Prolonged Alcohol Consumption Research Articles

PSTPIP2 protects against alcoholic liver injury and invokes STAT3-mediated suppression of apoptosis

Alcoholic liver injury (ALI) stands as a prevalent affliction within the spectrum of complex liver diseases. Prolonged and excessive alcohol consumption can pave the way for liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Recent findings have unveiled the protective role of proline serine-threonine phosphatase interacting protein 2 (PSTPIP2) in combating liver ailments. However, the role of PSTPIP2 in ALI remains mostly unknown. This study aimed to determine the expression profile of PSTPIP2 in ALI and to uncover the mechanism through which PSTPIP2 affects the survival and apoptosis of hepatocytes in ALI, using both ethyl alcohol (EtOH)-fed mice and an EtOH-induced AML-12 cell model. We observed a consistent decrease in PSTPIP2 expression both in vivo and in vitro. Functionally, we assessed the impact of PSTPIP2 overexpression on ALI by administering adeno-associated virus 9 (AAV9)-PSTPIP2 into mice. The results demonstrated that augmenting PSTPIP2 expression significantly shielded against liver parenchymal distortion and curbed caspase-dependent hepatocyte apoptosis in EtOH-induced ALI mice. Furthermore, enforcing PSTPIP2 expression reduced hepatocyte apoptosis in a stable PSTPIP2-overexpressing AML-12 cell line established through lentivirus-PSTPIP2 transfection in vitro. Mechanistically, this study also identified signal transducer and activator of transcription 3 (STAT3) as a direct signaling pathway regulated by PSTPIP2 in ALI. In conclusion, our findings provide compelling evidence that PSTPIP2 has a regulatory role in hepatocyte apoptosis via the STAT3 pathway in ALI, suggesting PSTPIP2 as a promising therapeutic target for ALI.

Could Alcohol-Related Cognitive Decline Be the Result of Iron-Induced Neuroinflammation?

Excessive and prolonged alcohol use can have long-term severe neurological consequences. The mechanisms involved may be complicated; however, new evidence seems to indicate the involvement of iron accumulation and neuroinflammation. Prolonged alcohol consumption has been linked to the accumulation of iron in specific regions of the brain. Evidence suggests that excess iron in the brain can trigger microglia activation in response. This activation leads to the release of pro-inflammatory cytokines and reactive oxygen species, which can cause damage to neurons and surrounding brain tissue. Additionally, iron-induced oxidative stress and inflammation can disrupt the blood-brain barrier, allowing immune cells from the periphery to infiltrate the brain. This infiltration can lead to further neuroinflammatory responses. Inflammation in the brain subsequently disrupts neuronal networks, impairs synaptic plasticity, and accelerates neuronal cell death. Consequently, cognitive functions such as memory, attention, and decision-making are compromised. Additionally, chronic neuroinflammation can hasten the development and progression of neurodegenerative diseases, further exacerbating cognitive impairment. Therefore, alcohol could act as a trigger for iron-induced neuroinflammation and cognitive decline. Overall, the mechanisms at play here seem to strongly link alcohol with cognitive decline, with neuroinflammation resulting from alcohol-induced iron accumulation playing a pivotal role.

Oral administration of coenzyme Q10 ameliorates memory impairment induced by nicotine-ethanol abstinence through restoration of biochemical changes in male rat hippocampal tissues

Substance abuse among adolescents has become a growing issue throughout the world. The significance of research on this life period is based on the occurrence of neurobiological changes in adolescent brain which makes the individual more susceptible for risk-taking and impulsive behaviors. Alcohol and nicotine are among the most available drugs of abuse in adolescents. Prolonged consumption of nicotine and alcohol leads to drug dependence and withdrawal which induce various dysfunctions such as memory loss. Coenzyme Q10 (CoQ10) is known to improve learning and memory deficits induced by various pathological conditions such as Diabetes mellitus and Alzheimer's disease. In the present study we investigated whether CoQ10 treatment ameliorates memory loss following a nicotine-ethanol abstinence. Morris water maze and novel object recognition tests were done in male Wistar rats undergone nicotine-ethanol abstinence and the effect of CoQ10 was assessed on at behavioral and biochemical levels. Results indicated that nicotine-ethanol abstinence induces memory dysfunction which is associated with increased oxidative and inflammatory response, reduced cholinergic and neurotrophic function plus elevated Amyloid-B levels in hippocampi. CoQ10 treatment prevented memory deficits and biochemical alterations. Interestingly, this ameliorative effect of CoQ10 was found to be dose-dependent in most experiments and almost equipotential to that of bupropion and naloxone co-administration. CoQ10 treatment could effectively improve memory defects induced by nicotine-ethanol consumption through attenuation of oxidative damage, inflammation, amyloid-B level and enhancement of cholinergic and neurotrophic drive. Further studies are required to assess the unknown side effects and high dose tolerability of the drug in human subjects.

