Predominantly Pro-Inflammatory Phenotype with Mixed M1/M2 Polarization of Peripheral Blood Classical Monocytes and Monocyte-Derived Macrophages among Patients with Excessive Ethanol Intake.

Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD). We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers (EADs). PB samples from 20 EADs and 22 healthy controls were collected for isolation of CD14+ monocytes and short-term culture with LPS/IFNγ, IL4/IL13, or without stimulation.

Genetic susceptibility to telomere shortening through the rs2293607 polymorphism is associated with a greater risk of alcohol use disorder.

Telomere shortening is usually considered a biomarker of ageing. Harmful alcohol use promotes accelerated biological ageing and alcohol use disorders (AUDs) are associated with short telomere length (TL). This study was conducted to examine the relationship of TL to AUD and determine whether single nucleotide polymorphisms (SNPs) in TERC and TERT modulate this association.

Circulating MicroRNAs in Extracellular Vesicles as Potential Biomarkers of Alcohol-Induced Neuroinflammation in Adolescence: Gender Differences.

Current studies evidence the role of miRNAs in extracellular vesicles (EVs) as key regulators of pathological processes, including neuroinflammation and neurodegeneration. As EVs can cross the blood-brain barrier, and EV miRNAs are very stable in peripheral circulation, we evaluated the potential gender differences in inflammatory-regulated miRNAs levels in human and murine plasma EVs derived from alcohol-intoxicated female and male adolescents, and whether these miRNAs could be used as biomarkers of neuroinflammation. We demonstrated that while alcohol intoxication lowers anti-inflammatory miRNA (mir-146a-5p, mir-21-5p, mir-182-5p) levels in plasma EVs from human and mice female adolescents, these EV miRNAs increased in males.

Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAs in alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), two diseases that share common underlying mechanisms and pathological characteristics.

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men.

Background: Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation.

Gender differences in the inflammatory cytokine and chemokine profiles induced by binge ethanol drinking in adolescence.

Heavy binge drinking in adolescence can cause long-term cognitive and behavioral dysfunctions. Recent experimental evidence indicates the participation of immune system activation in the effects of ethanol in the adolescent brain and suggests gender differences. The present study aims to assess plasma cytokine and chemokine levels in male and female adolescents and young adults during acute alcohol intoxication and to correlate these results with the toll-like receptor 4 (TLR4) response.

Alcoholic liver disease and hepatitis C virus infection.

Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population.

Histone Deacetylase Gene Expression Following Binge Alcohol Consumption in Rats and Humans.

Background: Alcohol binge drinking is one of the most common patterns of excessive alcohol use and recent data would suggest that histone deacetylases (HDACs) gene expression profiling could be useful as a biomarker for psychiatric disorders.

Methods: This study aimed to characterize the gene expression patterns of Hdac 1-11 in samples of rat peripheral blood, liver, heart, prefrontal cortex, and amygdala following repeated binge alcohol consumption and to determine the parallelism of Hdac gene expression between rats and humans in peripheral blood. To accomplish this goal, we examined Hdac gene expression following 1, 4, or 8 alcohol binges (3 g/kg, orally) in the rat, in patients who were admitted to the hospital emergency department for acute alcohol intoxication, and in rats trained in daily operant alcohol self-administration.

Altered Distribution of Peripheral Blood Maturation-Associated B-Cell Subsets in Chronic Alcoholism.

Background: Although decreased counts of peripheral blood (PB) B cells-associated with an apparently contradictory polyclonal hypergammaglobulinemia-have been reported in chronic alcoholism, no information exists about the specific subsets of circulating B cells altered and their relationship with antibody production. Here, we analyzed for the first time the distribution of multiple maturation-associated subpopulations of PB B cells in alcoholism and its potential relationship with the onset of liver disease.

Methods: PB samples from 35 male patients-20 had alcoholic hepatitis (AH) and 15 chronic alcoholism without liver disease (AWLD)-were studied, in parallel to 19 male healthy donors (controls).

Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis.

Unlabelled: We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases.

Prevalence of hepatitis C virus infection in alcoholic patients: cohort study and systematic review.

Aims: Prevalence of chronic hepatitis C virus (HCV) infection among alcoholics is thought to be higher than in the general population, although prevalence rates reported are quite variable. Our study is aimed to analyze HCV prevalence in a cohort of alcoholics and to perform a systematic review on this topic.

Patients And Methods: A total of 396 alcoholic patients consecutively referred to our Alcoholism Unit were included.

Decreased peripheral blood CD4+/CD25+ regulatory T cells in patients with alcoholic hepatitis.

Background: Development of alcoholic hepatitis (AH) may be favored by the activation of the innate immune response. Recently, decreased numbers of circulating regulatory T cells (Tregs) have been reported in diseases associated with an immune activation status, but no studies have focused so far, in investigating the distribution of Tregs in chronic alcoholism and its potential association with liver disease. Here, we analyzed for the first time the frequency of peripheral blood (PB) Tregs and Treg subsets in AH and its relationship with the production of inflammatory cytokines by PB monocytes and dendritic cells (DCs).

Association of µ-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis.

Previous studies have suggested that the effect of naltrexone in patients with alcohol dependence may be moderated by genetic factors. In particular, the possession of the G allele of the A118G polymorphism of the µ-opioid receptor gene (OPRM1) has been associated with a better response to naltrexone, although controversial results have been reported. The aim of this paper is to combine previous findings by means of a systematic review and a meta-analysis.

