Effects Of Chronic Alcohol Consumption Research Articles

Nucleoredoxin Redox Interactions Are Sensitized by Aging and Potentiated by Chronic Alcohol Consumption in the Mouse Liver.

Aging is characterized by increased reactive species, leading to redox imbalance, oxidative damage, and senescence. The adverse effects of alcohol consumption potentiate aging-associated alterations, promoting several diseases, including liver diseases. Nucleoredoxin (NXN) is a redox-sensitive enzyme that targets reactive oxygen species and regulates key cellular processes through redox protein-protein interactions. Here, we determine the effect of chronic alcohol consumption on NXN-dependent redox interactions in the liver of aged mice. We found that chronic alcohol consumption preferentially promotes the localization of NXN either into or alongside senescent cells, declines its interacting capability, and worsens the altered interaction ratio of NXN with FLII, MYD88, CAMK2A, and PFK1 proteins induced by aging. In addition, carbonylated protein and cell proliferation increased, and the ratios of collagen I and collagen III were inverted. Thus, we demonstrate an emerging phenomenon associated with altered redox homeostasis during aging, as shown by the declining capability of NXN to interact with partner proteins, which is enhanced by chronic alcohol consumption in the mouse liver. This evidence opens an attractive window to elucidate the consequences of both aging and chronic alcohol consumption on the downstream signaling pathways regulated by NXN-dependent redox-sensitive interactions.

Influence of green tea on alcohol aggravated neurodegeneration of cortex, cerebellum and hippocampus of STZ-induced diabetic rats

The main aim of this study was to evaluate the cytotoxic effects of chronic alcohol consumption on various regions of diabetic brain and preventive role of GTE. Clinical, experimental and histopathological observations indicate chronic, excessive alcohol consumption aggravates the free radical-mediated oxidative and nitrosative stress in several tissues including brain. Treatment with Epigallocatechin gallate (EGCG) significantly reduced the levels of oxidative/nitrosative stress paradigms, increased glutathione (GSH) levels and enhanced the activities of antioxidant enzymes. Histopathology evaluation revealed the possible influence of EGCG in reversing alcohol exacerbated diabetes-induced damage in cortex, cerebellum and hippocampus of brain. Furthermore, these studies have provided evidence to show how EGCG can exactly occupy the position in functional sites of nNOS (neuronal nitric oxide synthase) and induce a conformational change, inhibition of enzymatic activity and prevention of neurodegeneration/necrotic changes of tissue, in comparison with the rosiglitazone and glibenclamide. To summarise, this research has offered useful information on the action of EGCG that would provide potential protection against ethanol exacerbated diabetic brain damageand additional evidence for the use of EGCG as a lead compound for drug discovery.

The effect of chronic alcohol exposure on spatial memory and BDNF–TrkB- PLCγ1 signaling in the hippocampus of male and female mice

Alcohol is a commonly used drug worldwide, and abuse of alcohol has become a serious public health problem. Alcohol consumption over time can cause cognitive deficits and memory impairment, which is thought to be associated with changes in the hippocampus. Given previously known effects of brain-derived neurotrophic factor (BDNF) in regulating synaptic plasticity and learning and memory, we investigated the effect of chronic alcohol consumption on spatial memory impairment in both sexes and changes in BDNF signaling in the hippocampus. After 4 weeks of intermittent access to 20% alcohol, memory impairment in both male and female mice was evaluated using the Morris water maze and the expression of BDNF, TrkB, phosphorylation of PLCγ1 (p-PLCγ1) and PLCγ1 in the hippocampus was examined using Western blot. As expected, females spent longer escape latencies during the training phase, and both sexes spent shorter time in the target quadrant. Furthermore, after 4 weeks 20% alcohol exposure, we found significantly decreased expression levels of BDNF in the hippocampus of female mice but increased levels in male mice. TrkB and PLCγ1 expression showed no significant change in the hippocampus of both sexes. These findings suggest that chronic alcohol exposure may induce spatial memory impairment in both sexes and opposite changes in expression of BDNF and p-PLCγ1 in the hippocampus of males and females.

