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Chronic Alcohol Consumption (chronic + alcohol_consumption)

Distribution by Scientific Domains

Medical Sciences	87%
Life Sciences	7%

Selected Abstracts

Chronic Alcohol Consumption Is Associated With an Increased Cytotoxic Profile of Circulating Lymphocytes That May Be Related With the Development of Liver Injury

ALCOHOLISM, Issue 5 2010
Francisco Javier Laso
Background:, Apoptosis has recently emerged as a key component of acute and chronic liver diseases and it could be related to alcoholic liver disease. In the present study, we attempted to analyze the cytotoxic profile of circulating lymphocytes in chronic alcoholic patients grouped according to ethanol intake status and presence of liver disease. Methods:, We investigate the phenotypic and functional behavior of different compartments of peripheral blood (PB) cytotoxic T and natural killer (NK) cells in chronic alcoholic patients without liver disease and active ethanol intake (AWLD group; n = 22), and in subjects with alcohol liver cirrhosis (ALC group; n = 22). Results:, AWLD patients showed an expansion of both CD4+/CD8+ cytotoxic T cells and NK/T cells, in association with an enhanced cytolytic activity against K562 cells and a higher ability to induce in vitro expression of the pro-apoptotic protein APO2.7 in HepG2 cells. Conversely, ethanol intake in ALC patients was associated with decreased NK cell numbers, a reduced cytotoxic activity against K562 cells without significant changes in the expression of APO2.7, and a pro-fibrotic profile of cytokine secretion. Conclusions:, Overall, our results suggest that alcoholic patients display different phenotypical and functional changes in circulating PB cytotoxic lymphocytes according to the presence of alcoholic liver disease, which could be related to the development and progress of liver injury. [source]

Chronic Alcohol Consumption Disrupted Cholesterol Homeostasis in Rats: Down-Regulation of Low-Density Lipoprotein Receptor and Enhancement of Cholesterol Biosynthesis Pathway in the Liver

ALCOHOLISM, Issue 3 2010
Zhigang Wang
Background:, Chronic alcohol consumption causes alcoholic liver disease, which is associated, or initiated, with dysregulated lipid metabolism. Very recent evidence suggested that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver diseases, however, the effects of chronic alcohol exposure on cholesterol homeostasis have not been well studied and underlying mechanisms behind are still elusive. Methods:, Male Sprague,Dawley rats weighing 250 ± 5.5 g (mean ± SEM) divided into 2 groups (8 rats per group) and pair-fed with liquid diets containing (in percent of energy intake) 18% protein, 35% fat, 12% carbohydrate, and 35% either ethanol (ethanol diet) or an isocaloric maltose-dextrin mixture (control diet), according to Lieber and De Carli, for 4 weeks. Results:, Long-term excessive alcohol feeding to rats caused fatty liver and liver injury, which was associated with disrupted cholesterol homeostasis, characterized by increased hepatic cholesterol levels and hypercholesterolemia. Hepatic cholesterol increases were concomitant with constantly activated sterol regulatory element-binding protein-2 (SREBP-2) in the liver and increased expression of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol de novo synthesis, indicating enhanced cholesterol biosynthesis. Alcohol-induced hypercholesterolemia was accompanied by decreased LDL receptor (LDLr) levels in the liver. Further investigations revealed that chronic alcohol exposure increased hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) contents to down-regulate LDLr via a post-translational mechanism. Moreover, alcohol feeding suppressed extracellular signal-regulated kinase (ERK) activation in the liver. In vitro studies showed that inhibition of ERK activation was associated with decreased LDLr expression in HepG2 cells. Conclusions:, Our study provides the first evidence that both increased PCSK9 expression and suppressed ERK activation in the liver contributes to alcohol-induced hypercholesterolemia in rats. [source]

Exogenous IL-15 in Combination With IL-15R, Rescues Natural Killer Cells From Apoptosis Induced by Chronic Alcohol Consumption

ALCOHOLISM, Issue 3 2009
Hui Zhang
Background:, Chronic alcohol consumption reduces the percentage and number of peripheral natural killer (NK) cells in mice and in humans. The underlying mechanism for these changes is only partly known. We recently found that chronic alcohol consumption inhibits NK cell release from the bone marrow (BM) and that this is associated with a decrease in splenic NK cells. The number of peripheral NK cells is tightly controlled by homeostatic proliferation. It is not known whether this mechanism is initiated in response to the reduction in splenic NK cells, or if so, why the steady state levels of NK cells are not restored. Methods:, To examine this mechanism, female C57BL/6 mice were given 20% w/v alcohol in the drinking water for 3 months. NK cell proliferation and apoptosis were determined before and after treatment with IL-15 alone or combined with its alpha receptor. Results:, Chronic alcohol consumption invoked homeostatic proliferation of splenic NK cells in an attempt to return NK cells to normal levels; however, this did not happen due to enhanced apoptosis of NK cells relative to proliferation. Chronic alcohol consumption decreased IL-15 producing cells in the spleen but not in the BM. The numbers of NK cells in the alcohol-consuming mice returned to normal levels in the spleen and were higher than normal in the BM after 2 daily injections of IL-15; however, the enhanced rate of apoptosis due to alcohol consumption was not decreased in the spleen or BM. Combined IL-15 and IL-15R, treatment decreased apoptosis of NK cells from alcohol-consuming mice to levels similar to untreated water-drinking mice and greatly increased the percentage and number of NK cells in both the spleen and BM. Conclusion:, Chronic alcohol consumption causes a self-unrecoverable loss of NK cells in the spleen by compromising NK cell release from the BM and enhancing splenic NK cell apoptosis that can be reversed with IL-15/IL-15R, treatment. [source]