Identification of genes regulated by trait sensitivity to negative feedback and prolonged alcohol consumption in rats.

The results of our previous studies demonstrated that low sensitivity to negative feedback (NF) is associated with increased vulnerability to the development of compulsive alcohol-seeking in rats. In the present study, we investigated the molecular underpinnings of this relationship. Using TaqMan Gene Expression Array Cards, we analyzed the expression of the genes related to NF sensitivity and alcohol metabolism in three cortical regions (medial prefrontal cortex [mPFC], anterior cingulate cortex [ACC], orbitofrontal cortex [OFC]) and two subcortical regions (nucleus accumbens [Nacc], amygdala [Amy]). Gene expression differences were confirmed at the protein level with Western blot. Sensitivity to NF was characterized by differences in Gad2, Drd2, and Slc6a4 expression in the ACC, Maoa in the mPFC, and Gria1, Htr3a, and Maoa in the OFC. Chronic alcohol consumption was associated with differences in the expression of Comt and Maoa in the ACC, Comt, Adh1, and Htr2b in the mPFC, Adh1, and Slc6a4 in the Nacc, Gad2, and Htr1a in the OFC, and Drd2 in the Amy. Interactions between the sensitivity to NF and alcohol consumption were observed in the expression of Gabra1, Gabbr2, Grin2a, Grin2b, and Grm3 in the ACC, and Grin2a in the OFC. The observed differences were confirmed at the protein level for MAO-A in the mPFC, and ADH1 in the mPFC and Nacc. Our findings contribute to a better understanding of the molecular mechanisms underlying the relationship between trait sensitivity to NF and compulsive alcohol consumption.

Recent insight into the role of macrophage in alcohol-associated liver disease: a mini-review

Alcohol-associated liver disease (ALD) is a condition that develops due to prolonged and excessive alcohol consumption. It encompasses various stages of liver damage, including fatty liver, alcoholic hepatitis, and cirrhosis. Immune cells, particularly macrophages, of various types play a significant role in the onset and progression of the disease. Macrophages observed in the liver exhibit diverse differentiation forms, and perform a range of functions. Beyond M1 and M2 macrophages, human macrophages can polarize into distinct phenotypes in response to various stimuli. Recent advancements have improved our understanding of macrophage diversity and their role in the progression of ALD. This mini-review provides a concise overview of the latest findings on the role and differentiation of macrophages in ALD. Additionally, it discusses potential therapeutic targets associated with macrophages and explores potential therapeutic strategies.

Sirtuin 1 alleviates alcoholic liver disease by inhibiting HMGB1 acetylation and translocation.

Alcoholic liver disease (ALD) encompasses a spectrum of liver disorders resulting from prolonged alcohol consumption and is influenced by factors such as oxidative stress, inflammation, and apoptosis. High Mobility Group Box 1 (HMGB1) plays a pivotal role in ALD due to its involvement in inflammation and immune responses. Another key factor, Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, is known for its roles in cellular stress responses and metabolic regulation. Despite individual studies on HMGB1 and SIRT1 in ALD, their specific molecular interactions and combined effects on disease advancement remain incompletely understood. Alcohol-induced liver injury (ALI) models were established using HepG2 cells and male C57BL/6 mice. HMGB1 and SIRT1 expressions were assessed at the mRNA and protein levels usingreverse transcription-quantitative polymerase chain reaction, western blot, and immunofluorescence staining. The physical interaction between HMGB1 and SIRT1 was investigated using co-immunoprecipitation and immunofluorescence co-expression analyses. Cellular viability was evaluated using the CCK-8 assay. In patients with clinical ALI, HMGB1 mRNA levels were elevated, while SIRT1 expression was reduced, indicating a negative correlation between the two. ALI models were successfully established in cells and mice, as evidenced by increased markers of cellular and liver damage. HMGB1 acetylation and translocation were observed in both ALI cells and mouse models. Treatment with the SIRT1 agonist, SRT1720, reversed the upregulation of HMGB1 acetylation, nuclear translocation, and release in the ethyl alcohol (EtOH) group. Furthermore, SIRT1 significantly attenuated ALI. Importantly, in vivo binding was confirmed between SIRT1 and HMGB1. SIRT1 alleviates HMGB1 acetylation and translocation, thereby ameliorating ALI.

