Chronic Alcohol Intake Research Articles

Cannabinoid 1 Receptor Antagonists Play a Neuroprotective Role in Chronic Alcoholic Hippocampal Injury Related to Pyroptosis Pathway.

Alcohol use disorders affect millions of people worldwide, and there is growing evidence that excessive alcohol intake causes severe damage to the brain of both humans and animals. Numerous studies on chronic alcohol exposure in animal models have identified that many functional impairments are associated with the hippocampus, which is a structure exhibiting substantial vulnerability to alcohol exposure. However, the precise mechanisms that lead to structural and functional impairments of the hippocampus are poorly understood. Herein, we report a novel cell death type, namely pyroptosis, which accounts for alcohol neurotoxicity in mice. For this study, we used an in vivo model to induce alcohol-related neurotoxicity in the hippocampus. Adult male C57BL/6 mice were treated with 95% alcohol vapor either alone or in combination with selective cannabinoid receptor antagonists or agonists, and VX765 (Belnacasan), which is a selective caspase-1 inhibitor. Alcohol-induced in vivo pyroptosis occurs because of an increase in the levels of pyroptotic proteins such as nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), caspase-1, gasdermin D (GSDMD), and amplified inflammatory response. Our results indicated that VX765 suppressed the expression of caspase-1 and inhibited the maturation of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Additionally, chronic alcohol intake created an imbalance in the endocannabinoid system and regulated 2 cannabinoid receptors (CB1R and CB2R) in the hippocampus. Specific antagonists of CB1R (AM251 and AM281) significantly ameliorated alcohol-induced pyroptosis signaling and inactivated the inflammatory response. Alcohol induces hippocampal pyroptosis, which leads to neurotoxicity, thereby indicating that pyroptosis may be an essential pathway involved in chronic alcohol-induced hippocampal neurotoxicity. Furthermore, cannabinoid receptors are regulated during this process, which suggests promising therapeutic strategies against alcohol-induced neurotoxicity through pharmacologic inhibition of CB1R.

Hemorrhagic chickenpox

<span>Chickenpox (varicella) is self-limited disease caused by Varicella-Zoster virus (VZV). Hemorrhagic manifestation is rare complication in immunocompromised patient. Here we report a case of rare form of hemorrhagic chickenpox due to chronic alcohol intake. The course of illness was very fulminant and rapid.</span>

Bifidobacterium breve ATCC15700 pretreatment prevents alcoholic liver disease through modulating gut microbiota in mice exposed to chronic alcohol intake

Abstract Gut microbiota has been identified as a key player in the development of alcoholic liver disease (ALD). Targeting gut microbiota with probiotic intervention will be an attractive approach to prevent ALD. Here, we investigated the effects of probiotic Bifidobacterium breve ATCC15700 (ATCC15700) on liver injury and gut microbiota in mice exposed to chronic alcohol intake. Our results showed that oral administration of ATCC15700 significantly decreased endotoxemia, maintained immune homeostasis, and alleviated alcohol-induced liver injury. ATCC15700 also promoted intestinal barrier function by enhancing the expressions of tight junction proteins in alcohol-treated mice. Moreover, analysis of gut microbiota showed that ATCC15700 normalized the structure and composition of the alcohol-disrupted gut microbiota. Correlation between gut microbiota and liver injury parameters revealed that specific bacteria, including S24_7, unclassified Clostridiales, Butyricicoccus, Oscillospira, Ruminococcus, Mucispirillum and unclassified Lachnospiraceae, were predominantly associated with ALD. In conclusion, ATCC15700 protected alcohol-exposed mice against liver injury via modulating gut micobiota.

PDE5 inhibitor sildenafil attenuates cardiac microRNA 214 upregulation and pro-apoptotic signaling after chronic alcohol ingestion in mice.