Effects of Chronic Alcohol Consumption and Iron Deficiency on Maternal Folate Status and Reproductive Outcome in Mice

The influence of chronic alcohol consumption with or without iron deficiency on reproductive performance and folate status was studied. Female CBA/J mice were fed isocaloric liquid diets prior to and during pregnancy. A 2 × 2 factorial design was employed with ethanol-derived calories (EDC) and iron (Fe) as dietary variables. Groups received 0% EDC and 30 ppm Fe (CA); 0% EDC and 2 ppm Fe (CD); 20% EDC and 30 ppm Fe (EA); and 20% EDC and 2 ppm Fe (ED). Animals were killed on day 18 of gestation. Mean body weights were reduced in CD, EA and ED groups, while daily caloric intakes reduced only in CD and ED groups. Maternal values for hemoglobin, transferrin saturation and red cell folates decreased with iron deficiency and/or 20% EDC; hematocrit, serum iron and serum folates decreased only with iron deficiency. Blood ethanol levels were similar in EA and ED groups. Maternal liver total lipids and alcohol dehydrogenase activity increased only with 20% EDC, while dihydrofolate reductase activity decreased with iron deficiency and/or 20% EDC. Iron deficiency and/or 20% EDC adversely affected gestational performances in mice as indicated by increased resorptions and decreased percentages of live fetuses/litters and live fetal weights. Data indicate that iron deficiency and/or chronic ethanol consumption induce adverse effects on maternal reproductive performance of CBA/J mice possibly via alteration of folate metabolism.

Chronic alcohol-induced dysbiosis of the gut microbiota and gut metabolites impairs sperm quality in mice.

Studies have indicated that the ethanol exposure impairs the gut microbiota, At the same time, high levels of alcohol exposure damage sperm in mice. However, whether the gut microbiota is involved in mediating the effects of alcohol on sperm quality remains unclear. This study aimed to assess the effect of chronic alcohol consumption on intestinal microbiota in mice and analyze the potential pathophysiological effect of altered intestinal microbiota on sperm quality. We established a mouse model of chronic alcohol consumption by allowing male C57 mice to freely ingest 10% ethanol for 10 weeks, and collected the fecal microbiota of the male mice in the chronic drinking group (alcohol) and the control group (control) and transplanted the specimens into the transplant groups (the alcohol-fecal microbiota transplantation [FMT] group and the control-FMT group). Sperm quality was significantly decreased in the alcohol-FMT group compared with the control-FMT group. Gut microbiota analysis revealed that the abundance of 11 operational taxonomic units (OTUs) was altered in the alcohol-FMT group. Nontargeted metabolomics identified 105 differentially altered metabolites, which were mainly annotated to amino acids, lipids, glycerophosphoethanolamine, organic oxygenic compounds, organic acids and their derivatives, steroids, and flavonoids. In particular, the oxidative phosphorylation pathway, which is the key to spermatogenesis, was significantly enriched in the alcohol-FMT group. Moreover, compared with the control-FMT group, the alcohol-FMT group presented significantly higher serum endotoxin and inflammatory cytokine levels, with more pronounced T cell and macrophage infiltration in the intestinal lamina propria and elevated levels of testicular inflammatory cytokines. In addition, RNA sequencing showed significant differences in the expression of testis-related genes between the alcohol-FMT group and the control-FMT group. In particular, the expression of genes involved in gamete meiosis, testicular mitochondrial function, and the cell division cycle was significantly reduced in alcohol-FMT mice. In conclusion, these findings indicated that intestinal dysbiosis induced by chronic alcohol consumption may be an important factor contributing to impaired sperm quality. Chronic alcohol consumption induces intestinal dysbiosis, which then leads to metabolic disorders, elevated serum endotoxin and inflammatory cytokine levels, testicular inflammation, abnormal expression of related genes, and ultimately, impaired sperm quality. These findings are potentially useful for the treatment of male infertility.

