Differential effects of moderate chronic ethanol consumption on neurobehavior, white matter glial protein expression, and mTOR pathway signaling with adolescent brain maturation.

Adolescent brains are highly vulnerable to heavy alcohol exposure. Increased understanding of how alcohol adversely impacts brain maturation may improve treatment outcomes. This study characterizes short-term versus long-term effects of ethanol feeding on behavior, frontal lobe glial proteins, and mTOR signaling.

Tissue Microarray Lipidomic Imaging Mass Spectrometry Method: Application to the Study of Alcohol-Related White Matter Neurodegeneration.

Central nervous system (CNS) white matter pathologies accompany many diseases across the lifespan, yet their biochemical bases, mechanisms, and consequences have remained poorly understood due to the complexity of myelin lipid-based research. However, recent advances in matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) have minimized or eliminated many technical challenges that previously limited progress in CNS disease-based lipidomic research. MALDI-IMS can be used for lipid identification, semi-quantification, and the refined interpretation of histopathology.

The Differential Effects of Chronic Alcohol and Cigarette Smoke Exposures on Cognitive-Behavioral Dysfunction in Long Evans Rats.

Background And Objective: Chronic heavy alcohol consumption and daily cigarette smoking are the most prevalent substance use problems in the U.S., including Veterans.

Therapeutic Effects of Myriocin in Experimental Alcohol-Related Neurobehavioral Dysfunction and Frontal Lobe White Matter Biochemical Pathology.

Background & Objective: Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained deficits in cognition, learning, and memory. Correspondingly, chronic heavy or repeated binge alcohol exposures in humans and experimental models alter myelin lipid composition leading to build-up of ceramides which can be neurotoxic and broadly inhibitory to brain functions.

Myriocin Treatment Reverses Alcohol-Induced Alterations in Polyunsaturated Fatty Acid-Containing Phospholipid Expression in the Liver.

Chronic heavy alcohol exposure causes steatohepatitis manifested by abnormal intra-hepatocyte accumulation of lipid and parenchymal inflammation. Attendant alterations in polyunsaturated fatty acid (PUFA)-containing phospholipids could cause alcoholic liver disease (ALD) to progress by promoting oxidative stress, inflammation, and fibrogenesis. Previously we showed that myriocin, a serine palmitoyltransferase inhibitor, ameliorates experimental alcohol-induced steatohepatitis.

Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities.

Background: The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco-specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism.

Objective: We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both.

Methods: 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks.

Imaging mass spectrometry of frontal white matter lipid changes in human alcoholics.

Background: Chronic alcohol use disorders (AUD) are associated with white matter (WM) degeneration with altered myelin integrity. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) enables high throughput analysis of myelin lipid biochemical histopathology to help characterize disease mechanisms.

Purpose: This study utilized MALDI-IMS to investigate frontal lobe WM myelin lipid abnormalities in AUD.

Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl--Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model.

Alcohol-induced white matter (WM) degeneration is linked to cognitive-motor deficits and impairs insulin/insulin-like growth factor (IGF) and Notch networks regulating oligodendrocyte function. Ethanol downregulates Aspartyl-Asparaginyl--Hydroxylase (ASPH) which drives Notch. These experiments determined if alcohol-related WM degeneration was linked to inhibition of ASPH and Notch.

Progressive white matter atrophy with altered lipid profiles is partially reversed by short-term abstinence in an experimental model of alcohol-related neurodegeneration.

Chronic ethanol exposure causes white matter (WM) atrophy and degeneration with major impairments in the structural integrity of myelin. Since myelin is composed of oligodendrocyte lipid-rich membranes, understanding the consequences and reversibility of alcohol-related oligodendrocyte dysfunction in relation to myelin structure could provide new insights into the pathogenesis of WM degeneration and potential strategies for treatment. Adult male Long Evans rats were pair-fed with isocaloric liquid diets containing 0% or 26% ethanol (caloric) for 3 or 8 weeks.

Altered temporal lobe white matter lipid ion profiles in an experimental model of sporadic Alzheimer's disease.

Background: White matter is an early and important yet under-evaluated target of Alzheimer's disease (AD). Metabolic impairments due to insulin and insulin-like growth factor resistance contribute to white matter degeneration because corresponding signal transduction pathways maintain oligodendrocyte function and survival.