Proteomic Analysis Demonstrates Adolescent Vulnerability to Lasting Hippocampal Changes Following Chronic Alcohol Consumption

ALCOHOLISM, Issue 1 2009
Garth A. Hargreaves
Background:, Excessive teenage alcohol consumption is of great concern because alcohol may adversely alter the developmental trajectory of the brain. The aim of the present study was to assess whether chronic intermittent alcohol intake during the adolescent period alters hippocampal protein expression to a greater extent than during adulthood. Methods:, Adolescent [postnatal day (PND) 27] and adult (PND 55) male Wistar rats were given 8 hours daily access to beer (4.44% ethanol v/v) in addition to ad libitum food and water for 4 weeks. From a large subject pool, subgroups of adolescent and adult rats were selected that displayed equivalent alcohol intake (average of 6.1 g/kg/day ethanol). The 4 weeks of alcohol access were followed by a 2-week alcohol-free washout period after which the hippocampus was analyzed using 2-DE proteomics. Results:, Beer consumption by the adult group resulted in modest hippocampal changes relative to alcohol naïve adult controls. The only changes observed were an up-regulation of citrate synthase (a precursor to the Krebs cycle) and fatty acid binding protein (which facilitates fatty acid metabolism). In contrast, adolescent rats consuming alcohol showed more widespread hippocampal changes relative to adolescent controls. These included an increase in cytoskeletal protein T-complex protein 1 subunit epsilon (TCP-1) and a decrease in the expression of 10 other proteins, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), triose phosphate isomerise, alpha-enolase, and phosphoglycerate kinase 1 (all involved in glycolysis); glutamate dehydrogenase 1 (an important regulator of glutamate); methylmalonate-semialdehyde dehydrogenase (involved in aldehyde detoxification); ubiquitin carboxyl-terminal hydrolase isozyme L1 (a regulator of protein degradation); and synapsin 2 (involved in synaptogenesis and neurotransmitter release). Conclusions:, These results suggest the adolescent hippocampus is more vulnerable to lasting proteomic changes following repeated alcohol exposure. The proteins most affected include those related to glycolysis, glutamate metabolism, neurodegeneration, synaptic function, and cytoskeletal structure. [source]

Opposing Effects of Chronic Alcohol Consumption on Hepatic Gluconeogenesis for Female Versus Male Rats

ALCOHOLISM, Issue 10 2005
Ken D. Sumida
Abstract: Background: The impact of chronic alcohol consumption on hepatic gluconeogenesis (HGN) between males and females is unknown. To determine the effects of chronic alcohol consumption (8 weeks) on HGN, the isolated liver perfusion technique was used on 24-hr-fasted male and female Wistar rats. Methods: After surgical isolation, livers were perfused (single pass) for 30 min with Krebs-Henseleit bicarbonate buffer and fresh bovine erythrocytes with no added substrate (washout period). After the washout period, livers were perfused with lactate (10 mM) and [U- 14C]lactate (15,000 dpm/ml) using the recirculation method. Results: There was no significant difference in HGN between males and females fed the control diet. In contrast, the females chronically fed the ethanol diet (FE) had significantly lower HGN rates (2.73 ± 0.37 ,mol/min × g liver protein,1), whereas males fed the ethanol diet (ME) had significantly higher HGN rates (4.99 ± 0.45 ,mol/min × g liver protein,1) than controls (3.83 ± 0.34 ,mol/min × g liver protein,1). Concomitant decreases were also observed for both 14C-lactate incorporation into 14C-glucose and rates of lactate uptake for FE, while corresponding increases were observed for 14C-lactate incorporation into 14C-glucose for ME. The livers from ME were able to convert a greater percentage of the lactate into glucose, resulting in the elevation in gluconeogenic capacity. Conclusion: Chronic alcohol consumption lowers the hepatic gluconeogenic capacity from lactate in females and elevates HGN in males. [source]

