by lowering lipid peroxidation and reactive oxygen species formation as well as decreasing protein oxidation. However, CLO did not reduce the release of lactate dehydrogenase nor increase the activity of superoxide dismutase. Results showed that CLO could decrease neurological deficit score, attenuate brain water content, and reduce cerebral infarct volume, leading to neuroprotection during cerebral ischemia-reperfusion injury. Our studies indicate that CLO flavonoids can be taken as a natural antioxidant and bacteriostastic substance in food and pharmaceutical industry. The molecular mechanisms of CLO could be at least partially attributed to the antioxidant properties and subsequently inhibiting activation of casepase-3. All experimental procedures and protocols were approved on May 16, 2016 by the Experimental Animal Ethics Committee of Xinjiang Medical University of China (approval No. IACUC20160516-57).
| S-EPMC6921342 | biostudies-literature
Project description:The reduced incidence, morbidity, and mortality of stroke among humans with strong social support have been well-documented; however, the mechanisms underlying these socially mediated phenomena remain unknown, but may involve oxytocin (OT), a hormone that modulates some aspects of social behavior in humans and other animals.In the present study, adult male mice were socially isolated (housed individually) or socially paired (housed with an ovariectomized female); social pairing increased hypothalamic OT gene expression. To determine whether a causal relationship exists between increased OT and improved stroke outcome, mice were treated with exogenous OT or OT receptor antagonist beginning 1 week before induction of experimental stroke via middle cerebral artery occlusion.Relative to social isolation, social housing attenuated infarct size, neuroinflammation, and oxidative stress following experimental stroke; the neuroprotective effect of social housing was eliminated by receptor antagonist treatment. In contrast, administration of OT to socially isolated mice reproduced the neuroprotection conferred by social housing. We further report evidence for a direct suppressive action of OT on cultured microglia, which is a key instigator in the development of neuroinflammation after cerebral ischemia.These findings support the hypothesis that OT mediates the neuroprotective effect of social interaction on stroke outcome.
| S-EPMC3226880 | biostudies-literature
Project description:Inducible DNA repair via the base-excision repair pathway is an important prosurvival mechanism activated in response to oxidative DNA damage. Elevated levels of the essential base-excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 correlate closely with neuronal survival against ischemic insults, depending on the CNS region, protective treatments, and degree of insult. However, the precise mechanisms by which this multifunctional protein affords protection and is activated by upstream signaling pathways in postischemic neurons are not well delineated. Here we show that intracerebral administration of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenously occurring small neuropeptide, induces expression of APE1 in hippocampal neurons. Induction of APE1 expression requires PKA- and p38-dependent phosphorylation of cAMP response-element binding and activating transcription factor 2, which leads to transactivation of the APE1 promoter. We further show that PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. These effects occurred, at least in part, via enhanced APE1 expression. Furthermore, the DNA repair function of APE1 was required for PACAP-mediated neuroprotection. Thus, induction of DNA repair enzymes may be a unique strategy for neuroprotection against hippocampal injury.
| S-EPMC2840276 | biostudies-literature