Cannabinoid receptor 1 gene is associated with alcohol dependence.

Background: Alcohol dependence (AD) vulnerability is determined by a complex array of genetic factors. Given the potential role of endocannabinoid system in AD, polymorphisms within cannabinoid receptor 1 gene (CNR1) have been potentially associated with susceptibility to this disease. We thus aimed to examine the relationship between 3 allelic variants of CNR1 (rs6454674, rs1049353, and rs806368) and AD.

Chronic alcohol consumption is associated with an increased cytotoxic profile of circulating lymphocytes that may be related with the development of liver injury.

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).

Tumor necrosis factor polymorphisms and alcoholic liver disease: a HuGE review and meta-analysis.

The association between alcoholic liver disease (ALD) and tumor necrosis factor-alpha gene (TNFA) polymorphisms has been analyzed in several studies, but results have been conflicting. The main purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility to ALD. The authors surveyed studies on the relation between TNFA gene polymorphisms and ALD by means of an electronic database search.

A functional polymorphism of the NFKB1 gene increases the risk for alcoholic liver cirrhosis in patients with alcohol dependence.

Background: The genetic basis for the predisposition to alcoholic liver cirrhosis (ALC) remains unknown. Increasing evidence supports a role for the nuclear factor (NF)-kappaB, the NF-kappaB inhibitor alpha (NFKBIA), and the peroxisome proliferator-activated receptor (PPAR)-gamma in the pathogenesis of alcoholic liver disease, raising the possibility that common polymorphisms in genes encoding these molecules may confer susceptibility to ALC. The objective of this study was to analyze the relationship between common polymorphisms in NFKB1, NFKBIA, and PPARG2 genes and the presence of ALC.

Common polymorphisms in interleukin genes (IL4, IL6, IL8 and IL12) are not associated with alcoholic liver disease or alcoholism in Spanish men.

Background: Preliminary data suggest that polymorphisms in cytokine genes may be involved in the genetic predisposition to alcoholic liver cirrhosis or alcohol use disorders. We thus analyze the association between these diseases and the following polymorphisms: -33T>C IL4, -174 G>C IL6, -251 T>A IL8 and 1188 A>C IL12B.

Methods: 258 male alcoholics (161 without liver disease and 97 with liver cirrhosis) and 101 healthy controls were genotyped for the above mentioned polymorphisms.

A new genetic variant involved in genetic susceptibility to alcoholic liver cirrhosis: -330T>G polymorphism of the interleukin-2 gene.

Objective: Genetic factors may determine susceptibility to develop alcoholic liver cirrhosis, although it remains uncertain why only a minority of alcoholics suffers from this disease. A decrease in serum levels of interleukin-2 (IL-2) is usually found in alcoholic cirrhotics. In this study we examined the relationship between the -330T>G IL-2 gene (IL2) polymorphism and alcoholic liver cirrhosis.

Interleukin-10 gene polymorphism is associated with alcoholism but not with alcoholic liver disease.

Aims: To determine whether the functional polymorphism -592C>A of the interleukin (IL)-10 gene (IL10) influences the development of alcoholic liver disease or alcoholism in alcoholic Spanish subjects.

Methods: The -592C>A IL10 polymorphism was analyzed by the polymerase chain reaction and digestion with restriction enzymes in 257 male alcoholics [161 without alcoholic liver disease and 96 with alcoholic liver cirrhosis (ALC)] and 100 male healthy controls.

Results: We found no association between the -592C>A IL10 polymorphism and ALC.

Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells.

Background: Alcoholism is frequently associated with altered immune responses, limited information being available on its effects on dendritic cells (DC). In the present study we analyze the effects of chronic alcoholism on circulating DC.

Methods: For the first time we studied the numerical distribution of DC in peripheral blood (PB), their immunophenotype, and their ex vivo pattern of spontaneous cytokine secretion, in chronic alcoholic patients without liver disease (AWLD group; n=17) and active ethanol (EtOH) intake, as well as in subjects with alcohol liver cirrhosis (ALC group; n=21).

Production of inflammatory cytokines by peripheral blood monocytes in chronic alcoholism: relationship with ethanol intake and liver disease.

Background: Controversial results have been reported about the effects of alcoholism on the functionality of monocytes. In the present study we analyze the effects of chronic alcoholism on the intracellular production of inflammatory cytokines by peripheral blood (PB) monocytes.

Methods: Spontaneous and in vitro-stimulated production of interleukin (IL) 1alpha (TNFalpha) by PB monocytes was analyzed at the single level by flow cytometry in chronic alcoholics without liver disease and active ethanol (EtOH) intake (AWLD group), as well as in patients with alcohol liver cirrhosis (ALC group), who were either actively drinking (ALCET group) or with alcohol withdrawal (ALCAW group).

[Immune system and alcoholic liver disease].

It is well established that alcoholism is associated with imbalanced immune responses. To date, most relevant finding reported is the existence of an immunodepressed state which leads to a higher risk of suffering from severe infections in alcoholic patients. However, recent studies have shown that ethanol intake is followed by changes involving the synthesis and serum levels of specific cytokines as well as the activation of several different subsets of cytotoxic lymphocytes, that could be involved in the development of alcoholic liver disease.