Ендогенна та екзогенна нейростероїдна модуляція пам’яті щурів з алкогольною залежністю та агресивним типом поведінки

Alcoholism and chronic stress lead to impaired cognitive functions, which are regulated, in particular, by neurosteroid hormones. Exogenous administration of progesterone is one of the ways to influence the brain system of hormonal and neurotransmitter regulation. The effect of intranasal administration of low doses of progesterone on endogenous neurosteroid modulation of working and spatial memory in male rats with alcohol dependence and aggressive behavior was investigated. Alcohol dependence in male rats was modeled by voluntary intake of bread soaked in ethanol solution at a dose of 1.2 g/kg for 30 days. Aggressiveness was determined using the sensory contact method and the “partition” test. To study memory processes in rats, neuroethological methods of testing working (recognition of new objects) and spatial (orientation in the Barnes maze) memory were used. Progesterone was administered intranasally at a dose of 80 μg per rat for 10 days. Progesterone, testosterone, and cortisol levels were measured in the frontal neocortex (FC), hippocampus, and serum using enzyme-linked immunosorbent assay kits. The stimulatory effect of alcoholization on spatial memory and impairment of working memory in male rats with aggressive behavior was found. Zoosocial conflict on the background of prolonged alcohol consumption leads to impaired object recognition and spatial orientation against the background of neurosteroid imbalance: a decrease in progesterone and testosterone content in the FC, hippocampus, serum, and an increase in cortisol levels in these structures. Intranasal administration of progesterone to rats with alcohol dependence and aggressive behavior offsets the negative effects of confrontational relationships on working memory processes, restores the acquired experience to the baseline (however, the processes of object differentiation remain weakened); leads to improved spatial memory. The favorable effects of progesterone on memory are accompanied by a decrease in the imbalance of hormonal influences in brain structures with the restoration of progesterone and testosterone concentrations in the FC, hippocampus and serum against the background of weakening of stress-induced glucocorticoid activity. Therefore, intranasal administration of low doses of progesterone improves working and spatial memory in male rats with alcohol dependence and aggressive behavior due to the tendency to restore the balance of hormones (progesterone, testosterone, cortisol) in the brain structures responsible for memory.

Abstract 14241: Alcohol Exposure Among Patients With Dilated Cardiomyopathy: A Report From the DCM Precision Medicine Study

Introduction: Alcohol-related cardiomyopathy is characterized by cardiac dysfunction and dilatation due to prolonged and excessive alcohol (ETOH) consumption. This study aims to determine the prevalence, use patterns and genetic associations of ETOH exposure in patient with dilated cardiomyopathy (DCM) and their first-degree relatives (FDR). Hypothesis: 1. There is increased prevalence of EOTH use among patients who develop DCM. 2. Non-genetic co-morbidities are more common in patients who use ETOH and developed DCM. 3. Probands and FDR who use ETOH and develop DCM are more likely to have genetic variants. Methods: We analyzed clinical and genetic data on individuals aged 18 and older enrolled in the US DCM Precision Medicine Study. Partial and full DCM phenotypic expression were included in the analysis. The AUDIT-C score was used to evaluate the intensity of ETOH use. ETOH use and presence of DCM-related rare genetic variants were examined in FDRs using GEE type logistic mixed models adjusted for intra-family correlation and site heterogeneity. Results: A total of 2,595 subjects (1,188 probands and 1,407 FDRs) were included. Prior and current ETOH users were 270 (23%) and 546 (46%) for probands, and 30 (10%) and 168 (54%) for FDRs with DCM/partial DCM. Avg. years of drinking were 25.2 for probands and 24.0 for FDRs with DCM/partial DCM; the percent with AUDIT-C positive scores were 31.5 for probands and 32.7 for FDRs with DCM/partial DCM. In probands, moderate or high/severe ETOH use was more likely to be in men, white, Hispanic and those with </=12 yrs. of education (p<0.001). Patients drinking heavily were more likely to have hypertension, diabetes, hypercholesterolemia, and history of arrhythmia/conduction disease. Among FDRs, DCM/partial DCM was associated with the presence of DCM-related variants but not with moderate-severe drinking years in quartile after controlling for demographics and comorbidities. ETOH use did not modify the genetic effect on DCM/partial DCM. Conclusions: There is a high prevalence of prior or current ETOH use among probands and FDRs with DCM/partial DCM with an average ETOH use between 24-25 yrs. ETOH use was not found to associate with DCM or to modify the association between the presence of genetic variants and development of DCM.

