Neuroscience
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Practice Guideline
Interferon-gamma facilitates neurogenesis by activating Wnt/β-catenin cell signaling pathway via promotion of STAT1 regulation of the β-catenin promoter.
Interferon-gamma (IFN-γ) is critical for central nervous system (CNS) functions and it may be a promising treatment to stimulate CNS regeneration. However, previous studies reported inconsistent results, and the molecular mechanisms remain controversial. Here we show that IFN-γ-treated mice via intraperitoneal injection have elevated IFN-γ level in central hippocampus and superior cognitive behaviors IFN-γ could activates the level of protein expression of Wnt7a, β-catenin, and CyclinD1 in Wnt/β-catenin signaling pathway of mice hippocampus. ⋯ It is also discovered firstly that Wnt/β-catenin and JAK/STAT pathways form cross-links through STAT1. Promoting neurogenesis through immune stimulation might be a promising strategy for repairing the diseased/injured CNS. This study provides a scientific basis for immunomodulation to promote nerve regeneration and offer a new therapeutic direction for central nervous system regeneration.
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Stroke is a major cause of death and long-term disability. Recent evidence suggests that hypoxia-inducible factor 1α (HIF-1α), a transcription factor that regulates oxygen levels, plays a key role in neurological outcomes after ischemic stroke. Accordingly, we investigated the mechanism of HIF-1α on pyroptotic and apoptotic cells during ischemia/reperfusion (I/R). ⋯ YC-1 significantly reduced the mRNA and protein expression of NLRP3, IL-1β, IL-18, and caspase-1; significantly decreased infarction and pyroptotic cell death after 24 h of reperfusion; attenuated the neuroinflammatory response by reducing infiltration of CD68- and MPO-positive cells after 24 h of reperfusion; and reduced apoptotic cell death following ischemic stroke. We found that HIF-1α likely regulates inflammatory responses through the NLRP3 inflammasome complex, thus influencing both apoptotic and pyroptotic cell death after stroke. These findings suggest that future investigations are needed regarding HIF-1α and its role as a potential molecular target in the treatment of acute ischemic stroke.
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Binge drinking is a frequent pattern of ethanol consumption within Alcohol Use Disorders (AUDs). Binge-like ethanol exposure increases Poly(ADP-ribose) polymerase (PARP) expression and activity. PARP enzymes have been implicated in addiction and serve multiple roles in the cell, including gene expression regulation. ⋯ In our model, alcohol binge drinking induced specific alterations in the PFC expression of genes potentially involved in addiction. Pharmacological PARP inhibition proved effective in reversing these changes and preventing further alcohol consumption. Our results suggest an involvement of ethanol-induced PARP1 in reinforcing binge-like addictive behavior.
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PRRT2 loss-of-function mutations have been associated with familial paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis, and benign familial infantile seizures. Dystonia is the foremost involuntary movement disorder manifest by patients with PKD. Using a lacZ reporter and quantitative reverse-transcriptase PCR, we mapped the temporal and spatial distribution of Prrt2 in mouse brain and showed the highest levels of expression in cerebellar cortex. ⋯ In addition to impaired performance on several motor tasks, approximately 5% of Prrt2-/- mice exhibited overt PKD with clear face validity manifest as dystonia. In Prrt2 mutants, we found reduced parallel fiber facilitation at parallel fiber-Purkinje cell synapses, reduced Purkinje cell excitability, and normal cerebellar nuclear excitability, establishing a potential mechanism by which altered cerebellar activity promotes disinhibition of the cerebellar nuclei, driving motor abnormalities in PKD. Overall, our findings replicate, refine, and expand upon previous work with PRRT2 mouse models, contribute to understanding of paroxysmal disorders of the nervous system, and provide mechanistic insight into the role of cerebellar cortical dysfunction in dystonia.
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Neuroinflammation contributes to neuronal death in cerebral ischemia. Urolithin A (UA), a gut microbial metabolite of ellagic acid, has emerged as a potential anti-inflammatory agent. However, its roles and precise mechanisms in stroke remain unknown. ⋯ We also found that UA attenuated apoptosis by regulating apoptotic-related proteins. Meanwhile, UA treatment inhibited glial activation via affecting inflammatory signaling pathways, specifically by enhancing cerebral AMPK and IκBa activation while decreasing the activation of Akt, P65NFκB, ERK, JNK, and P38MAPK. Our findings reveal a key role of UA against ischemic stroke through modulating apoptosis and neuroinflammation in mice.