scholarly journals Acetaldehyde-Mediated Neurotoxicity: Relevance to Fetal Alcohol Spectrum Disorders

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Ming Tong ◽  
Lisa Longato ◽  
Quynh-GiaoLy Nguyen ◽  
William C. Chen ◽  
Amy Spaisman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Ethanol Metabolism ◽  
Toxic Metabolite ◽  
Prenatal Ethanol Exposure ◽  
Impaired Insulin ◽  
Insulin Responsiveness ◽  
Igf Signaling

Ethanol-induced neuro-developmental abnormalities are associated with impaired insulin and IGF signaling, and increased oxidative stress in CNS neurons. We examined the roles of ethanol and its principal toxic metabolite, acetaldehyde, as mediators of impaired insulin/IGF signaling and oxidative injury in immature cerebellar neurons. Cultures were exposed to 3.5 mM acetaldehyde or 50 mM ethanol ± 4-methylpyrazole (4-MP), an inhibitor of ethanol metabolism, and viability, mitochondrial function, oxidative stress, DNA damage, and insulin responsiveness were measured 48 hours later. Acetaldehyde or ethanol increased neuronal death and levels of 8-OHdG and 4-HNE, and reduced mitochondrial function. Ethanol inhibited insulin responsiveness, whereas acetaldehyde did not. 4-MP abated ethanol-induced oxidative stress and mitochondrial dysfunction, but failed to restore insulin responsiveness. Furthermore, alcohol and aldehyde metabolizing enzyme genes were inhibited by prenatal ethanol exposure; this effect was mediated by acetaldehyde and not ethanol + 4MP. These findings suggest that brain insulin resistance in prenatal alcohol exposure is caused by direct effects of ethanol, whereas oxidative stress induced neuronal injury is likely mediated by ethanol and its toxic metabolites. Moreover, the adverse effects of prenatal ethanol exposure on brain development may be exacerbated by down-regulation of genes needed for metabolism and detoxification of alcohol in the brain.

scholarly journals Acetaldehyde accelerates HCV-induced impairment of innate immunity by suppressing methylation reactions in liver cells

2015 ◽  
Vol 309 (7) ◽  
pp. G566-G577 ◽  
Author(s):  
Murali Ganesan ◽  
Jinjin Zhang ◽  
Tatiana Bronich ◽  
Larisa I. Poluektova ◽  
Terrence M. Donohue ◽  
...  
Keyword(s):  
Alcohol Exposure ◽  
Liver Cells ◽  
Ethanol Exposure ◽  
Ethanol Metabolism ◽  
In Vivo Studies ◽  
Temporary Increase ◽  
Hcv Rna ◽  
Induced Apoptosis ◽  
Induced Defects

Alcohol exposure worsens the course and outcomes of hepatitis C virus (HCV) infection. Activation of protective antiviral genes is induced by IFN-α signaling, which is altered in liver cells by either HCV or ethanol exposure. However, the mechanisms of the combined effects of HCV and ethanol metabolism in IFN-α signaling modulation are not well elucidated. Here, we explored a possibility that ethanol metabolism potentiates HCV-mediated dysregulation of IFN-α signaling in liver cells via impairment of methylation reactions. HCV-infected Huh7.5 CYP2E1+ cells and human hepatocytes were exposed to acetaldehyde (Ach)-generating system (AGS) and stimulated with IFN-α to activate IFN-sensitive genes (ISG) via the Jak-STAT-1 pathway. We observed significant suppression of signaling events by Ach. Ach exposure decreased STAT-1 methylation via activation of protein phosphatase 2A and increased the protein inhibitor of activated STAT-1 (PIAS-1)-STAT-1 complex formation in both HCV+ and HCV− cells, preventing ISG activation. Treatment with a promethylating agent, betaine, attenuated all examined Ach-induced defects. Ethanol metabolism-induced changes in ISGs are methylation related and confirmed by in vivo studies on HCV+ transgenic mice. HCV- and Ach-induced impairment of IFN signaling temporarily increased HCV RNA levels followed by apoptosis of heavily infected cells. We concluded that Ach potentiates the suppressive effects of HCV on activation of ISGs attributable to methylation-dependent dysregulation of IFN-α signaling. A temporary increase in HCV RNA sensitizes the liver cells to Ach-induced apoptosis. Betaine reverses the inhibitory effects of Ach on IFN signaling and thus can be used for treatment of HCV+ alcohol-abusing patients.