How are different clusters of physical activity, sedentary, sleep, smoking, alcohol, and dietary behaviors associated with cardiometabolic health in older adults? A cross-sectional latent class analysis

BackgroundStudies to date that investigate combined impacts of health behaviors, have rarely examined device-based movement behaviors alongside other health behaviors, such as smoking, alcohol, and sleep, on cardiometabolic health markers. The aim of this study was to identify distinct classes based on device-assessed movement behaviors (prolonged sitting, standing, stepping, and sleeping) and self-reported health behaviors (diet quality, alcohol consumption, and smoking status), and assess associations with cardiometabolic health markers in older adults.MethodsThe present study is a cross-sectional secondary analysis of data from the Mitchelstown Cohort Rescreen (MCR) Study (2015–2017). In total, 1,378 older adults (aged 55–74 years) participated in the study, of whom 355 with valid activPAL3 Micro data were included in the analytical sample. Seven health behaviors (prolonged sitting, standing, stepping, sleep, diet quality, alcohol consumption, and smoking status) were included in a latent class analysis to identify groups of participants based on their distinct health behaviors. One-class through to six-class solutions were obtained and the best fit solution (i.e., optimal number of classes) was identified using a combination of best fit statistics (e.g., log likelihood, Akaike’s information criteria) and interpretability of classes. Linear regression models were used to test associations of the derived classes with cardiometabolic health markers, including body mass index, body fat, fat mass, fat-free mass, glycated hemoglobin, fasting glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, systolic and diastolic blood pressure.ResultsIn total, 355 participants (89% of participants who were given the activPAL3 Micro) were included in the latent class analysis. Mean participant ages was 64.7 years and 45% were female. Two distinct classes were identified: “Healthy time-users” and “Unhealthy time-users”. These groups differed in their movement behaviors, including physical activity, prolonged sitting, and sleep. However, smoking, nutrition, and alcohol intake habits among both groups were similar. Overall, no clear associations were observed between the derived classes and cardiometabolic risk markers.DiscussionDespite having similar cardiometabolic health, two distinct clusters were identified, with differences in key behaviors such as prolonged sitting, stepping, and sleeping. This is suggestive of a complex interplay between many lifestyle behaviors, whereby one specific behavior alone cannot determine an individual’s health status. Improving the identification of the relation of multiple risk factors with health is imperative, so that effective and targeted interventions for improving health in older adults can be designed and implemented.

Harnessing the potential of probiotics in the treatment of alcoholic liver disorders.

In the current scenario, prolonged consumption of alcohol across the globe is upsurging an appreciable number of patients with the risk of alcohol-associated liver diseases. According to the recent report, the gut-liver axis is crucial in the progression of alcohol-induced liver diseases, including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Despite several factors associated with alcoholic liver diseases, the complexity of the gut microflora and its great interaction with the liver have become a fascinating area for researchers due to the high exposure of the liver to free radicals, bacterial endotoxins, lipopolysaccharides, inflammatory markers, etc. Undoubtedly, alcohol-induced gut microbiota imbalance stimulates dysbiosis, disrupts the intestinal barrier function, and trigger immune as well as inflammatory responses which further aggravate hepatic injury. Since currently available drugs to mitigate liver disorders have significant side effects, hence, probiotics have been widely researched to alleviate alcohol-associated liver diseases and to improve liver health. A broad range of probiotic bacteria like Lactobacillus, Bifidobacteria, Escherichia coli, Sacchromyces, and Lactococcus are used to reduce or halt the progression of alcohol-associated liver diseases. Several underlying mechanisms, including alteration of the gut microbiome, modulation of intestinal barrier function and immune response, reduction in the level of endotoxins, and bacterial translocation, have been implicated through which probiotics can effectively suppress the occurrence of alcohol-induced liver disorders. This review addresses the therapeutic applications of probiotics in the treatment of alcohol-associated liver diseases. Novel insights into the mechanisms by which probiotics prevent alcohol-associated liver diseases have also been elaborated.

Prolonged alcohol consumption influences microRNA expression in the nucleus accumbens of the rat brain.

The microRNA (miR) species analyzed in this study are involved in molecular mechanisms of TLR4 and TLR7 signaling, mediating the development of neuroinflammation and neurodegeneration. We have investigated the expression levels of miR-let7b, miR-96, miR-182, miR-155, and the mRNA content of HMGB1, TLR3, TLR4 in the nucleus accumbens (NAc) of the brain of rats exposed to long-term alcoholization. The long-term alcoholization caused a decrease in miR-let7b, miR-96, miR-182, and TLR7 mRNA levels; this was accompanied by an increase in miR-155, TLR4, and Hmgb1 mRNA levels in the NAc of rat brain. TLR7 is functionally linked to miR-let7b. The data of a simultaneous decrease in miR-let7b and TLR7 mRNA are of interest for further studies; they may indicate on the lack of functionally significant links between Hmgb1 and the miR-let7b-TLR7 system in NAc. The existing evidence of a functional relationship between TLR4 with miR-155 and miR-182 and our observations on their expression changes during chronic alcoholization are very interesting and require further investigation. The suggestion about the development of neuroinflammatory process in NAc under prolonged alcohol exposure are relevant for studying the level of TLR gene expression in NAc, as well as the expression of miR species, which may have a functional relationship with the TLR system.