Binocular vision parameters in chronic heavy alcoholics: Short-term outcomes of alcohol detoxification

Background: Alcohol consumption is rising in developing countries such as India, and alcohol addiction has systemic and ocular impacts. This study aimed to investigate the binocular functions of chronic heavy alcoholics before and after alcohol detoxification.
 Methods: A prospective before–after study was designed and conducted at Treda De-Addiction Centre, Bengaluru, India. Males in the age range of 30–40 years who had been alcohol addicts for more than six years and met the inclusion criteria were recruited. We performed a routine optometric examination followed by detailed binocular vision assessment, including accommodative, vergence, and oculomotor tests on the first day of rehabilitation and one month after initiation of rehabilitation.
 Results: Twenty-five males with of the age (mean ± standard deviation [SD]) 36.24 ± 4.33 years were evaluated. The pre- and post-detoxification mean ± SD of the monocular (right eye: 5.98 ± 3.50, 6.60 ± 3.49; left eye: 6.18 ± 3.69, 7.10 ± 3.78) and binocular accommodative facility (7.10 ± 3.93, 7.40 ± 4.51) did not change significantly (all P > 0.05). Eighteen (72%) of the participants had non-strabismic binocular vision anomalies (NSBVA), among whom the accommodative infacility and convergence insufficiency were higher in frequency and remained constant after alcohol detoxification. Furthermore, the binocular vision parameters showed no statistically significant difference between the pre- and post-detoxification values (all P > 0.05).
 Conclusions: The binocular vision parameters did not change significantly after one month of alcohol detoxification in the chronic heavy drinkers. Most long-term alcoholics had NSBVA with no change after rehabilitation, indicating that short-term alcohol detoxification may not aid in the recovery of binocular parameters. However, further validation is required. Assessing the impact of vision therapy in addition to a longer period of abstinence can confirm or refute the persistence of observed effects of chronic alcohol consumption on binocular functions and NSBVA in this population.

Effect of chronic alcohol consumption on brain structure in males with alcohol use disorder without a familiar history of alcoholism

Structural brain damages caused by chronic alcohol consumption have been extensively reported. However, the neuroimaging findings in people with alcohol use disorder (AUD) are relatively inconsistent. This inconsistency may be due to the influence of different variables that are not always considered, such as the presence of a family history of alcoholism (FHA). The main aim of this research is to study the gray (GM) and white matter (WM) volumes in male participants with AUD without FHA compared to healthy control males (HC) without FHA. For this study, we included 19 participants with AUD without FHA and 18 HC males without FHA. T1-weighted images were acquired with a General Electric Signa Exite 1.5 T scanner. GM and WM tissues were calculated using Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL). All analyses were controlled for age and total brain volume. The statistical threshold was calculated with AlphaSim and further adjusted to account for the non-isotropic smoothness of structural images, according to Hayasaka et al. (2004). The obtained main results showed that, relative to the HC group, the participants with AUD without FHA had significantly lower GM in several brain structures, reflecting relatively purely the effects of chronic alcohol intake on brain volume. GM structure integrity is relevant for the efficient functioning of low and high-order cognitive processes used in everyday life, and its damage seems to be related to the severity/intensity/chronicity of the AUD. As such, it becomes relevant to assess and follow brain structural changes through the dependence course.

Effect of chronic alcohol consumption on myocardial apoptosis in the rat model of isoproterenol-induced myocardial injury and investigation on the cardioprotective role of calpain inhibitor 1

We investigated the presence of myocardial apoptosis on isoproterenol (ISO)-induced myocardial injury (MI) after long-term high dose alcohol consumption and examined the antiapoptotic role of calpain inhibitor 1. Male Wistar Albino rats (n = 108) were divided into six groups: Control, alcohol (ethanol was given during 30 days for chronic alcohol consumption), MI (150 mg/kg ISO injection at last two days of alcohol consumption), alcohol + MI, alcohol + MI + calpain inhibitor 1 (10 mg/kg inhibitor was injected at 15 min before ISO injections) and Dimethyl Sulfoxide (DMSO) groups. Biochemical, histological, and morphometric methods determined apoptosis levels in the heart tissue of rats. Cytochrome c, caspase 3, and calpain levels were significantly high in alcohol, MI, and alcohol + MI groups. In contrast, mitochondrial cardiolipin content was found to be low in alcohol, MI, and alcohol + MI groups. These parameters were close to the control group in the therapy group. Histological and morphometric data have supported biochemical results. As a result of our biochemical data, myocardial apoptosis was seen in the alcohol, MI, and especially alcohol after MI groups. Calpain inhibitor 1 reduced apoptotic cell death and prevented myocardial tissue injury in these groups. The efficiency of calpain inhibitor was very marked in MI after long-term high dose alcohol consumption.