scholarly journals Acetaldehyde Content and Oxidative Stress in the Deleterious Effects of Alcohol Drinking on Rat Uterine Horn

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Lara Romina Buthet ◽  
María Eugenia Maciel ◽  
Leandro Néstor Quintans ◽  
Carmen Rodríguez de Castro ◽  
Martín Hernán Costantini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alcohol Exposure ◽  
Protein Carbonyl ◽  
Ethanol Exposure ◽  
Uterine Horn ◽  
Significant Finding ◽  
Hormonal Changes ◽  
Protein Carbonyl Content ◽  
Acetaldehyde Production ◽  
And Oxidative Stress

After alcohol exposure through a standard Lieber and De Carli diet for 28 days, a severe atrophy in the rat uteirne horn was observed, accompanied by significant alterations in its epithelial cells. Microsomal pathway of acetaldehyde production was slightly increased. Hydroxyl radicals were detected in the cytosolic fraction, and this was attributed to participation of xanthine oxidoreductase. They were also observed in the microsomal fraction in the presence of NADPH generating system. No generation of 1-hydroxyethyl was evidenced. Thet-butylhydroperoxide-induced chemiluminescence analysis of uterine horn homogenates revealed a significant increase in the chemiluminiscence emission due to ethanol exposure. In the animals repeatedly exposed to alcohol, sulfhydryl content from uterine horn proteins was decreased, but no significant changes were observed in the protein carbonyl content from the same samples. Minor but significant decreasing changes were observed in the GSH content accompanied by a tendency to decrease in the GSH/GSSG ratio. A highly significant finding was the diminished activity content of glutathione peroxidase. Results suggest that acetaldehyde accumulation plus the oxidative stress may play an additional effect to the alcohol-promoted hormonal changes in the uterus reported by others after chronic exposure to alcohol.

scholarly journals Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

2021 ◽  
Vol 22 (13) ◽  
pp. 7083
Author(s):  
Malgorzata Lopatynska-Mazurek ◽  
Lukasz Komsta ◽  
Ewa Gibula-Tarlowska ◽  
Jolanta H. Kotlinska
Keyword(s):  
Oxidative Stress ◽  
Prefrontal Cortex ◽  
Learning And Memory ◽  
Fetal Alcohol Spectrum Disorders ◽  
Ethanol Exposure ◽  
Prenatal Ethanol Exposure ◽  
Aversive Learning ◽  
Fetal Alcohol ◽  
Spectrum Disorders ◽  
Fetal Alcohol Spectrum

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

Insulin resistance of gluconeogenic pathways in neonatal rats after prenatal ethanol exposure

2004 ◽  
Vol 286 (3) ◽  
pp. R554-R559 ◽  
Author(s):  
Li Chen ◽  
Tong Zhang ◽  
B. L. G. Nyomba
Keyword(s):  
Insulin Resistance ◽  
Subcutaneous Fat ◽  
Intraperitoneal Administration ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Peroxisome Proliferator ◽  
Prenatal Ethanol Exposure ◽  
Rt Pcr ◽  
Hepatic Expression ◽  
Adiponectin Mrna