Risk Factors Assessment of Musculoskeletal Disorders among Professional Vehicle Drivers in India Using an Ordinal Priority Approach

Professional driving involves sitting in uncomfortable positions, navigating difficult terrain and roads, and occasionally conducting small repairs and other auxiliary transportation duties while at work for long periods. Drivers who engage in these activities may develop a variety of musculoskeletal disorders (MSDs). MSDs in professional drivers are accompanied by several risk factors. In this study, the various risk factors for MSD have been identified through the literature reviews, discussions with professional drivers, and consultations with ergonomics specialists. This study employed the ordinal priority approach (OPA), a multi-criteria decision-making (MCDM) technique, to rank the identified risk variables for MSD in order of importance. The same OPA method has also been used to identify the group of professional drivers who use eight different types of vehicles and are more likely to develop MSDs. The analyses findings show that the five main risk factors for MSDs among drivers are prolonged sitting, restricted posture, working hours, alcohol consumption, and uncomfortable seating. Additionally, among all drivers regarded as professionals, truck drivers are found to be the most at risk. For the study’s conclusions to be validated, a sensitivity analysis was also carried out. The results of this study are anticipated to help formulate strategies for lowering these hazards through the ergonomic design of drivers’ cabins by automobile OEMs (Original Equipment Manufacturers) and vehicle scheduling by concerned transportation organizations to reduce driver tiredness.

Розвиток оксидативного стресу у лабораторних щурів за алкогольної інтоксикації

Introduction: the imbalance between the formation of reactive oxygen species (ROS) and the ability of cells to neutralize them is characterized as oxidative stress and occurs in almost any pathological condition. Reactions to convert ethanol to acetic acid are accompanied by an increase in ROS production. Given the prevalence of alcohol abuse and the contribution of oxidative stress to the development of pathological conditions, we formulated the aim of our work: to assess the impact of chronic alcohol intoxication on the development of oxidative stress in the mucous membranes of the digestive tract, liver, serum and bone of laboratory rats. Materials and Methods: the experiment was performed on 2-month-old rats of both sexes. The method of alcoholization is “semi-voluntary”. The experimental groups were given ethanol with 5 % drinking water at the beginning of the experiment and gradually increased to 15 %. The duration of the experiment is 108 days. Catalase activity (a marker of the antioxidant system) and malonic dialdehyde content (an indicator of the degree of lipid peroxidation) were determined in the serum, liver, jaw bone, mucous membranes of the mouth, stomach, small intestine, and colon of rats. The antioxidant-prooxidant index was calculated from the values ​​of these indicators. Results: prolonged consumption of alcohol by males and females led to a decrease in catalase activity in the tissues of the digestive tract from 16.0 % in the large intestinal to 25.0 % in the small intestinal mucosa, and, conversely, to increase in the jaws. the mucous membrane of the oral cavity and liver increased by 1.2–38.6 %. Chronic alcohol consumption increased the concentration of malonic dialdehyde in the mucous membranes of the gastrointestinal tract by 20.3–96.6 %, in serum – by 20.4–33.3 %, bone tissue – by 44.8–58.7 %. The balance between antioxidants and prooxidants in tissues most clearly reflects the antioxidant-prooxidant index. Alcohol consumption contributed to the reduction of antioxidant-prooxidant index in the tissues of the digestive tract by 37.6–65.0 %, in the liver by 24.7 %, in serum by 38.3 %, in the jaws by 4.2–15.9 %. In the mucous membrane of the oral cavity, this figure increased by 6.0–10.0 %. Conclusions: According to the results of our study, oxidative stress induced by ethanol developed to a greater extent in the mucous membrane of the small intestine, and to a lesser extent – in the mucous membrane of the mouth and jaw bone. Female tissues are more resistant to the development of oxidative stress due to prolonged alcohol consumption.