Alcohol inhibits alveolar fluid clearance through the epithelial sodium channel via the A2 adenosine receptor in acute lung injury.

Chronic alcohol abuse increases the risk of mortality and poor outcomes in patients with acute respiratory distress syndrome. However, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the effects of chronic alcohol consumption on lung injury and clarify the signaling pathways involved in the inhibition of alveolar fluid clearance (AFC). In order to produce rodent models with chronic alcohol consumption, wild-type C57BL/6 mice were treated with alcohol. A2a adenosine receptor (AR) small interfering (si)RNA or A2bAR siRNA were transfected into the lung tissue of mice and primary rat alveolar type II (ATII) cells. The rate of AFC in lung tissue was measured during exposure to lipopolysaccharide (LPS). Epithelial sodium channel (ENaC) expression was determined to investigate the mechanisms underlying alcohol-induced regulation of AFC. In the present study, exposure to alcohol reduced AFC, exacerbated pulmonary edema and worsened LPS-induced lung injury. Alcohol caused a decrease in cyclic adenosine monophosphate (cAMP) levels and inhibited α-ENaC, β-ENaC and γ-ENaC expression levels in the lung tissue of mice and ATII cells. Furthermore, alcohol decreased α-ENaC, β-ENaC and γ-ENaC expression levels via the A2aAR or A2bAR-cAMP signaling pathways in vitro. In conclusion, the results of the present study demonstrated that chronic alcohol consumption worsened lung injury by aggravating pulmonary edema and impairing AFC. An alcohol-induced decrease of α-ENaC, β-ENaC and γ-ENaC expression levels by the A2AR-mediated cAMP pathway may be responsible for the exacerbated effects of chronic alcohol consumption in lung injury.

White matter integrity in alcohol-dependent patients with long-term abstinence.

Based on association studies on amounts of alcohol consumed and cortical and subcortical structural shrinkage, we investigated the effect of chronic alcohol consumption on white matter pathways using probabilistic tractography.Twenty-three alcohol-dependent men (with an average sobriety of 13.1 months) from a mental health hospital and 22 age-matched male healthy social drinkers underwent 3T magnetic resonance imaging. Eighteen major white matter pathways were reconstructed using the TRActs Constrained by UnderLying Anatomy tool (provided by the FreeSurfer). The hippocampal volumes were estimated using an automated procedure. The lifetime drinking history interview, Alcohol Use Disorder Identification Test, Brief Michigan Alcoholism Screening Test, and pack-years of smoking were also evaluated.Analysis of covariance controlling for age, cigarette smoking, total motion index indicated that there was no definite difference of diffusion parameters between the 2 groups after multiple comparison correction. As hippocampal volume decreased, the fractional anisotropy of the right cingulum-angular bundle decreased. Additionally, the axial diffusivity of right cingulum-angular bundle was positively correlated with the alcohol abstinence period.The results imply resilience of white matter in patients with alcohol dependence. Additional longitudinal studies with multimodal methods and neuropsychological tests may improve our findings of the changes in white matter pathways in patients with alcohol dependence.