Effect of Chronic Alcohol Consumption on Total Plasma Homocysteine Level in Rats

ALCOHOLISM, Issue 3 2000
Felix Stickel
Background: Chronic alcoholism in humans is associated with the development of hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6, Population-based studies indicate that folate is the strongest vitamin determinant of hyperhomocysteinemia and, in most settings, folate supplementation effectively lowers elevated homocysteine levels. However, it is not clear whether folate deficiency is the cause of alcoholrelated hyperhomocysteinemia. Methods: In the present study, 10 male Sprague Dawley® rats were fed ethanol-containing Lieber- DeCarli diets with 13 mg of folic acid per kilogram of diet. This represents a folate intake more than 20 times the basal requirement. Ethanol represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol). The same number of rats were pair-fed with isocaloric control diets that contained an identical level of folate in which ethanol was entirely replaced by maltodextrin. Results: At the end of 4 weeks, alcohol-fed rats did not show any significant reduction in plasma or hepatic folate concentrations, plasma pyridoxal-5,-phosphate concentration, or plasma vitamin B12 concentration. On the other hand, alcohol-fed rats were significantly hyperhomocysteinemic (17.24 ± 4.63 ,mol/liter,p < 0.01) compared to the nonalcohol group (10.73 ± 2.76 ,mol/liter). Alcohol-fed rats also had a significantly lower hepatic S-adenosylmethionine and higher hepatic S-adenosylhomocysteine levels. Conclusions: Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is related to interference with one-carbon metabolism, and not through vitamin depletion. [source]

Chronic alcohol consumption increases the sensitivity of rat liver mitochondrial respiration to inhibition by nitric oxide

HEPATOLOGY, Issue 1 2003
Aparna Venkatraman
Chronic alcohol consumption is a well-known risk factor for hepatic injury, and mitochondrial damage plays a significant role in this process. Nitric oxide (NO) is an important modulator of mitochondrial function and is known to inhibit mitochondrial respiration. However, the impact of chronic alcohol consumption on NO-dependent control of liver mitochondrial function is unknown. This study examines the effect of alcohol exposure on liver mitochondria in a rat model and explores the interaction of NO and mitochondrial respiration in this context. Mitochondria were isolated from the liver of both control and ethanol-fed rats after 5 to 6 weeks of alcohol consumption. Mitochondria isolated from ethanol-treated rats showed a significant decrease in state 3 respiration and respiratory control ratio that was accompanied by an increased sensitivity to NO-dependent inhibition of respiration. In conclusion, we show that chronic alcohol consumption leads to increased sensitivity to the inhibition of respiration by NO. We propose that this results in a greater vulnerability to hypoxia and the development of alcohol-induced hepatotoxicity. [source]

Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver

HEPATOLOGY, Issue 2 2002
Ping Zhao
Chronic alcohol consumption may potentiate acetaminophen (APAP) hepatotoxicity through enhanced formation of N -acetyl- p -benzoquinone imine (NAPQI) via induction of cytochrome P450 2E1 (CYP2E1). However, CYP2E1 induction appears to be insufficient to explain the claimed magnitude of the interaction. We assessed the role of selective depletion of liver mitochondrial glutathione (GSH) by chronic ethanol. Rats were fed the Lieber-DeCarli diet for 10 days or 6 weeks. APAP toxicity in liver slices (% glutathione- S -transferase , released to the medium, GST release) and NAPQI toxicity in isolated liver mitochondria (succinate dehydrogenase inactivation, SDH) from these rats were compared with pair-fed controls. Ethanol induced CYP2E1 in both the 10-day and 6-week groups by ,2-fold. APAP toxicity in liver slices was higher in the 6-week ethanol group than the 10-day ethanol group. Partial inhibition of NAPQI formation by CYP2E1 inhibitor diethyldithiocarbamate to that of pair-fed controls abolished APAP toxicity in the 10-day ethanol group only. Ethanol selectively depleted liver mitochondrial GSH only in the 6-week group (by 52%) without altering cytosolic GSH. Significantly greater GSH loss and APAP covalent binding were observed in liver slice mitochondria of the 6-week ethanol group. Isolated mitochondria of the 6-week ethanol group were ,50% more susceptible to NAPQI (25-165 ,mol/L) induced SDH inactivation. This increased susceptibility was reproduced in pair-fed control mitochondria pretreated with diethylmaleate. In conclusion, 10-day ethanol feeding enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial GSH. [source]

Chronic alcohol consumption augments loss of sialic acid residues and alters erythrocyte membrane charge in type II diabetic patients

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 5 2008
Serkan Degirmenci
Abstract In this study, the effects of alcohol consumption on erythrocyte membrane properties in type 2 diabetic patients were investigated. Therefore, we measured total and lipid-bound sialic acid (LSA) levels, sialidase activities, and erythrocyte membrane negative charge. Three groups, including control group (n = 20), alcohol-consuming diabetic patients group (n = 14), and diabetic patients without alcohol consumption group (n = 42), were created. Plasma total sialic acid (TSA) levels of the alcohol-consuming diabetic group were elevated as compared to the healthy control and diabetic group (p < 0.001 and p < 0.01, respectively). TSA levels of the diabetic group were significantly elevated as compared to the healthy control group (p > 0.001). Plasma LSA levels of the alcohol-consuming diabetic group were higher than that in the healthy control and diabetic group (p < 0.05 and p < 0.05, respectively). LSA levels of the diabetic group were found to be high as compared to the healthy control group (p < 0.05). Plasma sialidase activities of the alcohol-consuming diabetic group and diabetic group were significantly elevated as compared to the healthy control group (p < 0.05 and p < 0.05, respectively). Sialidase activities of the alcohol-consuming diabetic group were elevated as compared to the diabetic group, but this was not statistically significant (p > 0.05). Erythrocyte membrane negativity levels of the alcohol-consuming diabetic group and diabetic group were significantly decreased (p < 0.001 and p < 0.001, respectively) as compared to the healthy control group. Erythrocyte membrane negativity levels of the alcohol-consuming diabetic group were decreased as compared to the diabetic group, but this was not statistically significant (p > 0.05). In conclusion, our results indicate that chronic alcohol consumption may augment membrane alterations in type 2 diabetic patients. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:320,327, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20243 [source]