A clinical case of arrhythmogenic right ventricular dysplasia (ADP)

The difficulties of diagnosis and management of patients with alcohol-induced heart lesions, features of the clinic of alcoholic cardiomyopathy are highlighted. Excessive and prolonged alcohol consumption increases the risk of developing acute and chronic heart failure, cardiac arrhythmias and aggravates existing cardiovascular diseases. At the same time, due to insufficient assessment of the origin of cardiac manifestations (patients often hide or downplay the fact of alcohol abuse), patients do not always receive specific treatment. The management of such patients presents significant difficulties, taking into account, among other things, the defeat of the gastrointestinal tract, central and peripheral nervous system and should be carried out jointly with doctors of other specialties.

The Effects of Electroacupuncture via Chronically Implanted Electrodes on Alcohol Drinking and Withdrawal Signs in Rats

BackgroundIn the United States, more than 14 million adults suffer from alcohol use disorder (AUD). We proposed a stress-free method of electroacupuncture (EA) using chronically implanted electrodes. We aimed to develop an effective method of EA for treating AUD by testing various stimulation locations and parameters, and then investigate the effects of the daily EA on alcohol consumption and withdrawal signs in rats. Materials and MethodsSprague-Dawley rats were trained to voluntarily drink ethanol under the intermittent access two-bottle choice procedure. By the end of four weeks, rats with ethanol consumption ≥1.5 g/kg/24 h were considered alcohol-dependent and included in an acute and prolonged experiments. The acute study was designed to investigate the effects of EA with different parameters and at different locations. EA treatment was applied at bilateral ST36 alone or bilateral ST36 and HT7 acupoints for 30 minutes. We investigated the effects of EA on 24-hour alcohol consumption, preference ratio (alcohol drink vs total drink), alcohol withdrawal signs (AWS), and prolonged alcohol consumption. Each animal served as its own control. Results1) By the end of week 4, 70% of rats became alcohol-dependent. 2) Following ethanol withdrawal, there was a gradual increase in AWS over time that peaked at two hours and dropped at six hours. Among the tested stimulation parameters and locations: 3) The best stimulation location was ST36 alone, and the best stimulation parameters were a combination of 100 and 2 Hz. EA at best stimulation location and parameters reduced ethanol intake by 27% (p < 0.05 vs baseline) and marginally reduced preference ratio by 23% (p = 0.05 vs baseline). 4) EA reduced AWS at two- and four-hours following ethanol withdrawal (p ≤ 0.03 each vs no EA). 5) Daily EA (for five consecutive days) resulted in a substantial reduction in ethanol intake and preference ratio by 44% and 47%, respectively (p = 0.002 each). ConclusionsThis work shows the potential of this novel method of EA for the treatment of AUD. Further studies are warranted to investigate the mechanisms through which EA exerts its effects.

Gut Microbiota: Target for Modulation of Gut-Liver-Adipose Tissue Axis in Ethanol-Induced Liver Disease.

Consumption of alcohol (ethanol) in various forms has been an integral part of human civilization. Since ages, it also has been an important cause of death and health impairment across the globe. Ethanol-mediated liver injury, known as alcoholic liver disease (ALD), is caused by surplus intake of alcohol. Several studies have proposed the different pathways that may be lead to ALD. One of the factors that may affect the cytochrome P450 (CYP2E1) metabolic pathway is gut dysbiosis. The gut microbiota produces various compounds that play an important role in regulating healthy functions of distal organs such as the adipose tissue and liver. Dysbiosis causes bacteremia, hepatic encephalopathy, and increased intestinal permeability. Recent clinical studies have found better understanding of the gut and liver axis. Another factor that may affect the ALD pathway is dysfunction of adipose tissue metabolism. Moreover, dysfunction of adipose tissue leads to ectopic fat deposition within the liver and disturbs lipid metabolism by increasing lipolysis/decreasing lipogenesis and impaired glucose tolerance of adipose tissue which leads to ectopic fat deposition within the liver. Adipokine secretion of resistin, leptin, and adiponectin is adversely modified upon prolonged alcohol consumption. In the combination of these two factors, a proinflammatory state is developed within the patient leading to the progression of ALD. Thus, the therapeutic approach for treatments and prevention for liver cirrhosis patients must be focused on the gut-liver-adipose tissue network modification with the use of probiotics, synbiotics, and prebiotics. This review is aimed at the effect of ethanol on gut and adipose tissue in both rodent and human alcoholic models.