Chronic ethanol consumption increases susceptibility to influenza A virus infections via alteration of memory CD8 T cell responses

Abstract Alcoholism is estimated to contribute to approximately 95,000 deaths within the United States per year making it the third leading preventable cause of death. These alcohol-related deaths are due, in part, to the increased risk of severe disease that human alcoholics have during bacterial and viral infections. Our laboratory has previously shown using a mouse model of chronic ethanol consumption that increased disease severity during a primary influenza A virus (IAV) infection is due to deficits in the developing IAV-specific CD8 T cell response. However, unlike mice, human alcoholics have likely been exposed to IAV prior to the onset of alcohol consumption. Therefore, we determined the effects of chronic alcohol consumption on pre-existing IAV immunity. Our results show that mice with established immunity to IAV that then chronically consumed alcohol (IAV-immune➞EtOH) exhibited increased morbidity and mortality to secondary heterologous IAV challenge compared to IAV-immune mice that then consumed water (IAV-immune➞H2O). IAV-immune➞EtOH mice also showed deficits in IAV-specific killing of target cells and a reduction in the number of IAV-specific CD8 T cells compared to IAV-immune ➞H2O mice. Finally, our results show that following a heterologous IAV challenge, the fold-increase of IAV-specific CD8 T cells within the lungs of IAV-immune➞EtOH was reduced compared to IAV-immune➞H2O mice. Interestingly, IAV-immune➞EtOH mice had reduced expression of CXCL10 and CXCL11 within their lungs, suggesting defects in cell trafficking. Overall, these data and our prior studies demonstrate that chronic alcohol consumption negatively impacts both the naïve and memory compartments of the CD8 T cell response to IAV infection.

Oridonin Attenuates the Effects of Chronic Alcohol Consumption Inducing Oxidative, Glycative and Inflammatory Injury in the Mouse Liver.

Oridonin (Ori) is a diterpenoid naturally present in medicinal plants with a potential as an antioxidant agent. This study aimed to evaluate the hepatic anti-oxidative, anti-glycative and anti-inflammatory properties of Ori at 0.125 and 0.25% against chronic ethanol intake in mice. Mice were divided into five groups: i) normal diet group, ii) Ori group, iii) ethanol diet (Lieber-DeCarli liquid diet with ethanol) group, iv) ethanol diet plus 0.125% Ori and v) ethanol diet plus 0.25% Ori. After 8 weeks of Ori supplementation, blood and liver tissue were used for analyses. Ethanol increased the production of reactive oxygen species and nitric oxide, decreased glutathione content, and lowered the activity of glutathione peroxide, glutathione reductase and catalase. Ethanol suppressed the hepatic mRNA expression of nuclear factor E2-related factor 2. Ori supplements reversed these changes. Ethanol increased hepatic Ne-(carboxyethymethyl)-lysine (CML) and pentosidine levels, and enhanced aldose reductase (AR) activity and mRNA expression. Ori supplements at only 0.25% decreased CML and pentosidine levels, and lowered the AR activity as well as its mRNA expression. Ethanol increased the hepatic release of tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin (IL)-1beta and IL-6. Histological data showed that ethanol induced necrosis and inflammatory cell infiltration, while Ori supplements alleviated these inflammatory responses. Ethanol up-regulated the hepatic mRNA expression of nuclear factor kappa B, myeloperoxidase and p38. Ori supplements reversed these changes. These novel findings suggest that Ori could be used as a potent agent against alcohol-induced hepatotoxicity.

Chronic alcohol exposure reduces acetylated histones in the sleep-wake regulatory brain regions to cause insomnia during withdrawal

BackgroundAlcohol use disorder (AUD) develops after chronic and heavy use of alcohol. Insomnia, a hallmark of AUD, plays a crucial role in the development of AUD. However, the causal mechanisms are unknown. Since chronic alcohol reduces acetylated histones and disrupts the epigenome, we hypothesized that chronic alcohol exposure will reduce acetylated histones in wake-promoting regions of the brain to cause insomnia during alcohol withdrawal. MethodsAdult male C57BL/6J mice, surgically instrumented for electrophysiological monitoring of sleep-wakefulness, were exposed to chronic alcohol (6.8%) consumption using Lieber-DeCarli liquid diet. Three experiments were performed. First, the effect of chronic alcohol consumption was examined on sleep-wakefulness during 7 days of withdrawal. Second, the expression of acetylated histones, H3 lysine 14 (AcH3K14), was examined in two major sleep-wake regulatory brain regions: basal forebrain (BF) and lateral hypothalamus (LH) of the brain by using western blotting. Next, blockade of histone deacetylase, via systemic administration of TSA was examined on alcohol-induced changes in sleep-wakefulness. ResultsAlcoholic mice displayed a significant reduction in the quality and quantity of NREM sleep coupled with a significant increase in wakefulness that lasted for several days during alcohol withdrawal. In addition, alcoholic mice displayed a significant reduction in the expression of AcH3K14 in both BF and LH. Systemic administration of TSA significantly attenuated insomnia and improved the quality and quantity of sleep during alcohol withdrawal. ConclusionsBased on our results, we suggest that a causal relationship exists between reduced histone acetylation and insomnia during alcohol withdrawal.