Alcohol exposure during pregnancy is associated with fetal growth restriction and programs the offspring to insulin resistance later in life. The underlying mechanisms are still uncertain, but a dysregulation of gluconeogenesis and adipose hormones may be contributory. Newborn rats from dams that had been given ethanol (EtOH) or water (controls) during pregnancy were studied. Adiponectin mRNA was determined in subcutaneous fat by RT-PCR, and serum adiponectin was measured by RIA. Subsets of rats were killed before and after intraperitoneal administration of insulin, to determine, by RT-PCR, the hepatic expression of gluconeogenic enzymes and that of the transcription factor peroxisome proliferator-activated receptor-coactivator (PGC)-1, which promotes gluconeogenesis. EtOH offspring had delayed hypoglycemic response to insulin but normal adiponectin mRNA and serum levels compared with controls. The inhibitory response of the gluconeogenic enzyme phospho enol- pyruvate carboxykinase (PEPCK) and PGC-1 mRNAs to insulin was blunted in EtOH offspring compared with controls. The data suggest that intrauterine EtOH exposure causes insulin resistance of genes for PGC-1 and PEPCK early in life.

scholarly journals Moderate chronic fetal alcohol exposure causes a motor learning deficit in adult outbred Swiss-Webster mice

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1896 ◽  
Author(s):  
Tyler H. Reekes ◽  
H. Thomas Vinyard III ◽  
William Echols ◽  
Andrew J. Eubank III ◽  
Michael D. Bouldin ◽  
...  
Keyword(s):  
Motor Learning ◽  
Open Field ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Human Condition ◽  
Learning Ability ◽  
Cognitive Responses ◽  
Barnes Maze ◽  
Prenatal Ethanol Exposure ◽  
Fetal Alcohol

Prenatal ethanol exposure can negatively affect development, causing physical and/or cognitive deficits in the offspring. Behavioral changes are typically characterized during childhood, but they can also persist into adulthood. The extent of Fetal Alcohol Spectrum Disorder (FASD) abnormalities depends upon the amount and manner of ethanol intake, leading to a large variety of animal models. In order to mimic the genetically diverse human condition, we examined an outbred strain of mice exposed to chronic gestational ethanol and characterized subsequent behavioral alterations during adulthood. To detect deficits in cognitive ability and/or motor function, we ran the mice through tests designed to detect either memory/learning ability or motor strength/skill. We tested cognitive responses using the Barnes Maze and the Open Field Aversion Test, and motor skills using Kondziela’s Inverted Screen Test and the rotarod. As adults, the FASD mice showed no significant differences on grip strength, open field, or the Barnes maze; however, we found that outbred mice who had experienced moderate prenatal ethanol exposure were slower to learn the rotarod as adults, though they did not differ in overall performance. Our data suggest a specific FASD vulnerability in motor learning ability, and also open the door to further investigation on the effect of ethanol on brain areas involved in motor learning, including the striatum.

Folic acid prevents functional and structural heart defects induced by prenatal ethanol exposure

2021 ◽  
Author(s):  
Stephanie M Ford ◽  
Cameron J Pedersen ◽  
Matthew R Ford ◽  
Jun W Kim ◽  
Ganga H Karunamuni ◽  
...  
Keyword(s):  
Blood Flow ◽  
Folic Acid ◽  
Heart Diseases ◽  
Prenatal Alcohol Exposure ◽  
Heart Defects ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Endocardial Cushion ◽  
Prenatal Ethanol Exposure ◽  
Endocardial Cushions

