The NADPH Oxidase Inhibitor, Mitoapocynin, Mitigates DFP-Induced Reactive Astrogliosis in a Rat Model of Organophosphate Neurotoxicity.

NADPH oxidase (NOX) is a primary mediator of superoxides, which promote oxidative stress, neurodegeneration, and neuroinflammation after diisopropylfluorophosphate (DFP) intoxication. Although orally administered mitoapocynin (MPO, 10 mg/kg), a mitochondrial-targeted NOX inhibitor, reduced oxidative stress and proinflammatory cytokines in the periphery, its efficacy in the brain regions of DFP-exposed rats was limited. In this study, we encapsulated MPO in polyanhydride nanoparticles (NPs) based on 1,6-bis(p-carboxyphenoxy) hexane (CPH) and sebacic anhydride (SA) for enhanced drug delivery to the brain and compared with a high oral dose of MPO (30 mg/kg).

Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare.

Saracatinib/AZD0530 (SAR), a Src tyrosine kinase inhibitor, mitigates seizure-induced brain pathology in epilepsy models upon repeated oral dosing. However, repeated dosing is stressful and can be challenging in some seizing animals. To overcome this issue, we have incorporated SAR-in-Diet and compared serum pharmacokinetics (PK) and brain concentrations with conventional repeated oral dosing.

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.

Nrf2 Activation Protects Against Organic Dust and Hydrogen Sulfide Exposure Induced Epithelial Barrier Loss and Invasion.

Agriculture workers report various respiratory symptoms owing to occupational exposure to organic dust (OD) and various gases. Previously, we demonstrated that pre-exposure to hydrogen sulfide (HS) alters the host response to OD and induces oxidative stress. Nrf2 is a master-regulator of host antioxidant response and exposures to toxicants is known to reduce Nrf2 activity.

Mitoapocynin Attenuates Organic Dust Exposure-Induced Neuroinflammation and Sensory-Motor Deficits in a Mouse Model.

Increased incidences of neuro-inflammatory diseases in the mid-western United States of America (USA) have been linked to exposure to agriculture contaminants. Organic dust (OD) is a major contaminant in the animal production industry and is central to the respiratory symptoms in the exposed individuals. However, the exposure effects on the brain remain largely unknown.

Transcriptomic and ultrastructural evidence indicate that anti-HMGB1 antibodies rescue organic dust-induced mitochondrial dysfunction.

Exposure to organic dust (OD) in agriculture is known to cause respiratory symptoms including loss of lung function. OD exposure activates multiple signaling pathways since it contains a variety of microbial products and particulate matter. Previously, we have shown how OD exposure leads to the secretion of HMGB1 and HMGB1-RAGE signaling, and how this can be a possible therapeutic target to reduce inflammation.

Organic dust exposure induces stress response and mitochondrial dysfunction in monocytic cells.

Exposure to airborne organic dust (OD), rich in microbial pathogen-associated molecular patterns (PAMPs), is shown to induce lung inflammation. A common manifestation in lung inflammation is altered mitochondrial structure and bioenergetics that regulate mitochondrial ROS (mROS) and feed a vicious cycle of mitochondrial dysfunction. The role of mitochondrial dysfunction in other airway diseases is well known.

Organic dust-induced mitochondrial dysfunction could be targeted via cGAS-STING or cytoplasmic NOX-2 inhibition using microglial cells and brain slice culture models.

Organic dust (OD) exposure in animal production industries poses serious respiratory and other health risks. OD consisting of microbial products and particulate matter and OD exposure-induced respiratory inflammation are under investigation. However, the effect of OD exposure on brain remains elusive.

Pre-exposure to hydrogen sulfide modulates the innate inflammatory response to organic dust.

Animal production units produce and store many contaminants on-site, including organic dust (OD) and hydrogen sulfide (HS). Workers in these settings report various respiratory disease symptoms. Both OD and HS have shown to induce lung inflammation.

HMGB1-RAGE Signaling Plays a Role in Organic Dust-Induced Microglial Activation and Neuroinflammation.

Occupational exposure to contaminants in agriculture and other industries is known to cause significant respiratory ailments. The effect of organic dust on lung inflammation and tissue remodeling has been actively investigated over many years but the adverse effect of organic dust-exposure on the central vital organ brain is beginning to emerge. Brain microglial cells are a major driver of neuroinflammation upon exposure to danger signals.

Ethyl pyruvate reduces organic dust-induced airway inflammation by targeting HMGB1-RAGE signaling.

Background: Animal production workers are persistently exposed to organic dust and can suffer from a variety of respiratory disease symptoms and annual decline in lung function. The role of high mobility group box-1 (HMGB1) in inflammatory airway diseases is emerging. Hence, we tested a hypothesis that organic dust exposure of airway epithelial cells induces nucleocytoplasmic translocation of HMGB1 and blocking this translocation dampens organic dust-induced lung inflammation.

Off-Target drug effects resulting in altered gene expression events with epigenetic and "Quasi-Epigenetic" origins.

This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale.