Munksgaardduckworth0953

Together, our findings reveal the existence of a previously unidentified DUSP15-ERK1/2-Notch signaling axis, which could potentially play a role in neuronal differentiation and neurological disease.Cocaine use disorder is a major health crisis that is associated with increased oxidative stress and neuroinflammation. While the role of NLRP3 inflammasome in mediating neuroinflammation is well-recognized, whether cocaine induces this response remains unexplored. Based on the premise that cocaine induces both reactive oxygen species (ROS) as well as microglial activation, we hypothesized that cocaine-mediated microglial activation involves both ROS and NLRP3 signaling pathways. We examined activation of the NLRP3 pathway in microglia exposed to cocaine, followed by validation in mice administered either cocaine or saline for 7 days, with or without pretreatment with the NLRP3 inhibitor, MCC950, and in postmortem cortical brain tissues of chronic cocaine-dependent humans. We found that microglia exposed to cocaine exhibited significant induction of NLRP3 and mature IL-1β expression. Intriguingly, blockade of ROS (Tempol) attenuated cocaine-mediated priming of NLRP3 and microglial activation (CD11b). Blockade of NLRP3 by both pharmacological (MCC950) as well as gene silencing (siNLRP3) approaches underpinned the critical role of NLRP3 in cocaine-mediated activation of inflammasome and microglial activation. Pretreatment of mice with MCC950 followed by cocaine administration for 7 days mitigated cocaine-mediated upregulation of mature IL-1β and CD11b, in both the striatum and the cortical regions. Selleckchem A-769662 Furthermore, cortical brain tissues of chronic cocaine-dependent humans also exhibited upregulated expression of the NLRP3 pathway mediators compared with non-cocaine dependent controls. Collectively, these findings suggest that cocaine activates microglia involving the NLRP3 inflammasome pathway, thereby contributing to neuroinflammation. NLRP3 can thus be considered as a potential therapeutic target for alleviating cocaine-mediated neuroinflammation.Alzheimer's disease (AD) is the most common late-onset dementia characterized by the deposition of extracellular amyloid plaques and formation of intracellular neurofibrillary tangles, which eventually lead to neuronal loss and cognitive deficits. Multiple lines of evidence indicate that mitochondrial dysfunction is involved in the initiation and progression of AD. As essential machinery for mitochondrial quality control, mitophagy plays a housekeeping role in neuronal cells by eliminating dysfunctional or excessive mitochondria. At present, mounting evidence support that the activity of mitophagy markedly declines in human brains during aging. Impaired mitophagy and mitochondrial dysfunction were causally linked to bioenergetic deficiency, oxidative stress, microglial activation, and chronic inflammation, thereby aggravating the Aβ and tau pathologies and leading to neuron loss in AD. This review summarizes recent evidence for age-associated mitophagy decline during human aging and provides an overview of mitochondrial dysfunction involved in the process of AD. It also discusses the underlying mechanisms through which defective mitophagy leads to neuronal cell death in AD. Therapeutic interventions aiming to restore mitophagy functions can be used as a strategy for ameliorating AD pathogenesis.Along with emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, a myriad of neurologic symptoms, associated with structural brain changes, were reported. In this paper, we provide evidence to critically discuss the claim that the survived patients could possibly be at increased risk for neurodegenerative diseases via various mechanisms. This virus can directly invade the brain through olfactory bulb, retrograde axonal transport from peripheral nerve endings, or via hematogenous or lymphatic routes. Infection of the neurons along with peripheral leukocytes activation results in pro-inflammatory cytokine increment, rendering the brain to neurodegenerative changes. Also, occupation of the angiotensin-converting enzyme 2 (ACE-2) with the virus may lead to a decline in ACE-2 activity, which acts as a neuroprotective factor. Furthermore, acute respiratory distress syndrome (ARDS) and septicemia induce hypoxemia and hypoperfusion, which are locally exacerbated due to the hypercoagulable state and micro-thrombosis in brain vessels, leading to oxidative stress and neurodegeneration. Common risk factors for COVID-19 and neurodegenerative diseases, such as metabolic risk factors, genetic predispositions, and even gut microbiota dysbiosis, can contribute to higher occurrence of neurodegenerative diseases in COVID-19 survivors. However, it should be considered that severity of the infection, the extent of neurologic symptoms, and the persistence of viral infection consequences are major determinants of this association. Importantly, whether this pandemic will increase the overall incidence of neurodegeneration is not clear, as a high percentage of patients with severe form of COVID-19 might probably not survive enough to develop neurodegenerative diseases.Neonatal hypoxia-ischemia (HI) is among the main causes of mortality and morbidity in newborns. Experimental studies show that the immature rat brain is less susceptible to HI injury, suggesting that changes that occur during the first days of life drastically alter its susceptibility. Among the main developmental changes observed is the mitochondrial function, namely, the tricarboxylic acid (TCA) cycle and respiratory complex (RC) activities. Therefore, in the present study, we investigated the influence of neonatal HI on mitochondrial functions, redox homeostasis, and cell damage at different postnatal ages in the hippocampus of neonate rats. For this purpose, animals were divided into four groups sham postnatal day 3 (ShP3), HIP3, ShP11, and HIP11. We initially observed increased apoptosis in the HIP11 group only, indicating a higher susceptibility of these animals to brain injury. Mitochondrial damage, as determined by flow cytometry showing mitochondrial swelling and loss of mitochondrial membrane potential, was also demonstrated only in the HIP11 group.