Abusive chronic alcohol consumption can cause metabolic and functional derangements in the heart and is a risk factor for development of non-ischemic cardiomyopathy. microRNA 214 (miR-214) is a molecular sensor of stress signals that negatively impacts cell survival. Considering cardioprotective and microRNA modulatory effects of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, we investigated the impact of chronic alcohol consumption on cardiac expression of miR-214 and its anti-apoptotic protein target, Bcl-2 and whether sildenafil attenuates such changes. Adult male FVB mice received unlimited access to either normal liquid diet (control), alcohol diet (35% daily calories intake), or alcohol + sildenafil (1mg/kg/day, p.o.) for 14weeks (n = 6-7/group). The alcohol-fed groups with or without sildenafil had increased total diet consumption and lower body weight as compared with controls. Echocardiography-assessed left ventricular function was unaltered by 14-week alcohol intake. Alcohol-fed group had 2.6-fold increase in miR-214 and significant decrease in Bcl-2 expression, along with enhanced phosphorylation of ERK1/2 and cleavage of PARP (marker of apoptotic DNA damage) in the heart. Co-ingestion with sildenafil blunted the alcohol-induced increase in miR-214, ERK1/2 phosphorylation, and maintained Bcl-2 and decreased PARP cleavage levels. In conclusion, chronic alcohol consumption triggers miR-214-mediated pro-apoptotic signaling in the heart, which was prevented by co-treatment with sildenafil. Thus, PDE5 inhibition may serve as a novel protective strategy against cardiac apoptosis due to chronic alcohol abuse.

Chronic Alcohol Intake Exacerbates Cardiac Dysfunction After Myocardial Infarction.

Alcohol intake is a risk factor for cardiovascular diseases. This study was designed to investigate whether chronic alcohol intake affects myocardial infarction (MI)-induced cardiac remodeling and heart failure. Eight-week-old male C57BL/6 mice were randomly divided into four groups: Sham group (Sham), MI plus drinking water group (MI+Vehicle), and MI plus daily alcohol intake for 6weeks with or without gavage of additional alcohol every 3days (MI+Alcohol and MI+Alcohol+G). The MI were induced by permanent left anterior descending (LAD) coronary artery ligation surgery before vehicle or alcohol treatment. The blood alcohol concentration (BAC), cardiac function, release of cardiac enzymes, pathological changes and mitochondrial function were measured. As expected, supplementation of alcohol in drinking water significantly increased random BAC in mice. Long-term exposure to alcohol further reduced body weight, ejection fraction and fractional shortening in comparison with the MI+Vehicle group. Histopathological data showed that alcohol increased fibrosis in infarct zone, which was well correlated with the functional decline. Also, as compared to the MI+Vehicle group, the adenosine diphosphate-supported respiratory function of freshly isolated cardiac mitochondria was inhibited in the MI+Alcohol+G group. Besides, upon MI-induced cardiac damage, we did not observe further changes in heart weight, cardiomyocyte enlargement in remote zone, exercise capacity, lung edema and the release of cardiac enzyme after chronic alcohol intake. Our study demonstrated that chronic daily alcohol exposure exacerbated MI-induced cardiac dysfunction, which is related to promoted myocardial fibrosis and inhibited mitochondrial function.

A cross-sectional study of chronic liver disease patients complicating to hepatic osteodystrophy

Background: Hepatic osteodystrophy encompasses the spectrum of metabolic bone diseases in chronic liver disease (CLD) patients. CLD causing changes in BMD is well known. Although BMD evaluation in CLD cirrhosis are recommended by societies of British and American gastroenterology ,very less number of literature exist from India and none from the North-eastern region of India. Aim of the study to determine the association and severity of bone mineral density changes in patients with CLD and to correlate it with different aetiologies and severity of CLD.Methods: This cross-sectional study which included 79 patients with CLD was conducted in RIMS, Manipur from September 2017 to August 2019. All CLD patients of age 18-60 years were included. DEXA scan and other related blood investigations were performed.Results: Chronic alcohol intake (56.9%), viral infection (20.3%) and mixed (17.7%) were the main aetiology of CLD in our study. Seventy three (92.4%) of the total 79 patients had low BMD (Osteopenia in 29 (36.7%) and osteoporosis in 44 (55.7%) patients). Osteoporosis was detected in 53.4% of alcohol related Cirrhosis, 25%of viral liver disease. Majority of the severe CLD patients (Child class C) had osteoporosis (70.6%) as compared to less severe groups (23.5% and 36.4% in class B and A respectively).Conclusions: CLD patients have high prevalence of osteoporosis. Severity of liver disease, alcoholic liver disease, serum calcium and vitamin D deficiency predisposes to osteoporosis in these patients. Hence early screening of BMD is necessary in CLD patients.