Methods: This study utilized a model of sporadic AD in which adult Long Evans rats administered intracerebral streptozotocin (i.

Differential Sphingolipid and Phospholipid Profiles in Alcohol and Nicotine-Derived Nitrosamine Ketone-Associated White Matter Degeneration.

Background: Alcohol-mediated neurodegeneration is associated with white matter (WM) atrophy due to targeting of myelin and oligodendrocytes. However, variability in disease severity suggests cofactors contribute to WM degeneration. We examined the potential cofactor role of the tobacco-specific nitrosamine, nicotine-derived nitrosamine ketone (NNK), because smoking causes WM atrophy and most heavy drinkers consume tobacco products.

Comparative Analysis of Lipid Extracts and Imaging Mass Spectrometry for Evaluating Cerebral White Matter Biochemical Pathology in an Experimental Second-Hand Cigarette Smoke Exposure Model.

Background: White matter injury and degeneration are common features of developmental and aging-associated diseases, yet their pathobiological bases are poorly understood. However, recent advances in Matrix-Assisted Laser Desorption Ionization (MALDI) instruments and chemistry have provided critical tools for myelin-lipid analytical research.

Design: This study characterizes Cigarette Smoke (CS) exposure effects on frontal lobe lipid ion profiles in adult male A/J mice that had been exposed to air for 8 weeks (A8), CS for 4 (CS4) or 8 weeks (CS8), or CS8 followed by 2 weeks recovery (CS8+R).

Bisphenol A sulfonation is impaired in metabolic and liver disease.

Background: Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood.

Review of matrix-assisted laser desorption ionization-imaging mass spectrometry for lipid biochemical histopathology.

Matrix-Assisted Laser Desorption Ionization-Imaging Mass Spectrometry (MALDI-IMS) is a rapidly evolving method used for the in situ visualization and localization of molecules such as drugs, lipids, peptides, and proteins in tissue sections. Therefore, molecules such as lipids, for which antibodies and other convenient detection reagents do not exist, can be detected, quantified, and correlated with histopathology and disease mechanisms. Furthermore, MALDI-IMS has the potential to enhance our understanding of disease pathogenesis through the use of "biochemical histopathology".

Potential contributions of the tobacco nicotine-derived nitrosamine ketone (NNK) in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease.

Aims: Alcoholic liver disease (ALD) is linked to binge drinking and cigarette smoking. Heavy chronic ± binge alcohol, or low-level exposures to dietary nitrosamines cause steatohepatitis with insulin resistance and oxidative stress in animal models. This study examines hepatotoxic effects of sub-mutagenic exposures to tobacco-specific nitrosamine (NNK) in relation to ALD.

Downregulation of sulfotransferase expression and activity in diseased human livers.

Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics.

Molecular characterization of novel sulfotransferases from the tick, Ixodes scapularis.

Background: Ixodes scapularis, commonly known as the blacklegged or deer tick, is the main vector of Lyme disease in the United States. Recent progress in transcriptome research has uncovered hundreds of different proteins expressed in the salivary glands of hard ticks, the majority of which have no known function, and include many novel protein families. We recently identified transcripts coding for two putative cytosolic sulfotransferases in these ticks which recognized phenolic monoamines as their substrates.

Monoamine neurotransmitters as substrates for novel tick sulfotransferases, homology modeling, molecular docking, and enzyme kinetics.

Blacklegged ticks (Ixodes scapularis) transmit the causative agent of Lyme disease in the Northeastern United States. Current research focuses on elucidating biochemical pathways that may be disrupted to prevent pathogen transmission, thereby preventing disease. Genome screening reported transcripts coding for two putative sulfotransferases in whole tick extracts of the nymphal and larval stages.

Allosteric modulation of SULT2A1 by celecoxib and nimesulide: computational analyses.

We used protein-ligand docking and minimization to identify celecoxib as an allosteric modulator of SULT2A1-catalyzed estradiol sulfonation. Subsequent to celecoxib docking and complex minimization, conformational changes in SULT2A1 allowed estradiol docking to an alternative binding region with predicted preference for 17beta-OH-E(2) sulfonation over 3-OH-E(2) sulfonation.