The Effect of Smoking on the Association between Long-Term Alcohol Consumption and Dyslipidemia in a Middle-Aged and Older Population.

The joint effects of chronic alcohol consumption and smoking on dyslipidemia remain unclear in a prospective design. This study examined the effect of smoking on the association between long-term alcohol consumption and risk of incident dyslipidemia. A total of 4467 participants (1866 men and 2601women) aged 40-69years without dyslipidemia were recruited at baseline. Alcohol consumption was assessed biennially using a questionnaire and classified as light, moderate or heavy drinker. Smoking status was examined at baseline and categorized into non-smokers and current smokers. Dyslipidemia was defined as the presence of one or more of following: hypertriglyceridemia (triglyceride ≥200mg/dL), hypercholesterolemia (total cholesterol ≥240mg/dL), low high-density lipoprotein-cholesterol (HDL-C)<40mg/dL, or high low-density lipoprotein cholesterol ≥160mg/dL. During a follow-up period of 12years, 2872 (64.3%) participants developed dyslipidemia. In non-smoking men, light or moderate alcohol consumption was associated with a lower risk of incident dyslipidemia such as hypertriglyceridemia and hypercholesterolemia, whereas this association was not observed in current smoking men. Unlike non-smokers, the duration of alcohol drinking > 10years was associated with a higher risk of hypertriglyceridemia in current smoking men (hazard ratio=1.57, 95% confidence interval: 1.07-2.30, P=0.020). In addition, alcohol consumption was inversely associated with low HDL-C regardless of smoking status. In women, alcohol consumption was inversely associated with dyslipidemia hypercholesterolemia and low HDL-C regardless of alcohol amount. Smoking crucially confounds the association between long-term alcohol consumption and dyslipidemia, particularly in hypertriglyceridemia and hypercholesterolemia.

Chronic ethanol consumption causes lesions in CD8 T cell memory and is associated with increased susceptibility to influenza A virus infections

Abstract Chronic alcohol consumption is associated with increased risk of severe disease during both bacterial and viral infections. We have previously shown that this increased disease severity during a primary influenza A virus (IAV) infection is due to deficits in the developing IAV-specific CD8 T cell response. Recent studies have highlighted that human alcoholics have increased susceptibility to IAV infections, even though they likely possess pre-existing immune memory to IAV. However, the effects of chronic alcohol consumption on pre-existing immune memory responses have not been explored. Here, our results show that mice previously exposed to IAV infection that then consumed alcohol (IAV-immune➞EtOH) exhibited increased morbidity and mortality to secondary heterologous IAV challenge compared to IAV-immune mice that had consumed water (IAV-immune➞H2O). This increased susceptibility in IAV-immune➞EtOH mice was associated with reduced IAV-specific killing of target cells. Furthermore, we observed a universal numerical reduction of all memory CD8 T cell subsets within the lungs of IAV-immune➞EtOH mice compared to IAV-immune➞H2O mice. Finally, our results show that IAV-specific CD8 T cell recall responses upon secondary IAV challenge are altered in IAV-immune➞EtOH mice, particularly within the lung tissue, and were associated with reduced expression of CXCL10 and CXCL11, suggesting defects in cell trafficking. Overall, these data demonstrate that the negative impacts of chronic alcohol consumption occur across the full CD8 T cell compartment, including both the naïve and memory response, contributing to lesions in the development of de novo CD8 T cell and pre-existing memory CD8 T cell responses.