Antioxidant properties of plant polyphenols in the counteraction of alcohol-abuse induced damage: Impact on the Mediterranean diet

Polyphenols are antioxidants contained in plants as olive and grape. As part of the Mediterranean diet, they may decrease the risk of cancer, of chronic and neurodegenerative diseases. Alcohol consumption plays a detrimental effect on health, causing tissue damage and disrupting the metabolism of Neurotrophins (NTs). NTs are crucial proteins for the life cycle of neuronal and non-neuronal cells. Alcohol abuse elicits changes in NTs levels in the brain and in other target organs, however, it was observed minor damage in animals early exposed to red wine, probably due to the antioxidant effects of polyphenols. Indeed, data show that resveratrol or other polyphenols extracted from the olive can effectively counteract serum free radicals’ formation caused by chronic alcohol intake, contrasting also alcohol-induced NTs liver elevation. The aim of the present review is to update pieces of evidences about the antioxidant properties of polyphenols and their role in counteracting alcohol-induced damage.

Association of Noncognitive Life Skills With Mortality at Middle and Older Ages in England

Noncognitive life skills are patterns of behavior, thoughts, and feelings that complement cognitive ability in promoting positive economic and educational outcomes. These positive attributes have been associated with favorable social and health outcomes at older ages, but their combined association with survival is not known. To evaluate the association of the combination of 5 noncognitive life skills with mortality, and to explore the role of sociodemographic, health, cognitive, and behavioral factors in explaining associations. This cohort study used data from wave 5 of the English Longitudinal Study of Ageing, conducted in 2010. Participants included adults 52 years and older. Associations of scores on 5 noncognitive life skills, including conscientiousness, perseverance, emotional stability, optimism, and control, with all-cause mortality were analyzed for a mean (SD) of 7.2 (1.3) years. Data analyses were completed in November 2019. Response to wave 5 of the English Longitudinal Study of Ageing. Noncognitive life skills scores, including conscientiousness, perseverance, emotional stability, optimism, and control, were measured by questionnaire. The main outcome was all-cause mortality, and the associations with noncognitive life skills scores were analyzed using Cox proportional hazards regressions models to estimate hazard ratios per 1-SD increase in score. A total of 7850 participants (mean [SD] age, 66.5 [9.0] years; 4333 [55.2%] women) were included. Combined life skill score was positively associated with survival, with a hazard ratio of 0.81 (95% CI, 0.72-0.90) per 1-SD increase in positive attributes after adjustment for age, sex, race/ethnicity, childhood socioeconomic status, educational attainment, baseline chronic disease, depressive symptoms, cognitive function, mobility impairment, social isolation, smoking, physical activity, alcohol intake, and fruit and vegetable consumption (P < .001). Excluding deaths during 24 months after baseline as a check for reverse causation showed the same pattern (adjusted hazard ratio, 0.79; 95% CI, 0.70-0.89; P < .001). Associations were maintained after each life skill was omitted in turn from the aggregate score, indicating that no single positive attribute accounted for the protective association. These findings suggest that noncognitive life skills are associated with survival at older ages. Whether training and education programs could enhance these attributes and influence mortality risk is not known, but fostering and maintaining life skills may be important in later life.

Effects of Alcohol and Cocaine in a Mutant Mouse Model of Predisposition to Post-Traumatic Stress Disorder.

