Alcohol induced hepatic retinoid depletion is associated with the induction of multiple retinoid catabolizing cytochrome P450 enzymes

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.

Chronic Alcohol Exposure Alters Gene Expression and Neurodegeneration Pathways in the Brain of Adult Mice

Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD.

In Vivo Study of Nasal Bone Reconstruction with Collagen, Elastin and Chitosan Membranes in Abstainer and Alcoholic Rats

The aim of the present study was to evaluate the use of collagen, elastin, or chitosan biomaterial for bone reconstruction in rats submitted or not to experimental alcoholism. Wistar male rats were divided into eight groups, submitted to chronic alcohol ingestion (G5 to G8) or not (G1 to G4). Nasal bone defects were filled with clot in animals of G1 and G5 and with collagen, elastin, and chitosan grafts in G2/G6, G3/G7, and G4/G8, respectively. Six weeks after, all specimens underwent radiographic, tomographic, and microscopic evaluations. Bone mineral density was lower in the defect area in alcoholic animals compared to the abstainer animals. Bone neoformation was greater in the abstainer groups receiving the elastin membrane and in abstainer and alcoholic rats receiving the chitosan membrane (15.78 ± 1.19, 27.81 ± 0.91, 47.29 ± 0.97, 42.69 ± 1.52, 13.81 ± 1.60, 18.59 ± 1.37, 16.54 ± 0.89, and 37.06 ± 1.17 in G1 to G8, respectively). In conclusion, osteogenesis and bone density were more expressive after the application of the elastin matrix in abstainer animals and of the chitosan matrix in both abstainer and alcoholic animals. Chronic alcohol ingestion resulted in lower bone formation and greater formation of fibrous connective tissue.

CHARACTER AND FREQUENCY OF COMPLICATIONS IN PATIENTS WITH POLYTRAUMA AND CHRONIC ALCOHOL INTOXICATION

Purpose. Identify patterns of traumatic disease and characterize complications in patients with polytrauma (PT) and chronic alcohol intoxication (CAI). Materials and methods. Case histories of 39 victims with PT and alcohol history at age 19-60 years who were undergoing treatment at the Prof. Meshchaninov Kharkov City Clinical Emergency Hospital in 2016. Patient inclusion criteria: age 19-60, damage of two or more anatomical functional areas, severity of traumatic injury on the ISS scale 9-25 points, Glasgow coma scores ≥14 at the time of admission, absence of craniocerebral trauma, the absence of general anesthesia. Results. The average age of patients was 37.4 ± 9.4 years. Among these groups of patients were 29 men (74%), which is 2.9 times the number of women 10 (26%). Attention is drawn to the fact that the most important part of the victims (28.2%) was precisely the patients of the young able-bodied age. Infectious complications that developed in the early and late period of traumatic disease in victims with CAI are the main causes of death in PT - patients and induce a negative prognosis for survival. During analyzing the timing of the development of purulent-septic complications in this group of patients, we came to the conclusion that they occur on average at 7.2 ± 2.4 days. Among the infectious complications of PT in patients with CAI were pneumonia (28.2%), sepsis (7.6%), peritonitis (7.6%), pleural empyema (5.1%), osteomyelitis (5.1%). Non-infectious complications, in contrast to infectious, manifested from the first hours of injury and reached maximum development during the period by 2.3 ± 0.8 days, they were the main trigger for the development of severe infectious complications in the early period of traumatic disease. Noninfectious complications were consisted by delirium - in 29 patients, which increased the patients duration at intensive care unit on 39,6 ± 5 3 hours. These complications significantly increased the severity of the PT patients with CAI. With a higher incidence, it occurred in hyperactive, (62%) patients with delirium, and mixed (38%) form. Attention is drawn to the fact that patients with fatal outcome (29 cases), delirium was observed significantly more frequently (χ2 to include Yeats = 3.641, p <0.05) was found in 25 patients. Less frequently in patients occurred thrombosis 5(12.8%) and fat embolism syndrom 2 (5.1%). Conclusions. Most often, multiple injuries with history of alcohol use are obtained by young working aged men. The cause of injury in more than 60% of cases is accidents. 82% of the victims were in the state of alcohol intoxication during their hospitalization. On average, the terms of stay of patients with ICU are 64.9 ± 23.7 hours, although with the development of complications, these terms increase to 103.2 ± 14.2 hours. In patients with CAI there is a complicated course of traumatic disease. Among the infectious complications that develop at 7.2 ± 2.4 days, pneumonia, sepsis and peritonitis predominate. The most common non-infectious complications were delirium, thrombophlebitis thrombosis, fat embolism. Risk of fatal outcome in patients with delirium in 6.25 times higher than in patients without acute encephalopathy. Thus, the treatment of patients with a history of with polytrauma and chronic alcohol intoxication is an extremely important medical problem that needs further study and improvement.

Effects of Different Green Tea Extracts on Chronic Alcohol Induced-Fatty Liver Disease by Ameliorating Oxidative Stress and Inflammation in Mice

Alcoholic fatty liver disease (AFLD) is a common chronic liver disease and has become a critical global public health problem. Green tea is a popular drink worldwide and contains several bioactive compounds. Different green teas could contain diverse compounds and possess distinct bioactivities. In the present study, the effects of 10 green teas on chronic alcohol induced-fatty liver disease in mice were explored and compared. The results showed that several green teas significantly reduced triacylglycerol levels in serum and liver as well as the aminotransferase activities in mice at a dose of 200 mg/kg, suggesting that they possess hepatoprotective effects. Moreover, several green teas remarkably decreased the expression of cytochrome P450 2E1, the levels of malondialdehyde and 4-hydroxynonenoic acid, and the contents of proinflammatory cytokines, indicating that they could alleviate oxidation damage and inflammation induced by chronic alcohol exposure. In addition, Seven Star Matcha Tea and Selenium-Enriched Matcha Tea could increase glutathione level. Furthermore, the main phytochemical components in green teas were determined and quantified by high-performance liquid chromatography, and the correlation analysis showed that gallic acid, gallocatechin, catechin, chlorogenic acid, and epigallocatechin gallate might at least partially contribute to protective effects on AFLD. In conclusion, Selenium-Enriched Chaoqing Green Tea, Xihu Longjing Tea, Taiping Houkui Tea, and Selenium-Enriched Matcha Tea showed the strongest preventive effects on AFLD. This research also provides the public with new insights about the effects of different green teas on AFLD.

Gut-derived Lipopolysaccharide Promotes Alcoholic Hepatosteatosis and Subsequent Hepatocellular Carcinoma by Stimulating Neutrophil Extracellular Traps Through TLR4

BackgroundBinge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and which increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and activation of neutrophil extracellular traps (NETs). MethodsSerum from both binge drinking and alcohol-avoiding patients was analyzed. Mouse models of chronical plus binge alcohol indued steatosis and HCC models were used. ResultsA marker of NETs formation, lipopolysaccharide, was significantly higher in alcoholic steatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE KO mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and genesis of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product lipopolysaccharide (LPS). When mice lacking TLR4 received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated. ConclusionFormation of NETs following LPS stimulation of TLR4 upon chronic alcohol usage leads to increased alcoholic steatosis and subsequent HCC.