Chronic Alcohol Consumption Disrupted Cholesterol Homeostasis in Rats: Down-Regulation of Low-Density Lipoprotein Receptor and Enhancement of Cholesterol Biosynthesis Pathway in the Liver

Exogenous IL-15 in Combination With IL-15R, Rescues Natural Killer Cells From Apoptosis Induced by Chronic Alcohol Consumption

Alcohol and Colorectal Cancer: The Role of Alcohol Dehydrogenase 1C Polymorphism

ALCOHOLISM, Issue 3 2009
Nils Homann
Background:, Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenase leading to elevated acetaldehyde concentrations following ethanol ingestion support the hypothesis that acetaldehyde may be responsible for this carcinogenic effect of alcohol. In Caucasians, a polymorphism of alcohol dehydrogenase 1C (ADH1C) exists resulting in different acetaldehyde concentrations following ethanol oxidation. Methods:, To evaluate whether the association between alcohol consumption and colorectal tumor development is modified by ADH1C polymorphism, we recruited 173 individuals with colorectal tumors diagnosed by colonoscopy and 788 control individuals without colorectal tumors. Genotyping was performed using genomic DNA extracted from whole blood followed by polymerase chain reaction. Results:, Genotype ADH1C*1/1 was more frequent in patients with alcohol-associated colorectal neoplasia compared to patients without cancers in the multivariate model controlling for age, gender, and alcohol intake (odds ratio = 1.674, 95% confidence interval = 1.110,2.524, 2-sided p from Wald test = 0.0139). In addition, the joint test of the genetic effect and interaction between ADH1C genotype and alcohol intake (2-sided p = 0.0007) indicated that the difference in ADH1C*1 polymorphisms between controls and colorectal neoplasia is strongly influenced by the alcohol consumption and that only individuals drinking more than 30 g ethanol per day with the genotype ADH1C*1/1 had an increased risk for colorectal tumors. Conclusions:, These data identify ADH1C homozygosity as a genetic risk marker for colorectal tumors in individuals consuming more than 30 g alcohol per day and emphasize the role of acetaldehyde as a carcinogenic agent in alcohol-related colorectal carcinogenesis. [source]

Opposing Effects of Chronic Alcohol Consumption on Hepatic Gluconeogenesis for Female Versus Male Rats

Reduction of Perforin, Granzyme B, and Cytokine Interferon , by Ethanol in Male Fischer 344 Rats

ALCOHOLISM, Issue 4 2003
Madhavi Dokur
Background: Chronic alcohol consumption can impair the immune system and predispose individuals to an increased risk of cancer and infection. Natural killer (NK) cells are the first line of defense against viral, bacterial, and fungal infections and play an important role in cellular resistance to malignancy and tumor metastasis. We have shown previously that ethanol administration suppresses NK cell cytolytic activity in male Fischer rats. This study analyzed the effects of ethanol on perforin, granzyme B, and the cytokine interferon (IFN)-,, factors that modulate NK cell cytolytic activity, to understand the molecular mechanism involved in ethanol's suppression of NK cell activity. Methods: A group of male Fischer rats was fed an ethanol-containing diet (8.7% v/v), whereas a control group was pair-fed an isocaloric diet. At the end of 2 weeks, animals were decapitated, and spleen tissues were immediately removed and used for analysis of NK cell cytolytic activity, perforin, granzyme B, and IFN-, messenger RNA (mRNA) or protein levels. The mRNA levels of perforin, granzyme B, and IFN-, were evaluated by quantitative real-time polymerase chain reaction, and protein levels of these factors were analyzed by Western blot, enzyme-linked immunosorbent assay, or enzymatic activity assay. Results: Ethanol reduced the NK cell cytolytic activity and decreased the mRNA expression of perforin, granzyme B, and IFN-, in ethanol-fed animals when compared with pair-fed animals. Ethanol also significantly reduced the protein levels of perforin and IFN-, and the enzyme activity of granzyme B in alcohol-fed animals as compared with pair-fed animals. Conclusions: These data suggest that chronic ethanol consumption may suppress NK cell cytolytic activity in male Fischer rats by decreasing the production, activity, or both of granzyme B, perforin, and IFN-,. [source]

Inhibition of Alcohol-Associated Colonic Hyperregeneration by ,-Tocopherol in the Rat

