Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases.

Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of neurodegenerative diseases, including Parkinson's, Alzheimer's and Huntington's diseases. Neurons, particularly dopaminergic (DAergic) ones, are highly vulnerable to mitochondrial stress; however, the cellular and molecular mechanisms underlying this vulnerability remain poorly understood. Previously, we demonstrated that protein kinase C delta (PKCδ) is highly expressed in DAergic neurons and mediates apoptotic cell death during neurotoxic stress via caspase-3-mediated proteolytic activation.

KCa3.1 Contributes to Neuroinflammation and Nigral Dopaminergic Neurodegeneration in Experimental models of Parkinson's Disease.

Chronic neuroinflammation and misfolded α-synuclein (αSyn) have been identified as key pathological correlates driving Parkinson's disease (PD) pathogenesis; however, the contribution of ion channels to microglia activation in the context of α-synucleinopathy remains elusive. Herein, we show that KCa3.1, a calcium-activated potassium channel, is robustly upregulated within microglia in multiple preclinical models of PD and, most importantly, in human PD and dementia with Lewy bodies (DLB) brains.

Manganese Exposure Enhances the Release of Misfolded α-Synuclein via Exosomes by Impairing Endosomal Trafficking and Protein Degradation Mechanisms.

Excessive exposure to manganese (Mn) increases the risk of chronic neurological diseases, including Parkinson's disease (PD) and other related Parkinsonisms. Aggregated α-synuclein (αSyn), a hallmark of PD, can spread to neighboring cells by exosomal release from neurons. We previously discovered that Mn enhances its spread, triggering neuroinflammatory and neurodegenerative processes.

Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy.

Background: Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs-atropine, oximes, benzodiazepines), if administered in < 20 min of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors.

Disease-Modifying Effects of a Glial-targeted Inducible Nitric Oxide Synthase Inhibitor (1400W) in Mixed-sex Cohorts of a Rat Soman (GD) Model of Epilepsy.

Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs- atropine, oximes, benzodiazepines), if administered in < 20 minutes of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors.

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model.

Organophosphate nerve agent (OPNA) exposure induces acute and long-term neurological deficits. OPNA exposure at sub-lethal concentrations induces irreversible inhibition of acetylcholinesterase and cholinergic toxidrome and develops (SE). Persistent seizures have been associated with increased production of ROS/RNS, neuroinflammation, and neurodegeneration.

DFP-Induced Status Epilepticus Severity in Mixed-Sex Cohorts of Adult Rats Housed in the Same Room: Behavioral and EEG Comparisons.

Sex is a biological variable in experimental models. In our previous diisopropylfluorophosphate (DFP) studies, female rats required a higher dose of DFP to achieve a somewhat similar severity of status epilepticus (SE) as males. In those studies, male and female rats were bought separately from the same vendor, housed in different rooms, and the DFP used was from different batches.

Environmental neurotoxic pesticide exposure induces gut inflammation and enteric neuronal degeneration by impairing enteric glial mitochondrial function in pesticide models of Parkinson's disease: Potential relevance to gut-brain axis inflammation in Parkinson's disease pathogenesis.

Despite the growing recognition that gastrointestinal (GI) dysfunction is prevalent in Parkinson's disease (PD) and occurs as a major prodromal symptom of PD, its cellular and molecular mechanisms remain largely unknown. Among the various types of GI cells, enteric glial cells (EGCs), which resemble astrocytes in structure and function, play a critical role in the pathophysiology of many GI diseases including PD. Thus, we investigated how EGCs respond to the environmental pesticides rotenone (Rot) and tebufenpyrad (Tebu) in cell and animal models to better understand the mechanism underlying GI abnormalities.

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology.

Modeling a real-world scenario of organophosphate nerve agent (OPNA) exposure is challenging. Military personnel are premedicated with pyridostigmine, which led to the development of OPNA models with pyridostigmine/oxime pretreatment to investigate novel therapeutics for acute and chronic effects. However, civilians are not premedicated with pyridostigmine/oxime.

PKC Delta Activation Promotes Endoplasmic Reticulum Stress (ERS) and NLR Family Pyrin Domain-Containing 3 (NLRP3) Inflammasome Activation Subsequent to Asynuclein-Induced Microglial Activation: Involvement of Thioredoxin-Interacting Protein (TXNIP)/Thioredoxin (Trx) Redoxisome Pathway.

A classical hallmark of Parkinson's disease (PD) pathogenesis is the accumulation of misfolded alpha-synuclein (αSyn) within Lewy bodies and Lewy neurites, although its role in microglial dysfunction and resultant dopaminergic (DAergic) neurotoxicity is still elusive. Previously, we identified that protein kinase C delta (PKCδ) is activated in post mortem PD brains and experimental Parkinsonism and that it participates in reactive microgliosis; however, the relationship between PKCδ activation, endoplasmic reticulum stress (ERS) and the reactive microglial activation state in the context of α-synucleinopathy is largely unknown. Herein, we show that oxidative stress, mitochondrial dysfunction, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, and PKCδ activation increased concomitantly with ERS markers, including the activating transcription factor 4 (ATF-4), serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1α (p-IRE1α), p-eukaryotic initiation factor 2 (eIF2α) as well as increased generation of neurotoxic cytokines, including IL-1β in aggregated αSyn-stimulated primary microglia.