Comorbidity between drug abuse and post-traumatic stress disorder (PTSD), a stress-related dysregulation of fear responses, is very high. While some drugs are known to increase fear and anxiety, there are only few data regarding interactions between voluntary drug consumption and fear memory. The spontaneous chronic consumption of either alcohol or cocaine under a 3-week free-choice progressive paradigm of alcohol (3/6/10%) or cocaine (0.2/0.4/0.6 mg/ml), was assessed in VGV transgenic mice, having full 5-HT2C receptor editing and displaying PTSD-like behaviors. The consequences of these drug consumptions on the potentiated contextual and cued fear conditioning responses of VGV mice were assessed. The effects of drugs on hippocampal brain-derived neurotrophic factor (Bdnf) mRNA were measured as its expression was previously found to be decreased in VGV mice. Chronic alcohol consumption was similar in WT and VGV mice. In the alcohol condition, fear acquisition was not different at the end of the learning session and cue-fear extinction was facilitated. Regarding cocaine, in contrast to WT mice, VGV mice did not increase their drug consumption along with increasing doses, an effect that might be related with enhanced drug stimuli discrimination via increased 5-HT2C receptors. Cocaine-intake VGV mice did not display the contextual fear generalization usually observed in control VGV mice. In addition, Bdnf expression was upregulated after either chronic alcohol or cocaine intake. Altogether, these results suggest that both chronic alcohol and cocaine voluntary oral consumptions can exert some therapeutic-like effects in a mutant model of PTSD predisposition.

Parkin deficiency accentuates chronic alcohol intake-induced tissue injury and autophagy defects in brain, liver and skeletal muscle

Alcoholism leads to organ injury including mitochondrial defect and apoptosis with evidence favoring a role for autophagy dysregulation in alcoholic damage. Parkin represents an autosomal recessive inherited gene for Parkinson's disease and an important member of selective autophagy for mitochondria. The association between Parkinson's disease and alcoholic injury remains elusive. This study aimed to examine the effect of parkin deficiency on chronic alcohol intake-induced organ injury in brain, liver and skeletal muscle (rectus femoris muscle). Adult parkin-knockout (PRK-/-) and wild-type mice were placed on Liber-De Carli alcohol liquid diet (4%) for 12weeks prior to assessment of liver enzymes, intraperitoneal glucose tolerance, protein carbonyl content, apoptosis, hematoxylin and eosin morphological staining, and mitochondrial respiration (cytochrome c oxidase, NADH:cytochrome c reductase and succinate:cytochrome c reductase). Autophagy protein markers were monitored by western blot analysis. Our data revealed that chronic alcohol intake imposed liver injury as evidenced by elevated aspartate aminotransferase and alanine transaminase, glucose intolerance, elevated protein carbonyl formation, apoptosis, focal inflammation, necrosis, microvesiculation, autophagy/mitophagy failure and dampened mitochondrial respiration (complex IV, complexes I and III, and complexes II and III) in the brain, liver and rectus femoris skeletal muscle. Although parkin ablation itself did not generate any notable effects on liver enzymes, insulin sensitivity, tissue carbonyl damage, apoptosis, tissue morphology, autophagy or mitochondrial respiration, it accentuated alcohol intake-induced tissue damage, apoptosis, morphological change, autophagy/mitophagy failure and mitochondrial injury without affecting insulin sensitivity. These data suggest that parkin plays an integral role in the preservation against alcohol-induced organ injury, apoptosis and mitochondrial damage.

Blueberry polyphenols play a preventive effect on alcoholic fatty liver disease C57BL/6 J mice by promoting autophagy to accelerate lipolysis to eliminate excessive TG accumulation in hepatocytes.

This study aims to explore blueberry polyphenols and its roles in nonalcoholic fatty liver disease (NAFLD) by relieving hepatic steatosis, and to understand alcoholic fatty liver disease (AFLD). Cell autophagy has been proved to promote lipid metabolism and is involved in the pathogenesis of AFLD; however, whether blueberry polyphenol affects autophagy is unknown. Therefore, our study analyzes the functions of blueberry polyphenol on AFLD and if its mechanisms are engaged with hepatocytes autophagy. We built the AFLD mice model via alcohol abduction, and the TG lipid droplets content detected the hepatic steatosis through ORO and HE stains. For blood lipid levels measurements, serum CHOL and TG concentrations were tests. For mechanism analysis, the lipogenic genes of SREBP1, FAS, and ACCα, and the lipodieretic genes of ATGL and Sirt1 were evaluated by qRT-PCR, as well as the autophagy proteins of p62; WB measured LC3-I and LC3-II. We found that chronic alcohol intake successfully induced AFLD occurrence with increased TG lipid droplets content in liver and serum CHOL and TG levels that accompanied by increased lipogenic and reduced lipodieretic mRNA levels, as well as enhancive p62 protein and decreased LC3-II/LC3-I proportion. However, after blueberry polyphenol intake, there were opposite outcomes happened. Moreover, blueberry polyphenol alone did not affect the lipid metabolism but promoted the hepatocytes autophagy at 200 mg/kg concentration. In summary, we are unparalleled that illustrated blueberry polyphenols can prevent AFLD development by promoting autophagy to accelerate lipid metabolism than to lighten hepatic steatosis.