ALCOHOLISM, Issue 1 2003
P. Vincon
Background: Chronic alcohol consumption results in colorectal mucosal hyperregeneration, a condition associated with an increased risk for colorectal cancer. Possible mechanisms may involve the effects of acetaldehyde and/or free radicals generated during alcohol metabolism. Vitamin E is part of the antioxidative defense system, and its concentration is decreased or its metabolic utilization increased in various tissues after chronic alcohol consumption. We wondered whether ,-tocopherol supplementation may prevent ethanol-induced colorectal cell cycle behavior and whether these changes were related to alterations in protein synthesis. Methods: Five groups of male Wistar rats, each consisting of 14 animals, received liquid diets as follows: group 1, alcohol; group 2, alcohol +,-tocopherol; group 3, control (i.e., isocaloric glucose); group 4; control (i.e., isocaloric glucose) +,-tocopherol. Group 5 was fed a solid chow diet ad libitum. After 4 weeks of feeding, immunohistology was performed with anti-proliferating cell nuclear antigen (PCNA) or anti-BCL2 antibodies. Fractional (ks) and absolute (Vs) rates of protein synthesis and rates of protein synthesis relative to RNA (kRNA) and DNA (kDNA) were measured with a flooding dose of L-[4- 3H] phenylalanine with complementary analysis of protein and nucleic acid composition. Results: The PCNA index was increased significantly in the colon after ethanol administration compared with controls (ethanol, 10.3 ± 2.3 vs. control, 6.51 ± 1.6% PCNA positive cells, p < 0.05), although neither the protein, RNA, and DNA concentrations nor ks, kRNA, kDNA, and Vs were affected. This increase in PCNA index was significantly diminished by coadministration of ,-tocopherol (ethanol +, - tocopherol, 7.86 ± 1.71% PCNA positive cells, p < 0.05) without significant alterations in protein synthetic parameters. A similar result was obtained for the PCNA index in the rectal mucosa (ethanol, 14.6 ± 4.4 vs. control, 12.1 ± 4.2% PCNA positive cell), although this did not reach statistical significance. Neither ethanol nor , - tocopherol feeding had any significant effect on BCL-2 expression in the colorectal mucosa. As with the colon, protein synthetic parameters in the mucosa were not affected by alcohol feeding at 4 weeks. These effects on colonic cell turnover without corresponding changes in protein synthesis thus represent a specific localized phenomenon rather than a general increase in anabolic processes in the tissue and reaffirm the hyperregenerative properties of chronic alcohol consumption. Conclusions: Alcohol-associated hyperproliferation could be prevented, at least in part, by supplementation with ,-tocopherol. This may support the hypothesis that free radicals are involved in the pathogenesis of alcohol-associated colorectal hyperproliferation. [source]

Early Alteration in Leukocyte Populations and Th1/Th2 Function in Ethanol-Consuming Mice

ALCOHOLISM, Issue 8 2001
Shawn Starkenburg
Background: Chronic alcohol consumption polarizes the immune response away from Th1-mediated cell-mediated immunity. In the present report we investigate the first onset of alteration in immune parameters during ethanol consumption in terms of changes in splenic leukocyte cellularity and surface phenotype as well as alterations in Th1 and Th2 function. Methods: BALB/c and C57BL/6 mice were fed ethanol-containing liquid diets, were pair-fed an isocaloric liquid control diet, or were fed solid diet and water ad libitum for up to 12 days. At intervals during the feeding period, splenic leukocytes were assessed for phenotypic markers by flow cytometry and for their ability to support antigen-induced interferon-, (IFN,) production in a coculture system. Mice were bled at intervals throughout the feeding period, and serum immunoglobin E (IgE) and alcohol levels were determined. Results: Data show that phenotypic and functional alterations occur within the first few days of alcohol consumption. Both liquid diets affect splenic cellularity, and by dietary day 5, ethanol-containing liquid diets further reduce B and NK cell numbers. The decline in B cells is accompanied by a concomitant decline in the amount of major histocompatibility complex class II expressed on this population. Functional alteration in Th1-mediated IFN, production occurred in the population fed ethanol-containing liquid diets by dietary day 5. Th2 function, as indicated by systemic serum IgE levels in these unimmunized mice, is increased by dietary day 6 to 8 and correlated with significant blood alcohol levels. Conclusions: Ethanol consumption by mice causes a rapid decrease in splenic cellularity accompanied by a decrease in Th1 function and a rapid increase in systemic IgE levels. [source]

Hypothalamic Function in Response to 2-Deoxy- d -Glucose in Long-Term Abstinent Alcoholics

ALCOHOLISM, Issue 5 2001
John C. Umhau
Background: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long-term sober alcoholics. Methods: To characterize HPA axis function in long-term sober alcoholics, we used a challenge paradigm with 2-deoxy-d-glucose (2-DG). An infusion of 2-DG (a nonmetabolizable glucose analog) induces a well-characterized stress response. In a previous study, our laboratory found an exaggerated corticotropin and cortisol response in alcoholics abstinent 3 weeks; in this investigation we compared the effects of an infusion of 2-DG on 19 healthy volunteers and 20 community-living alcoholics who had been abstinent more than 6 months. Results: In contrast to the previous study, long-term sober alcoholics did not have an exaggerated corticotropin and cortisol response after 2-DG. Conclusions: Previously observed abnormalities in cortisol regulation in 3-week-sober alcoholics may be related to the acute effects of recent alcohol consumption and withdrawal. Future investigations into the metabolic function of alcoholics, particularly investigations involving the HPA system, should consider the possibility that normalization may not occur until long-term abstinence has been achieved. [source]