Increased regurgitant blood flow has been linked to endocardial cushion defects and resultant congenital heart diseases (CHDs). Prenatal alcohol exposure (PAE) has been shown to alter early blood flow resulting in abnormal endocardial cushions and CHDs. Compounds, including folic acid (FA), mitigate PAE effects and prevent CHDs, but few studies have assessed their effects on blood flow. We modeled binge drinking in quail embryos at gastrulation. Embryos were exposed to ethanol alone, FA (3.2 μg/egg) alone, and the two simultaneously. We quantified in cardiac looping stages (equivalent to 4 weeks of human gestation) regurgitant blood flow with Doppler optical coherence tomography (OCT) and endocardial cushion volumes using OCT imaging. Incidences of abnormal body curvature and heart rates were also measured. Embryos exposed to ethanol showed significantly increased regurgitant blood flow compared to controls, while embryos given FA with ethanol had significantly reduced regurgitant blood flow but did not return to control levels. Ethanol exposure led to significantly smaller, abnormal endocardial cushions and the addition of FA improved their size, but they remained smaller than controls. Abnormal body curvatures after PAE were reduced in incidence but not fully prevented by FA. FA supplementation partially alleviated PAE induced abnormal cardiovascular function and morphology. Normal blood flow and endocardial cushions are both required to produce a healthy four-chambered heart. These findings support that FA supplementation should begin early in pregnancy to prevent heart as well as neural tube defects. Investigations into the efficacy of combinations of compounds to prevent PAE-induced defects is warranted.

scholarly journals Tributyrin Supplementation Protects Immune Responses and Vasculature and Reduces Oxidative Stress in the Proximal Colon of Mice Exposed to Chronic-Binge Ethanol Feeding

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
B. Glueck ◽  
Y. Han ◽  
G. A. M. Cresci
Keyword(s):  
Oxidative Stress ◽  
Immune Responses ◽  
Immune Function ◽  
Proximal Colon ◽  
Ethanol Exposure ◽  
The Body ◽  
Ethanol Metabolism ◽  
Gut Dysbiosis ◽  
Binge Ethanol Exposure ◽  
Binge Ethanol

Excessive ethanol consumption causes adverse effects and contributes to organ dysfunction. Ethanol metabolism triggers oxidative stress, altered immune function, and gut dysbiosis. The gut microbiome is known to contribute to the maintenance of intestinal homeostasis, and disturbances are associated with pathology. A consequence of gut dysbiosis is also alterations in its metabolic and fermentation byproducts. The gut microbiota ferments undigested dietary polysaccharides to yield short-chain fatty acids, predominantly acetate, propionate, and butyrate. Butyrate has many biological mechanisms of action including anti-inflammatory and immunoprotective effects, and its depletion is associated with intestinal injury. We previously showed that butyrate protects gut-liver injury during ethanol exposure. While the intestine is the largest immune organ in the body, little is known regarding the effects of ethanol on intestinal immune function. This work is aimed at investigating the effects of butyrate supplementation, in the form of the structured triglyceride tributyrin, on intestinal innate immune responses and oxidative stress following chronic-binge ethanol exposure in mice. Our work suggests that tributyrin supplementation preserved immune responses and reduced oxidative stress in the proximal colon during chronic-binge ethanol exposure. Our results also indicate a possible involvement of tributyrin in maintaining the integrity of intestinal villi vasculature disrupted by chronic-binge ethanol exposure.

scholarly journals Alcohol Metabolism Potentiates HIV-Induced Hepatotoxicity: Contribution to End-Stage Liver Disease

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 851 ◽  
Author(s):  
Murali Ganesan ◽  
Moses New-Aaron ◽  
Raghubendra Singh Dagur ◽  
Edward Makarov ◽  
Weimin Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Apoptotic Cell ◽  
Ethanol Exposure ◽  
Ethanol Metabolism ◽  
Hepatocyte Apoptosis ◽  
Immunodeficiency Virus ◽  
End Stage ◽  
Parenchymal Cells ◽  
Injury Progression