Розвиток запалення в травному тракті щурів після тривалого введення алкоголю

The purpose of the work was to experimentally study the chronic alcohol intoxication on the indicators of inflammation and lipid peroxidation in the gastrointestinal system. Materials and methods. Ethyl alcohol was added to the water for 2-month-old male rats, ranging from 5% to 15% for 108 days. In homogenates of mucous membranes of the gastrointestinal tract and liver, the activity of elastase enzymes, acid phosphatase and the concentration of malonic dialdehyde were determined, in serum – elastase activity and malonic dialdehyde content. Results and discussion. Biochemical research of one of the markers of inflammation (elastase activity) in rats found a probable increase of elastase activity in different parts of the digestive tract after prolonged alcohol consumption, regardless of the sex of the animals. Thus, in the serum of rats after the introduction of ethanol, the activity of elastase increased by 71.7%, in the oral mucosa – by 29.2%, in the gastric mucosa – by 55.5%, in the liver – by 29.0%. In the small and large intestine, the level of this marker of inflammation has changed slightly. The level of elastase activity shows the degree of accumulation of leukocytes in the tissues as a result of the development of the inflammatory process. Acid phosphatase activity in the oral mucosa of rats treated with ethanol increased by 47.4%, in the gastric mucosa – by 30.3%, in the mucous membrane of the small intestine – by 37.4%, in the mucous membrane of the colon – by 40.4%, in the liver – by 112.6%. Activation of acid phosphatase, along with other lysosomal enzymes, is the primary inflammatory response that triggers the production of mediators, which in turn cause secondary tissue alteration in subsequent stages of the inflammatory process. Therefore, the results obtained on the activation of acid phosphatase along with elastase indicate the presence of inflammation in the mucous membranes of the digestive tract, and especially in the liver of rats chronically treated with ethanol. The introduction of alcohol also led to an increase in the concentration of malonic dialdehyde in the mucous membranes: the oral cavity – by 20.3%, the stomach – by 32.3%, the small intestine – by 96.6%, the colon – by 50.2%, in the liver – by 39.4%, in serum – by 33.3%. A significant increase in the level of malonic dialdehyde in the tissues of the digestive tract of rats after long-term intake of ethanol is a sign of activation of lipid peroxidation and intensification of oxidative stress reactions. Conclusion. The results of the study of elastase activity indicate the development of inflammation in the mucous membranes of the gastrointestinal tract, liver and serum of rats under the influence of chronic administration of ethanol. Increased acid phosphatase activity in the tissues of the gastrointestinal tract after prolonged use of ethanol indicates damage to cell membranes, which is a consequence of inflammation. A significant increase in the level of malonic dialdehyde in the mucous membranes of the gastrointestinal tract, liver and serum of rats after chronic ethanol intake is a sign of intensification of oxidative stress reactions

Taurine modulates behavioral effects of intermittent ethanol exposure without changing brain monoamine oxidase activity in zebrafish: Attenuation of shoal- and anxiety-like responses, and abolishment of memory acquisition deficit

Prolonged alcohol consumption has been considered as an important risk factor for various diseases. Chronic ethanol (EtOH) intake is associated with deleterious effects on brain functions culminating in robust behavioral changes. Notably, drugs available to treat the effects of EtOH have low therapeutic efficacy so far. Taurine (TAU) appears as a promising neuroprotective molecule due to its pleiotropic action in the brain. Here, we investigated whether TAU plays a beneficial role in different behavioral domains of zebrafish submitted to an intermittent EtOH exposure model, specially focusing on social behavior, anxiety-like responses, and memory. Moreover, since monoamines play a role in EtOH-mediated responses, we also evaluated the influence of both TAU and EtOH exposures on brain monoamine oxidase (Z-MAO) activity. Fish were exposed to non-chlorinated water or 1% EtOH for 8 consecutive days (20 min per day). From the 5th day until the end of the experimental period (8th day), animals were kept in the absence or presence of TAU (42, 150, or 400 mg/L) 1 h per day immediately after EtOH exposure. Behavioral measurements started 24 h after the last EtOH exposure. We observed that TAU showed modest attenuating effects on shoaling behavior and anxiety-like responses, while 42 and 150 mg/L TAU abolished the memory acquisition deficit in the inhibitory avoidance task. Biochemical analysis revealed that TAU did not modulate EtOH-induced increase on brain Z-MAO activity. Collectively, our novel data show a potential beneficial effect of TAU in an intermittent EtOH exposure model in zebrafish. Moreover, these findings foster the growing utility of this aquatic species to investigate the neurobehavioral basis of EtOH- and TAU-mediated responses in vertebrates.