Heritability of the Blood Pressure Response to Acute Ethanol Exposure in Five Inbred Strains of Mice

ALCOHOLISM, Issue 10 2000
Daniel C. Hatton
Background: Chronic alcohol consumption is a major risk factor for hypertension. There is evidence in humans that the susceptibility to alcohol-related hypertension may vary based on genotype. As a first step in investigating the genetic basis for alcohol-related hypertension, the current study was designed to assess the heritability of the blood pressure response to acute ethanol exposure by using AKR/J (AK), C57BL/6J (B6), DBA/2J (D2), Balb/cJ (Balb), and A/J (A) mice. Methods: Mean arterial pressure (MAP) was recorded continuously for 24 hr in freely moving mice from an indwelling femoral catheter before we tested the effects of saline or ethanol (2 g/kg ip) on blood pressure. Results: Relative to saline, ethanol caused a pressor response that peaked within 10 min, followed by a decline in MAP. Strain A mice had a significantly greater pressor response to ethanol than other strains and did not show a decline in MAP below baseline. All other strains showed a progressive fall in blood pressure below baseline across the 60 min measurement interval. Heritability was estimated to be 0.62 for the pressor response and 0.64 for the maximal depressor response. Repeated doses of ethanol at 1 hr intervals in A and B6 mice (0,2,1.5,1.5,1.5 g/kg ip) resulted in a dose-dependent increase in MAP in A mice for the first three doses and a dose-dependent decrease in MAP in B6 mice that was independent of blood ethanol concentrations. Conclusion: The results indicate that there is a significant genetic component to the acute blood pressure response to ethanol. [source]

Effect of Chronic Alcohol Consumption on Total Plasma Homocysteine Level in Rats

RESEARCH FOCUS ON COMPULSIVE BEHAVIOUR IN ANIMALS: Compulsive alcohol drinking in rodents

ADDICTION BIOLOGY, Issue 4 2009
Valentina Vengeliene
ABSTRACT Upon prolonged alcohol exposure, the behaviour of an individual can gradually switch from controlled to compulsive. Our review is focused on the neurobiological mechanisms that might underlie this transition as well as the factors that are influencing it. Animal studies suggest that temporally increased alcohol consumption during post-abstinence drinking is accompanied by a loss of flexibility of the behaviour and therefore, could serve as a model for compulsive alcohol drinking. However, studies using different alcohol-preferring rat lines in the post-abstinence drinking model suggest that high alcohol consumption does not necessarily lead to the development of compulsive drinking. This indicates the significance of genetic predisposition to compulsive behaviour. Neuroimaging data show that chronic alcohol consumption affects the activity of several brain regions such as the extrapyramidal motor system and several areas of the prefrontal cortex including the orbitofrontal and anterior cingulate cortex. Similar changes in brain activity is seen in patients suffering from obsessive,compulsive disorder at baseline conditions and during provocation of obsessive thoughts and urge to perform compulsive-like rituals. This indicates that dysfunction of these regions may be responsible for the expression of compulsive components of alcohol drinking behaviour. Several brain neurotransmitter systems seem to be responsible for the switch from controlled to compulsive behaviour. In particular, hypofunctioning of monoaminergic systems and hyperfunctioning of glutamatergic systems may play a role in compulsive alcohol drinking. [source]

Blood pressure and vascular reactivity to endothelin-1, phenylephrine, serotonin, KCl and acetylcholine following chronic alcohol consumption in vitro

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2001
Tijen Utkan
Ethanol has been reported to cause hypertension, the mechanism of which is unknown. Therefore, the effect of chronic ethanol consumption on vascular responsiveness and blood pressure was investigated. Systolic blood pressure was recorded weekly by tail-cuff method. Aortic rings from rats fed chow ad libitum or pair-fed liquid diets containing either ethanol (7.2% v/v) or isocaloric carbohydrate for 4 weeks were placed in organ chambers for isometric tension measurement. There was a mild but significant elevation of the systolic blood pressure in the alcohol-fed rats by week 1 compared to baseline measurements and this remained higher. No significant changes in reactivity of rat isolated aortas to phenylephrine, serotonin, endothelin-1 (ET-1) and KCl were seen in chronic ethanol consumption. In addition, the sensitivity (i.e. pD2) of alcohol-fed aortic rings to the vasoconstrictors was also unchanged compared to controls. Chronic ethanol consumption, however, increased relaxation to acetylcholine with increased pD2 values, but did not alter relaxation to sodium nitroprusside, a cyclic guanosine monophosphate (cGMP)-dependent direct smooth muscle dilator. The results indicate that chronic ethanol consumption significantly potentiates endothelium-dependent relaxations in aortic rings, probably through interference with the production and/or the release of nitric oxide (NO) or adaptive alterations in muscarinic receptors on the endothelial cells, and that increased vascular responsiveness to several vasoconstrictors is not a mechanism responsible for the blood pressure elevation in the chronic alcohol consumption in rats. [source]