Pro-inflammatory signalling and gut-liver axis in non-alcoholic and alcoholic steatohepatitis: Differences and similarities along the path.

Non‐alcoholic fatty liver disease (NAFLD) and alcohol‐associated liver disease (ALD) represent a spectrum of injury, ranging from simple steatosis to steatohepatitis and cirrhosis. In humans, in fact, fatty changes in the liver, possibly leading to end‐stage disease, were observed after chronic alcohol intake or in conditions of metabolic impairment. In this article, we examined the features and the pro‐inflammatory pathways leading to non‐alcoholic and alcoholic steatohepatitis. The involvement of several events (hits) and multiple inter‐related pathways in the pathogenesis of these diseases suggest that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination treatment towards multiple pro‐inflammatory targets would eventually be required. Gut‐liver crosstalk is involved not only in the impairment of lipid and glucose homoeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis in both NAFLD and ALD. Modulation of the gut‐liver axis has been suggested as a possible therapeutic approach since gut‐derived components are likely to be involved in both the onset and the progression of liver damage. This review summarizes the translational mechanisms underlying pro‐inflammatory signalling and gut‐liver axis in non‐alcoholic and alcoholic steatohepatitis. With a multitude of people being affected by liver diseases, identification of possible treatments and the elucidation of pathogenic mechanisms are elements of paramount importance.

The Protective Role of Green Tea against Ethanol-mediated Bone Alterations in Adult Male Rabbits: Biochemical, Histological and Morphometrical Study

Background: Chronic alcohol abuse is a widespread clinical disorder. It leads to bone alterations, mainly osteoporosis. Next to water, tea (green or black) is the most widely consumed beverage in the world. Bone mineral density is affected by several compounds contained in tea extracts.Aim of the Work: Our work aimed to investigate the effects of alcohol on adult male rabbit's compact bone and the possible protective effect of green tea extract. (GTE)Material and Methods: Twenty-four young adult male rabbits were used. They were divided into equal 4 groups: normal control, green tea, ethanol (EtOH) and EtOH – green tea. After 120 days of treatment, all animals were anaesthetized and sacrificed. Blood ethanol and serum ionized calcium (iCa), phosphorus (P) and alkaline phosphatase (ALP) levels were estimated. Serum creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were estimated to determine renal and hepatic integrity. Femurs of each rabbit were processed for histological and morphometrical study.Results: Chronic alcohol ingestion resulted in a non_significant decrease in serum iCa level and a significant decrease in serum ALP activity. EtOH -treated rabbits did not differ from the controls in mean serum levels of ALT, AST, creatinine or phosphorus. Bone sections from EtOH- treated rabbits revealed multiple areas of degeneration in the thin cartilaginous plate. The trabeculae were thinner, shorter and fewer than those from controls. There was a significant decrease in osteoblast surface and a significant increase in osteoclast surface. Green tea supplementation resulted in marked improving of biochemical, histological and all histomorphometric parameters under investigation.Conclusion: From the foregoing, dangerous effects of alcohol on the bone became clear. So it is better to restrict its consumption. Natural products as green tea are able to protect against bone deterioration.

Gentiopicroside Ameliorates the Progression from Hepatic Steatosis to Fibrosis Induced by Chronic Alcohol Intake.