IMBALANCE OF ANTIOXIDANT-PROOXIDANT SYSTEM IN RAT'S JAW BONE TISSUE UNDER LONG-TERM INTRODUCTION OF ETHANOL

Introduction. Nowadays, it is unclear what the trigger for bone resorption under the influence of chronic alcohol consumption is. As the reactions of conversion of ethanol into acetic acid are accompanied by an increase in the production of reactive oxygen species, it can be assumed that the formation of oxidative stress with prolonged alcohol consumption occurs in bone tissue as well. Aim. Research of the effect of chronic administration of ethanol to females and males laboratory rats on indices of resorption, osteogenesis, the condition of the antioxidant-prooxidant system in bone tissue. Materials and Methods. 2-month old animals received from 5 % to 15 % of ethanol in their drinking water with gradual increase of the concentration. The lower jaws were segregated, and the degree of atrophy of the alveolar process was calculated. The activity of elastase, acidic (AcF) and alkaline phosphatase (AlF), superoxide dismutase (SOD), catalase, glutathione reductase and malonic dialdehyde (MDA) content were determined in the bone tissue homogenates. Results. Chronic alcohol consumption contributed to an increase in alveolar bone atrophy, increased activity of biochemical markers of bone resorption (elastase by 32.2 %, AcF – by 33.6 %), decreased osteogenesis (AlF activity by 32.4 %). Alcohol intoxication led to oxidative imbalance of bone tissue: a decrease in SOD activity by an average of 16.9 %, glutathione reductase activity by 36.2 %, increase in catalase activity by 35.9 % and an increase in MDA levels by 51.8 %. Conclusion. Chronic alcohol consumption stimulates atrophy of the alveolar process of the rat jaw, induces oxidative imbalance in bone tissue, which can be a trigger pathogenetic factor in further development of resorption pro-inflammatory processes in bone tissue and inhibition of bone formation.

Drinking Off(s) the Clock: Chronic Alcohol Suppresses Skeletal Muscle Molecular Clock

Circadian rhythms generated both centrally in the suprachiasmatic nucleus (SCN) and peripherally at the tissue level assist in the maintenance of physiological homeostasis, while circadian disruption is a characteristic of several diseases. The intrinsic skeletal muscle core clock has emerged as a key feature of metabolic control and influences several aspects of muscle physiology including contractile strength and mitochondrial content. Alcoholic muscle disease or myopathy is characterized by skeletal muscle weakness and myofiber atrophy resulting from the prolonged consumption of alcohol. Despite alcoholic myopathy being more prevalent than alcoholic liver disease, the entirety of mechanisms leading to its onset remains unknown. Alcohol disrupts normal cyclic expression of several core clock genes within the brain and liver, and we previously reported that acute alcohol intoxication disrupts the skeletal muscle core clock. Thus, the goal of this work was to determine whether the chronic consumption of alcohol dysregulates the skeletal muscle core molecular clock and clock-controlled genes (CCGs) in concert with alcoholic myopathy. Methods: C57BL/6Hsd female mice (12wks old) were pair fed a control liquid diet (CON) or an isocaloric ethanol (EtOH) containing liquid diet of increasing concentration (up to 32% kcal EtOH) for 7 weeks. Gastrocnemius muscles were collected from CON (n=4) and EtOH (n=3-4) mice every 4-hours for 24-hours. RNA was isolated, cDNA synthesized, and RT-PCR was performed. Results: Body weight and fat mass between groups was similar at sacrifice while liver mass was increased by alcohol. Lean mass assessed by MRI tended to be decreased by alcohol (p=0.06). Chronic alcohol consumption disrupted genes of the core clock including suppressing the rhythmic peak in expression of brain muscle ARNT like-1 (Bmal1), period (Per) 1 and 2, and cryptochrome 2 (Cry2). Genes involved in the regulation of Bmal1 also exhibited lower rhythmic peaks including Rev-erb (NR1D1) and myoblast determination protein 1 (MyoD), with significant reductions apparent at several of the 4-hour time points. The CCG D-box binding PAR BZIP transcription factor (DBP) was also suppressed at the end of the light phase and beginning of the dark active phase (ZT8 and ZT12). Skeletal muscle atrophy related genes forkhead box O1 (Foxo1), regulated in development and DNA damage response 1 (Redd1) and muscle RING-finger protein 1 (Murf1) were also altered by alcohol at the start of the dark (active) cycle. These data contrasted our previously described acute model in which subtle rhythmic shifts and large changes in the expression of several genes were observed specifically when blood alcohol levels (~4-12hr) were elevated. Therefore, there is a differential response of the skeletal muscle to acute and chronic alcohol consumption with prolonged intake leading to a lower amplitude of change over the 24-hour cycle of several core clock related genes. Future work will focus on determining the contribution of these disruptions to metabolic and functional perturbations characteristic of chronic alcoholic myopathy and the impact of these disruptions on the development of alcoholic myopathy.