S-adenosylhomocysteine sensitizes to TNF-, hepatotoxicity in mice and liver cells: A possible etiological factor in alcoholic liver disease

HEPATOLOGY, Issue 4 2004
Zhenyuan Song
In alcoholic liver disease, tumor necrosis factor-, (TNF,) is a critical effector molecule, and abnormal methionine metabolism is a fundamental acquired metabolic abnormality. Although hepatocytes are resistant to TNF,-induced killing under normal circumstances, previous studies have shown that primary hepatocytes from rats chronically fed alcohol have increased TNF, cytotoxicity. Therefore, there must be mechanisms by which chronic alcohol exposure "sensitizes" to TNF, hepatotoxicity. S-adenosylhomocysteine (SAH) is product of methionine in transsulfuration pathway and a potent competitive inhibitor of most methyltransferases. In this study, we investigated the effects of increased SAH levels on TNF, hepatotoxicity. Our results demonstrated that chronic alcohol consumption in mice not only decreased hepatic S-adenosylmethionine levels but also increased hepatic SAH levels, which resulted in a significantly decreased S-adenosylmethionine-to-SAH ratio. This was associated with significant increases in hepatic TNF, levels, caspase-8 activity, and cell death. In vitro studies demonstrated that SAH-enhancing agents sensitized hepatocytes to TNF, killing, and the death was associated with increased caspase-8 activity, which was blocked by a caspase-8 inhibitor. In addition, increased intracellular SAH levels had no effect on nuclear factor ,B activity induced by TNF,. In conclusion, these results provide a new link between abnormal methionine metabolism and abnormal TNF, metabolism in alcoholic liver disease. Increased SAH is a potent and clinically relevant sensitizer to TNF, hepatotoxicity. These data further support improving the S-adenosylmethionine-to-SAH ratio and removal of intracellular SAH as potential therapeutic options in alcoholic liver disease. Supplementary material for this article can be found on the HEPATOLOGYwebsite (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;40:989,997.) [source]

Chronic alcohol consumption increases the sensitivity of rat liver mitochondrial respiration to inhibition by nitric oxide

Chronic alcohol consumption augments loss of sialic acid residues and alters erythrocyte membrane charge in type II diabetic patients

Impact of Chronic Alcohol Ingestion on Cardiac Muscle Protein Expression

ALCOHOLISM, Issue 7 2010
Rachel L. Fogle
Background:, Chronic alcohol abuse contributes not only to an increased risk of health-related complications, but also to a premature mortality in adults. Myocardial dysfunction, including the development of a syndrome referred to as alcoholic cardiomyopathy, appears to be a major contributing factor. One mechanism to account for the pathogenesis of alcoholic cardiomyopathy involves alterations in protein expression secondary to an inhibition of protein synthesis. However, the full extent to which myocardial proteins are affected by chronic alcohol consumption remains unresolved. Methods:, The purpose of this study was to examine the effect of chronic alcohol consumption on the expression of cardiac proteins. Male rats were maintained for 16 weeks on a 40% ethanol-containing diet in which alcohol was provided both in drinking water and agar blocks. Control animals were pair-fed to consume the same caloric intake. Heart homogenates from control- and ethanol-fed rats were labeled with the cleavable isotope coded affinity tags (ICATÔ). Following the reaction with the ICATÔ reagent, we applied one-dimensional gel electrophoresis with in-gel trypsin digestion of proteins and subsequent MALDI-TOF-TOF mass spectrometric techniques for identification of peptides. Differences in the expression of cardiac proteins from control- and ethanol-fed rats were determined by mass spectrometry approaches. Results:, Initial proteomic analysis identified and quantified hundreds of cardiac proteins. Major decreases in the expression of specific myocardial proteins were observed. Proteins were grouped depending on their contribution to multiple activities of cardiac function and metabolism, including mitochondrial-, glycolytic-, myofibrillar-, membrane-associated, and plasma proteins. Another group contained identified proteins that could not be properly categorized under the aforementioned classification system. Conclusions:, Based on the changes in proteins, we speculate modulation of cardiac muscle protein expression represents a fundamental alteration induced by chronic alcohol consumption, consistent with changes in myocardial wall thickness measured under the same conditions. [source]