Daily Ethanol Drinking Followed by an Abstinence Period Impairs Bone Marrow Niche and Mitochondrial Function of Hematopoietic Stem/Progenitor Cells in Rhesus Macaques.

Unhealthy consumption of alcohol is a major public health crisis with strong associations between immunological dysfunctions, high vulnerability to infectious disease, anemia, and an increase in the risk of hematological malignancies. However, there is a lack of studies addressing alcohol-induced changes in bone marrow (BM) and hematopoiesis as fundamental aspects of immune system function. To address the effect of chronic alcohol consumption on hematopoietic stem and progenitor cells (HSPCs) and the BM niche, we used an established rhesus macaque model of voluntary alcohol drinking. A cohort of young adult male rhesus macaques underwent a standard ethanol self-administration protocol that allowed a choice of drinking alcohol or water 22hours/day with periods of forced abstinence that elevated subsequent intakes when alcohol availability resumed. Following the last month of forced abstinence, the monkeys were euthanized. HSPCs and bone samples were collected and analyzed in functional assays and by confocal microscopy. HSPCs from alcohol animals exhibited reduced ability to formgranulocyte-monocyte and erythroidcolonies in vitro. HSPCs also displayed a decrease in mitochondrial oxygen consumption linked to ATP production and basal respiratory capacity. Chronic alcohol use led to vascular remodeling of the BM niche, a reduction in the number of primitive HSPCs, and a shift in localization of HSPCs from an adipose to a perivascular niche. Our study demonstrates, for the first time, that chronic voluntary alcohol drinking in rhesus macaque monkeys leads to the long-term impairment of HSPC function, a reduction in mitochondrial respiratory activity, and alterations in the BM microenvironment. Further studies are needed to determine whether these changes in hematopoiesis are persistent or adaptive during the abstinent period and whether an initial imprinting to alcohol primes BM to become more vulnerable to future exposure to alcohol.

Chronic Alcohol Consumption is Inversely Associated with Insulin Resistance and Fatty Liver in Japanese Males.

We aimed to elucidate the effect of chronic alcohol consumption on fatty liver. We assessed the consumption of alcohol in 2429 Japanese males (mean age: 54.2 ± 9 years); they were classified according to average consumption into non-drinkers (ND), light drinkers (LD), moderate drinkers (MD), and heavy drinkers (HD). The prevalence of fatty liver was the lowest in the MD and highest in the ND group (p < 0.001), while obesity was not significantly different among the groups (p = 0.133). Elevated levels of alanine aminotransferase (ALT) were the lowest in the MD group (p = 0.011) along with resistance to insulin (homeostasis model assessment-insulin resistance (HOMA-IR)), which was highest in the ND group (p = 0.001). Chronic consumption of alcohol was independently and inversely associated with fatty liver and insulin resistance after adjusting for obesity, hypertension, fasting hyperglycemia, habit of drinking sweet beverages, physical activity, and age (odds ratios are as follows: ND, 1; LD, 0.682; MD, 0.771; HD, 0.840 and ND, 1; LD, 0.724; MD, 0.701; HD, 0.800, respectively). We found that regardless of the type of alcoholic beverage, chronic consumption of alcohol is inversely associated with insulin resistance and fatty liver in Japanese males. This study had limitations, most notably the lack of investigation into diet and nutrition.