In an era of improved survival due to modern antiretroviral therapy, liver disease has become a major cause of morbidity and mortality, resulting in death in 15–17% of human immunodeficiency virus (HIV)-infected patients. Alcohol enhances HIV-mediated liver damage and promotes the progression to advanced fibrosis and cirrhosis. However, the mechanisms behind these events are uncertain. Here, we hypothesize that ethanol metabolism potentiates accumulation of HIV in hepatocytes, causing oxidative stress and intensive apoptotic cell death. Engulfment of HIV-containing apoptotic hepatocytes by non-parenchymal cells (NPCs) triggers their activation and liver injury progression. This study was performed on primary human hepatocytes and Huh7.5-CYP cells infected with HIV-1ADA, and major findings were confirmed by pilot data obtained on ethanol-fed HIV-injected chimeric mice with humanized livers. We demonstrated that ethanol exposure potentiates HIV accumulation in hepatocytes by suppressing HIV degradation by lysosomes and proteasomes. This leads to increased oxidative stress and hepatocyte apoptosis. Exposure of HIV-infected apoptotic hepatocytes to NPCs activates the inflammasome in macrophages and pro-fibrotic genes in hepatic stellate cells. We conclude that while HIV and ethanol metabolism-triggered apoptosis clears up HIV-infected hepatocytes, continued generation of HIV-expressing apoptotic bodies may be detrimental for progression of liver inflammation and fibrosis due to constant activation of NPCs.

scholarly journals Modulatory Effect of Decalepis hamiltonii on Ethanol-Induced Neurotoxicity in Drosophila melanogaster

2018 ◽  
Vol 3 (2) ◽  
pp. 63-71
Author(s):  
Samaneh Raiszadeh Jahromi
Keyword(s):  
Oxidative Stress ◽  
Drosophila Melanogaster ◽  
Ache Activity ◽  
Alcohol Exposure ◽  
Natural Antioxidants ◽  
Ethanol Exposure ◽  
In Vivo Model ◽  
Root Extract ◽  
Protective Effects ◽  
Decalepis Hamiltonii

Ethanol is known to be an effective inducer of oxidative stress in the brain tissues. Drosophila melanogaster is suitable in vivo model system to study neurotoxic effects of ethanol. The behavioral responses, levels of oxidative markers, and activity of antioxidant enzymes have been investigated in ethanol-exposed Drosophila flies. The results showed that acute ethanol exposure leads to hyperactivity of flies. If alcohol exposure is prolonged then sedation has occurred in the experimental flies. The latter was measured by sensitivity time (ST50) and recovery time (RC50). The levels of ROS and LPO (as cellular markers of oxidative stress) are significantly increased in ethanol-exposed flies while GSH level was declined. Furthermore, higher activities of catalase (CAT) and superoxide dismutase (SOD) were observed in the same group of flies. Ethanol neurotoxicity became more evident when a remarkable decrease of acetylcholine esterase (AChE) activity was seen in ethanol-exposed fruit flies. To battle ethanol neurotoxicity natural antioxidants would be the best choice. According to previously reported studies on the antioxidant capacity of Decalepis hamiltonii (Dh) root extract, its protecting effect in this toxicity model has been investigated. Surprisingly, Dh aqueous extract treatment has increased the time of ST50 and decreased the RC50 values of ethanol-exposed flies. Moreover, we demonstrated that Dh pre-treatment can diminish the ROS and LPO levels. Dh treatment results in augment of GSH level and activity of CAT and SOD enzymes. Antioxidant potential of Dh could restore AChE activity too. This is the first report on protective effects of Dh natural antioxidants in Drosophila melanogaster against oxidative stress induced by ethanol.

scholarly journals NGF and BDNF Alterations by Prenatal Alcohol Exposure

2019 ◽  
Vol 17 (4) ◽  
pp. 308-317 ◽  
Author(s):  
Valentina Carito ◽  
Mauro Ceccanti ◽  
Giampiero Ferraguti ◽  
Roberto Coccurello ◽  
Stefania Ciafrè ◽  
...  
Keyword(s):  
Prenatal Alcohol Exposure ◽  
Neuronal Cell Death ◽  
Antioxidant Properties ◽  
Neuronal Cell ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Signalling Pathways ◽  
Prenatal Ethanol Exposure ◽  
Developmental Defects ◽  
Prenatal Alcohol

Background: It is now widely established that the devastating effects of prenatal alcohol exposure on the embryo and fetus development cause marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention. Objective: Both paternal and maternal alcohol exposure has been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure. Methods: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways. Results: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns. Conclusion: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce

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