Alcohol Abuse Enhances Pulmonary Edema in Acute Respiratory Distress Syndrome

ALCOHOLISM, Issue 10 2009
David M. Berkowitz
Background:, Pulmonary edema is a cardinal feature of the life-threatening condition known as acute respiratory distress syndrome (ARDS). Patients with chronic alcohol abuse are known to be at increased risk of developing and dying from ARDS. Based upon preclinical data, we hypothesized that a history of chronic alcohol abuse in ARDS patients is associated with greater quantities and slower resolution of pulmonary edema compared with ARDS patients without a history of alcohol abuse. Methods:, A PiCCOÔ transpulmonary thermodilution catheter was inserted into 35 patients within 72 hours of meeting American European Consensus Criteria definition of ARDS. Pulmonary edema was quantified as extravascular lung water (EVLW) and measured for up to 7 days in 13 patients with a history of chronic alcohol abuse and 22 patients without a history of chronic alcohol abuse. Results:, Mean EVLW was higher in patients with a history of chronic alcohol abuse (16.6 vs. 10.5 ml/kg, p < 0.0001). Patients with alcohol abuse had significantly greater EVLW over the duration of the study (RM-ANOVA p = 0.003). There was a trend towards slower resolution of EVLW in patients with a history of alcohol abuse (a decrease of 0.5 ml/kg vs. 2.4 ml/kg, p = 0.17) over the study period. A history of alcohol abuse conferred a greater than 3-fold increased risk of elevated EVLW [OR 3.16, (1.26 to 7.93)] using multivariate logistic regression analysis. Conclusions:, In patients who develop ARDS, alcohol abuse is associated with greater levels EVLW and a trend towards slower resolution of EVLW. Combined with mechanistic and preclinical evidence linking chronic alcohol consumption and ARDS, targeted therapies should be developed for these patients. [source]

Intestinal Dysbiosis: A Possible Mechanism of Alcohol-Induced Endotoxemia and Alcoholic Steatohepatitis in Rats

ALCOHOLISM, Issue 10 2009
Ece Mutlu
Background:, Clinical and animal data indicate that gut-derived endotoxin and other luminal bacterial products are necessary cofactors for development of alcoholic liver disease (ALD). Although gut leakiness is clearly an important cause of endotoxemia in ALD, it cannot fully explain endotoxemia in all ALD subjects and thus other factors may be involved. One possible factor is a change in gut microbiota composition (dysbiosis). Thus, the aim of our study was to interrogate the gut bacterial microbiota in alcohol-fed rats to see if chronic alcohol consumption affects gut bacteria composition. Method:, Male Sprague,Dawley rats were given either alcohol or dextrose intragastrically by gavage twice daily for up to 10 weeks. A subgroup of rats was also given either a probiotic (lactobacillus GG) or a prebiotic (oats) by gavage. Ileal and colonic mucosal-attached microbiota composition were interrogated by Length Heterogeneity PCR (LH-PCR) fingerprinting. Results:, Bacterial microbiota composition in alcohol-fed rats is not different from dextrose-fed rats at weeks 4 and 6. Mucosa-associated microbiota composition in the colon is altered at 10 weeks of daily alcohol gavage. Both LGG and oats prevented alcohol-induced dysbiosis up to 10 weeks of alcohol treatment. Conclusion:, Daily alcohol consumption for 10 weeks alters colonic mucosa-associated bacterial microbiota composition in rats. Our data showed, for the first time, that daily alcohol consumption can affect colonic microbiome composition and suggest that dysbiosis may be an important mechanism of alcohol-induced endotoxemia. Further studies are needed to determine how dysbiotic microbiota contributes to development of ALD and whether therapeutic interventions targeted towards dysbiotic microbiota can prevent complications of alcoholism like ALD. [source]

Hepcidin Regulation in Wild-Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol-Induced Hypoxic Response

ALCOHOLISM, Issue 8 2009
Mandy L. Heritage
Background,/Aims:, Expression of Hamp1, the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice (Hfe,/,). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe,/, mice. Methods:,Hfe,/, and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1,) was measured by western blot. Results:,Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe,/, mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1, protein levels were elevated in alcohol-fed wild-type animals compared with controls. Conclusion:, Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia. [source]

Exogenous IL-15 in Combination With IL-15R, Rescues Natural Killer Cells From Apoptosis Induced by Chronic Alcohol Consumption

Alterations in Brain Serotonin Synthesis in Male Alcoholics Measured Using Positron Emission Tomography

ALCOHOLISM, Issue 2 2009
Masami Nishikawa
Background:, A consistent association between low endogenous 5HT function and high alcohol preference has been observed, and a number of serotonergic manipulations (uptake blockers, agonists) alter alcohol consumption in animals and humans. Studies have also shown an inverse relationship between alcohol use and cerebrospinal fluid levels of serotonin metabolites, suggesting that chronic alcohol consumption produces alterations in serotonin synthesis or release. Methods:, The objective of the study was to characterize regional brain serotonin synthesis in nondepressed chronic alcoholics at treatment entry in comparison to normal nonalcoholic controls using PET and the tracer ,-[11C]-methyl- l -tryptophan. Results:, Comparisons of the alcoholics and controls by SPM found that there were significant differences in the rate of serotonin synthesis between groups. Serotonin synthesis was significantly lower among alcoholics in Brodmann Area (BA) 9, 10, and 32. However, serotonin synthesis among the alcoholics group was significantly higher than controls at BA19 in the occipital lobe and around the transverse temporal convolution in the left superior temporal gyrus (BA41). In addition, there were correlations between regional serotonin synthesis and a quantity-frequency measure of alcohol consumption. Regions showing a significant negative correlation with QF included the bilateral rectus gyri (BA11) in the orbitofrontal area, the bilateral medial frontal area (BA6), and the right amygdala. Conclusions:, Current alcoholism is associated with serotonergic abnormalities in brain regions that are known to be involved in planning, judgment, self-control, and emotional regulation. [source]