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson's Disease.

Astrocytic dysfunction has been implicated in Parkinson's disease (PD) pathogenesis. While the Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 signaling axis is known to play a role in PD-like neuropathology, the molecular mechanisms that govern this process remain poorly understood. Herein, we show that TWEAK levels are elevated in PD serum compared to controls.

Acute restraint stress reverses impaired LTP in the hippocampal CA1 region in mouse models of Alzheimer's disease.

Acute stress facilitates long-term potentiation (LTP) in the mouse hippocampus by modulating glucocorticoid receptors and ion channels. Here, we analysed whether this occurs in mouse models of Alzheimer's disease (AD) with impaired LTP induction. We found that a brief 30 min restraint stress protocol reversed the impaired LTP assessed with field excitatory postsynaptic potential recordings at cornu ammonis 3-1 (CA3-CA1) synapses in both Tg2576 and 5XFAD mice.

Avenanthramide-C Restores Impaired Plasticity and Cognition in Alzheimer's Disease Model Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and dementia with no effective treatment. Here, we investigated a novel compound from oats named avenanthramide-C (Avn-C), on AD-related memory impairment and behavioral deficits in transgenic mouse models. Acute hippocampal slices of wild-type or AD transgenic mice were treated with Avn-C in the presence or absence of oligomeric Aβ.

Nasal Cavity Administration of Melanin-Concentrating Hormone Improves Memory Impairment in Memory-Impaired and Alzheimer's Disease Mouse Models.

Melanin-concentrating hormone (MCH) is a highly conserved neuropeptide known to exhibit important functions in the brain. Some studies have reported that MCH improves memory by promoting memory retention. However, the precise molecular mechanisms by which MCH enhances memory impairment have yet to be fully elucidated.

Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia.

Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson's disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human α-synuclein (αSyn), which is the major component of PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent priming and activation of the microglial NLRP3 inflammasome.

Peroxidase-Mimicking Nanoassembly Mitigates Lipopolysaccharide-Induced Endotoxemia and Cognitive Damage in the Brain by Impeding Inflammatory Signaling in Macrophages.

Oxidative stress during sepsis pathogenesis remains the most-important factor creating imbalance and dysregulation in immune-cell function, usually observed following initial infection. Hydrogen peroxide (HO), a potentially toxic reactive oxygen species (ROS), is excessively produced by pro-inflammatory immune cells during the initial phases of sepsis and plays a dominant role in regulating the pathways associated with systemic inflammatory immune activation. In the present study, we constructed a peroxide scavenger mannosylated polymeric albumin manganese dioxide (mSPAM) nanoassembly to catalyze the decomposition of HO responsible for the hyper-activation of pro-inflammatory immune cells.

β-amyloid inhibits hippocampal LTP through TNFR/IKK/NF-κB pathway.

Objective The suppressive action of the acute application of oligomeric amyloid-β (Aβ) on hippocampal long-term potentiation (LTP) has been reported widely. Many mechanisms have been proposed for Aβ inhibited LTP induction. The inflammatory cytokine tumor necrosis factor-α (TNF-α) has also been reported to play a key role in this LTP inhibition through Aβ.

Levodopa (L-DOPA) attenuates endoplasmic reticulum stress response and cell death signaling through DRD2 in SH-SY5Y neuronal cells under α-synuclein-induced toxicity.

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in dopaminergic neurons. α-Synuclein (α-syn), a major protein component of LBs, is known to regulate synaptic plasticity, with a crucial role in memory and motor function in the central nervous system. Levodopa (L-3,4-dihydroxyphenylalanine; also known as L-DOPA) is considered the most effective medication for controlling the symptoms of PD.

Morin ameliorates chemically induced liver fibrosis in vivo and inhibits stellate cell proliferation in vitro by suppressing Wnt/β-catenin signaling.

The anti-fibrotic effect of morin was examined in LX-2 cells (culture-activated human hepatic stellate cells) and in diethylnitrosamine induced rat model of liver fibrosis. The in vitro study was designed to determine whether morin affects the survival of cultured LX-2 cells, while the in vivo study was designed to evaluate the antioxidant and anti-fibrotic efficacy of morin on diethylnitrosamine induced liver fibrosis in male albino Wistar rat. The activities of liver function enzymes in serum, liver lipid peroxide levels, activities of serum antioxidant enzymes and liver architecture were monitored to cast light on the antioxidant and hepatoprotective nature of morin.