In current study, we aimed to investigate whether the gentiopicroside (GPS) derived from Gentiana manshurica Kitagawa could block the progression of alcoholic hepatic steatosis to fibrosis induced by chronic ethanol intake. C57BL/6 mice were fed an ethanol-containing Lieber-DeCarli diet for 4 weeks. LX-2 human hepatic stellate cells were treated with GPS 1 h prior to transforming growth factor-β (TGF-β) stimulation, and murine hepatocyte AML12 cells were pretreated by GPS 1 h prior to ethanol treatment. GPS inhibited the expression of type I collagen (collagen I), α-smooth muscle actin (α-SMA) and tissue inhibitor of metal protease 1 in ethanol-fed mouse livers with mild fibrosis. In addition, the imbalanced lipid metabolism induced by chronic ethanol-feeding was ameliorated by GPS pretreatment, characterized by the modulation of lipid accumulation. Consistently, GPS inhibited the expression of collagen I and α-SMA in LX-2 cells stimulated by TGF-β. Inhibition of lipid synthesis and promotion of oxidation by GPS were also confirmed in ethanol-treated AML12 cells. GPS could prevent hepatic steatosis advancing to the inception of a mild fibrosis caused by chronic alcohol exposure, suggesting GPS might be a promising therapy for targeting the early stage of alcoholic liver disease.

Dietary Composition Exacerbates Sex Differences in Skeletal Muscle Myopathy following Chronic Alcohol Intake

Chronic alcohol consumption has been commonly reported to induce skeletal muscle loss, however data observing the impact of diet composition and alcohol on muscle mass, particularly between sexes, remains scarce.PURPOSETo observe how differences in dietary composition influence the effects of alcohol on skeletal muscle mass in male and female mice.METHODSC57BL/6 mice (n=72; m=36; f=36) aged 12‐weeks‐old were acclimated to a liquid diet for one‐week prior to randomization into either a control (CON: 35% FAT, 47% CHO, 18% PRO) or one of three alcohol (EtOH) treatment groups of differing dietary composition: high‐fat (HF: 35% FAT, 15% CHO, 18% PRO), low‐fat (LF: 12% FAT, 38% CHO, 18% PRO) or high‐protein (PRO: 12% FAT, 31% CHO, 25% PRO). Alcohol was incorporated into the diet and increased over time to a maximum intake of 32% kcal of the diet. Daily consumption of EtOH was assessed relative to body weight. After 7 weeks, the gastrocnemius (GAS) and quadriceps (QUAD) muscles were excised, along with the heart and spleen, which were weighed and expressed relative to body weight. Blood was taken at sacrifice for blood EtOH concentration (BAC); however, feeding status and therefore alcohol intake, was ad libitum up until the time of sample collection. Data were analyzed via 2‐way ANOVA for variables across time, and unpaired t‐tests were used to detect differences between diets and control groups, and between sexes within diets.RESULTSNo significant interactions nor main effects were observed for EtOH consumption between diets within each sex. A significant main effect of sex was observed for EtOH consumption within all diets, where females consumed more EtOH than males (HF: F=71.79, 5.18 ± 0.61 g/kg; LF: F=53.55, 4.37 ± 0.60 g/kg; PRO: F=38.45, 4.75 ± 0.77 g/kg; p’s &lt;0.0001). No main effect of diet was observed for either sex for BAC (p≥0.98) at sacrifice. Female GAS was significantly reduced in HF and LF compared to CON (−8.31 ± 3.74%, p=0.043; −10.53 ± 3.74%, p=0.01 respectively), while no changes were noted for Male GAS. Female QUAD was significantly reduced in HF and LF compared to CON (−10.81 ± 4.52%, p=0.03; −13.63 ± 3.58%, p&lt;0.01 respectively), while no changes were observed for male QUAD. Female heart weights were significantly reduced in HF and LF compared to CON (−12.35 ± 4.33%, p=0.01; −11.34 ± 3.88%, p&lt;0.01 respectively), while an increase in LF was observed in males (9.89 ± 2.55%, p&lt;0.01). Furthermore, female spleen weight was significantly reduced in LF and PRO (−18.39 ± 7.22%, p=0.02; −19.06 ± 6.45%, p=0.01 respectively), while no differences were noted for males.CONCLUSIONSDespite consuming equivalent amounts of EtOH between diets within each sex, females in HF and LF diets experienced significant muscle atrophy compared to CON, while no reductions were observed in PRO. However, this alcohol feeding protocol did not induce significant muscle atrophy in male mice. A possible explanation for these sex differences is that over time, female mice consumed significantly more EtOH relative to body weight than male mice, indicating potential dose‐dependent effects. These sex differences in EtOH preference and resulting alcohol dose require further examination for future work related to the development of alcoholic myopathy.