Adverse Effects of Chronic Alcohol Consumption

Chronic alcohol consumption has emerged as a leading cause of metabolic derangement in susceptible cohorts worldwide; ethanol has a high calorific value and excessive intake interferes with energy metabolism. It has a very high glycemic index, so the glucose homeostasis does not follow the normal physiological regulations in chronic consumption of ethanol. Chronic alcohol consumption is a global concern for its health issues. The detailed mechanism of alcohol-associated organ damage and health anomalies has been reviewed here. Almost all of its metabolic fates has minor to major impacts on any physiological process. The main rate-limiting markers of glucose homeostasis, i.e. NADH/NAD+ and ATP/ADP, are physiologically misjudged in ethanol consumption; as a result, excess acetoacetyl CoA becomes engaged in ketone body formation resulting in ketoacidosis. Ethanol induced ROS production and antioxidant depletion resulting in necrotic tissue damage especially in the stomach, intestine epithelial cells, and liver. Increased oxidative stress causes vascular dysfunction, NO deregulation, peripheral vascular resistance, increased blood pressure, and aldosterone-induced hypertension. Ethanol manipulates intracellular phosphorylation regulations by influencing MAPK and inflammatory molecule, like TNFa and IL-6, and transcriptional stress factor like NF-κβ, Nrf-2, and Hif-α via redox signalling. Activation of lipogenic factors and PPAR signalling drastically increase body fat accumulation. Direct damage to the pancreatic cells generates insulin resistance. Synergistic effects of several metabolic malfunctioning develop insulin resistance, chronic hyperglycaemia, and abnormal fat accumulation.

Chronic Ethanol Consumption Reduces Existing CD8 T Cell Memory and Is Associated with Lesions in Protection against Secondary Influenza A Virus Infections.

Chronic alcohol consumption is associated with an increased incidence of disease severity during pulmonary infections. Our previous work in a mouse model of chronic alcohol consumption has detailed that the primary influenza A virus (IAV)-specific CD8 T cell response in mice that consumed ethanol (EtOH) had a reduced proliferative capacity as well as the ability to kill IAV target cells. Interestingly, recent studies have highlighted that human alcoholics have an increased susceptibility to IAV infections, even though they likely possess pre-existing immunity to IAV. However, the effects of chronic alcohol consumption on pre-existing immune responses (i.e., memory) to IAV have not been explored. Our results presented in this study show that IAV-immune mice that then chronically consumed alcohol (X31→EtOH) exhibited increased morbidity and mortality following IAV re-exposure compared with IAV-immune mice that had consumed water (X31→H2O). This increased susceptibility in X31→EtOH mice was associated with reduced IAV-specific killing of target cells and a reduction in the number of IAV-specific CD8 T cells within the lungs. Furthermore, upon IAV challenge, recruitment of the remaining memory IAV-specific CD8 T cells into the lungs is reduced in X31→EtOH mice. This altered recruitment is associated with a reduced pulmonary expression of CXCL10 and CXCL11, which are chemokines that are important for T cell recruitment to the lungs. Overall, these results demonstrate that chronic alcohol consumption negatively affects the resting memory CD8 T cell response and reduces the ability of memory T cells to be recruited to the site of infection upon subsequent exposures, therein contributing to an enhanced susceptibility to IAV infections.

Effects of chronic alcohol consumption and withdrawal on the cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei of the rat: An unbiased stereological study

The brain cholinergic system comprises two main recognized subdivisions, the basal forebrain and the brainstem cholinergic systems. The effects of chronic alcohol consumption on the basal forebrain cholinergic nuclei have been investigated extensively, but there is only one study that has examined those effects on the brainstem cholinergic nuclei. The last one comprises the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei, which are known to give origin to the main cholinergic projection to the ventral tegmental area, a key brain region of the neural circuit, the mesocorticolimbic system, that mediates several behavioral and physiological processes, including reward. In the present study, we have examined, using stereological methods, the effects of chronic alcohol consumption (6 months) and subsequent withdrawal (2 months) on the total number and size of PPT and LDT choline acetyltransferase (ChAT)-immunoreactive neurons. The total number of PPT and LDT ChAT-immunoreactive neurons was unchanged in ethanol-treated and withdrawn rats. However, ChAT-immunoreactive neurons were significantly hypertrophied in ethanol-treated rats, an alteration that did not revert 2 months after ethanol withdrawal. These results show that prolonged exposure to ethanol leads to long-lasting, and potentially irreversible, cytoarchitectonic and neurochemical alterations in the brainstem cholinergic nuclei. These alterations suggest that the alcohol-induced changes in the brainstem cholinergic nuclei might play a role in the mechanisms underlying the development of addictive behavior to alcohol.