Immune Modulatory Effects of Caryophyllene Oxide in Alcohol Related Behaviors

Alcohol‐use disorder (AUD) is the third leading cause of preventable death in the United States following tobacco and obesity, and current treatments for AUD yield disappointing remission rates. Chronic alcohol intake has been established to negatively impact the body’s immune system, and the endocannabinoid system has been shown to modulate the abuse‐related effects of ethanol. In this study, and we investigated the effects of 30 mg/kg caryophyllene oxide ( BCPO), in two widely accepted animal models of AUD: two‐bottle choice ethanol consumption and ethanol‐induced conditioned place preference (CPP). Finally, we used multiplex bead‐based flow cytometry to evaluate the effect of BCPO on plasma level of cytokines following these behavioral assays. BCPO significantly decreased ethanol intake and preference without changing total fluid intake in mice that consumed high amounts of ethanol. In mice that consumed low amounts of ethanol, BCPO did not alter ethanol intake, preference, or total fluid intake. BCPO significantly attenuated the expression of an ethanol‐induced CPP. Following the CPP assay, we observed a significant decrease in circulating levels of IFNγ, TNFα, MCP1, IL12p70, IL1b, and IL10 which was reversed by treatment with BCPO. Our findings support the current knowledge that excessive consumption of alcohol may lead to immune suppression and predispose individuals to a number of infections as well as neoplastic diseases. This study expands and supports the use of immunoregulatory molecules as a viable target for the treatment of AUD.

Role of Alcohol Drinking in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), increase as the population ages around the world. Environmental factors also play an important role in most cases. Alcohol consumption exists extensively and it acts as one of the environmental factors that promotes these neurodegenerative diseases. The brain is a major target for the actions of alcohol, and heavy alcohol consumption has long been associated with brain damage. Chronic alcohol intake leads to elevated glutamate-induced excitotoxicity, oxidative stress and permanent neuronal damage associated with malnutrition. The relationship and contributing mechanisms of alcohol with these three diseases are different. Epidemiological studies have reported a reduction in the prevalence of Alzheimer’s disease in individuals who drink low amounts of alcohol; low or moderate concentrations of ethanol protect against β-amyloid (Aβ) toxicity in hippocampal neurons; and excessive amounts of ethanol increase accumulation of Aβ and Tau phosphorylation. Alcohol has been suggested to be either protective of, or not associated with, PD. However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects through the induction of Cytochrome P450 2E1 (CYP2E1) and an increase in the amount of α-Synuclein (αSYN) relevant to PD. The findings on the association between alcohol consumption and ALS are inconsistent; a recent population-based study suggests that alcohol drinking seems to not influence the risk of developing ALS. Additional research is needed to clarify the potential etiological involvement of alcohol intake in causing or resulting in major neurodegenerative diseases, which will eventually lead to potential therapeutics against these alcoholic neurodegenerative diseases.

Invasive intestinal mucormycosis in a 40-year old immunocompetent patient - a rarely reported clinical phenomenon: a case report

BackgroundMucormycosis is rare, life-threatening fungal infection. Frequently observed in those patients having underlying immunosuppression such as, diabetes, organ transplantation, Human immunodeficiency virus (HIV) infection, and elevated serum iron. However, invasive intestinal mucormycosis occurring in immunocompetent individuals without the traditional risk factors is extremely rare clinical phenomenon.Case presentationWe report a 40-year-old male patient who presented with 1 week history of diffuse abdominal pain and high grade fever, associated with vomiting and frequent loose stools. Has history of chronic alcohol ingestion. Otherwise, no past history of chronic medical illness, nor he had contact with individuals with similar illness. He was in a septic shock with multiple organ failure up on presentation to emergency room. Physical examination revealed icterus sclera with abdominal tenderness. He was immediately resuscitated using crystalloids, supported with inotrope, and antibiotics. Histopathological examination of tissue sample from colonic ulcer biopsy revealed invasive intestinal mucormycosis. Patient showed full clinical and histopathological resolution after course of parenteral Liposomal Amphotercin B.ConclusionThis case highlights the fact that, despite its life-threatening nature, it’s possible to treat patients with invasive intestinal mucormycosis with aggressive antifungal and supportive care without surgical intervention, provided that all the necessary supportive care were initiated early and the disease was diagnosed early and appropriate medical management was initiated timely. In addition, it’s important to consider intestinal mucormycosis even in patients who are immunocompetent without traditional risk factors.

Oxidative stress inhibition by resveratrol in alcohol-dependent mice.

Uncontrolled ingestion of alcohol has dramatic consequences on the entire organism that are also associated with the oxidation process induced by alcohol and elevate radical oxygen species. Resveratrol, a nonflavonoid phenol, shows well-documented antioxidant properties. We investigated the potential antioxidant ability of this natural compound in a mouse model of alcohol addiction. We administered (per os) for 60 d 10 mg · kg-1 · d-1 of resveratrol in alcoholic adult male mice. Oxidative stress was evaluated by measuring serum-free oxygen radicals defense and free oxygen radical levels. Resveratrol metabolites were measured in the serum of mice that were administered with resveratrol. Finally, the effect of resveratrol on the alcohol-induced alteration of brain-derived neurotrophic factors (BDNF) in the liver was investigated. Prolonged consumption of resveratrol strongly counteracts serum radical oxygen species formation caused by chronic alcohol intake without effects on natural, free oxygen radical defense. The presence of resveratrol metabolites in the serum only of animals supplemented with resveratrol potentiates the evidence that the antioxidant effect observed is due to the ingestion of the natural compound. Moreover, resveratrol supplementation can counteract alcohol-induced BDNF elevation in the liver, which is the main target of organ alcohol-induced damage. The consumption of resveratrol through metabolite formation may play a protective role by decreasing free radical formation and modulating the BDNF involved in hepatic disruption induced by chronic alcohol consumption. Further investigation into the mechanism underlying the protective effect could reinforce the potential use of resveratrol as a dietary supplement to prevent damage associated with chronic alcohol abuse.

Activation of Melanocortin-4 Receptor Inhibits Both Neuroinflammation Induced by Early Exposure to Ethanol and Subsequent Voluntary Alcohol Intake in Adulthood in Animal Models: Is BDNF the Key Mediator?

The concept that neuroinflammation induced by excessive alcohol intake in adolescence triggers brain mechanisms that perpetuate consumption has strengthened in recent years. The melanocortin system, composed of the melanocortin 4 receptor (MC4R) and its ligand α-melanocyte-stimulating hormone (α-MSH), has been implicated both in modulation of alcohol consumption and in ethanol-induced neuroinflammation decrease. Chronic alcohol consumption in adolescent rats causes a decrease in an α-MSH release by the hypothalamus, while the administration of synthetic agonists of MC4R causes a decrease in neuroinflammation and a decrease in voluntary alcohol consumption. However, the mechanism that connects the activation of MC4R with the decrease of both neuroinflammation and voluntary alcohol consumption has not been elucidated. Brain-derived neurotrophic factor (BDNF) has been implicated in alcohol drinking motivation, dependence and withdrawal, and its levels are reduced in alcoholics. Deficiencies in BDNF levels increased ethanol self-administration in rats. Further, BDNF triggers important anti-inflammatory effects in the brain, and this could be one of the mechanisms by which BDNF reduces chronic alcohol intake. Interestingly, MC4R signaling induces BDNF expression through the activation of the cAMP-responsive element-binding protein (CREB). We hypothesize that ethanol exposure during adolescence decreases the expression of α-MSH and hence MC4R signaling in the hippocampus, leading to a lower BDNF activity that causes dramatic changes in the brain (e.g., neuroinflammation and decreased neurogenesis) that predispose to maintain alcohol abuse until adulthood. The activation of MC4R either by α-MSH or by synthetic agonist peptides can induce the expression of BDNF, which would trigger several processes that lead to lower alcohol consumption.