Function of oxygen transport in the blood of patients in a state of alcohol deprivation in blood in vitro incubation with ethanol solution

Objective. To estimate the in vitro effect of ethanol on the function of oxygen transport in the blood of patients in a state of alcohol deprivation and in healthy donors.Materials and methods. We analyzed blood samples from 13 male patients aged 22–56 in a state of alcohol deprivation and 11 males aged 20-45 in whom this diagnosis was excluded. The blood was incubated with ethanol solution at a final concentration of 50 μmol/L. The parameters of the function of oxygen transport (р50, рО2, рСО2, рН, АВЕ, НСО3-, ТСО2,SВЕ, SBC) of the blood taken from the cubital vein using an ABL-330 “Radiometr” microgas analyzer were determined.Results. The patients in a state of alcohol deprivation reveal increased affinity of hemoglobin for oxygen, and their acid-base status of the blood becomes alkaline. When ethanol is added in vitro to the blood of patients, the affinity of hemoglobin for oxygen decreases.Conclusion. Decreased affinity of hemoglobin for oxygen upon the in vitro addition of ethanol in the examined patients indicates compensatory and adaptive changes in the oxygen transport of the blood in response to chronic ethanol consumption.

TLR4 Deficiency Affects the Microbiome and Reduces Intestinal Dysfunctions and Inflammation in Chronic Alcohol-Fed Mice

Chronic alcohol abuse causes an inflammatory response in the intestinal tract with damage to the integrity of the mucosa and epithelium, as well as dysbiosis in the gut microbiome. However, the role of gut bacteria in ethanol effects and how these microorganisms interact with the immune system are not well understood. The aim of the present study was to evaluate if TLR4 alters the ethanol-induced intestinal inflammatory response, and whether the response of this receptor affects the gut microbiota profile. We analyzed the 16S rRNA sequence of the fecal samples from wild-type (WT) and TLR4-knockout (TLR4-KO) mice with and without ethanol intake for 3 months. The results demonstrated that chronic ethanol consumption reduces microbiota diversity and causes dysbiosis in WT mice. Likewise, ethanol upregulates several inflammatory genes (IL-1β, iNOS, TNF-α) and miRNAs (miR-155-5p, miR-146a-5p) and alters structural and permeability genes (INTL1, CDH1, CFTR) in the colon of WT mice. Our results further demonstrated that TLR4-KO mice exhibit a different microbiota that can protect against the ethanol-induced activation of the immune system and colon integrity dysfunctions. In short, our results reveal that TLR4 is a key factor for determining the gut microbiota, which can participate in dysbiosis and the inflammatory response induced by alcohol consumption.

Lipid Lowering and Hepatoprotective Activity of Premna Tomentosa Leaf Extract (EPT) against Alcohol Induced Toxicity in Rats

The present study aims to determine the hepatoprotective and lipid lowering property of ethanolic leaf extract of Premna tomentosa (EPT) in alcohol induced hepatotoxicity. Chronic ethanol consumption is a significant danger factor in deciding liver disorders and other metabolic conditions through various mechanisms, including the regulation of the lipid metabolism. Medicinal plants are accepted to be a significant wellspring of new chemical substances with expected remedial impacts. Premna tomentosa (Verbenaceae) is a popular medicinal plant used extensively for the treatment of various ailments widely used in liver disorders. In the present research study, the male albino Wister rats were grouped (I-V) each consisting of 6 animals. In-vivo administration of 40 % ethanol (1 ml/100 gm b w/day) for 60 days resulted in a significant elevation in Total cholesterol, Triglycerides, LDL, and VLDL levels whereas the levels of HDL was found to be decreased when compared with the control rats. Liver tissues disclose central vein and sinusoidal capillary dilation, interface hepatitis, cytoplasmic vacuolization and mononuclear cell infiltration which confirms the intensity of liver damage due to chronic alcohol ingestion. Simultaneous EPT supplementation (500mg/kg and 750 mg/kg bw) to alcohol -intoxicated rats, reduced the levels of Total cholesterol, triglycerides, and lipoproteins consequential as analogized with the unsupplemented alcohol- treated rats. Liver of rats pre-treated with ethanolic extract of Premna tomentosa (500 mg and 750 mg) manifest reduced formation of interface hepatitis, vascular congestion, and fatty degeneration and exhibits more hepatoprotection compared with the rats pre-treated in Liv 52. The blood parameters were amplified by the histopathological perusal of the liver. The lipid -lowering property by the derivatives of cinnamic acid showed anticholesteremic activity. The results confirm the Hepatoprotective and lipid -lowering ability of Premna tomentosa in alcohol-treated rats.

The Timing and Effects of Low-Dose Ethanol Treatment on Acetaminophen-Induced Liver Injury

Acetaminophen (APAP) overdose is the major cause of drug-induced liver injury and acute liver failure. Approximately 10% of APAP is metabolized by cytochrome P450 (CYP2E1) into toxic N-acetyl-p-benzoquinone imine (NAPQI). CYP2E1 also contributes to ethanol metabolism, especially during conditions of high blood ethanol concentration. Acute and chronic ethanol consumption appears to have opposite effects on APAP-induced liver injury. We determined the effects of different doses, pre- and post-treatment, and various schedules of ethanol exposure in APAP-induced liver injury. Treatment with ethanol (0.5 g/kg) after 1 h of APAP (300 mg/kg) administration decreased serum ALT levels, histopathological features, and inflammatory cell infiltration. Moreover, ethanol treatment 1 h after APAP treatment reduced APAP-induced liver injury compared with later administration. Interestingly, ethanol pretreatment did not provide any protective effect. Furthermore, ethanol treatment was associated with a significant decrease in ERK and AKT phosphorylation during the acute injury phase. Ethanol exposure also increased CYP2E1 expression and decreased PCNA expression during the liver regeneration phase.

Transcriptional analysis of the response of C. elegans to ethanol exposure

Ethanol-induced transcriptional changes underlie important physiological responses to ethanol that are likely to contribute to the addictive properties of the drug. We examined the transcriptional responses of Caenorhabditis elegans across a timecourse of ethanol exposure, between 30 min and 8 h, to determine what genes and genetic pathways are regulated in response to ethanol in this model. We found that short exposures to ethanol (up to 2 h) induced expression of metabolic enzymes involved in metabolizing ethanol and retinol, while longer exposure (8 h) had much more profound effects on the transcriptome. Several genes that are known to be involved in the physiological response to ethanol, including direct ethanol targets, were regulated at 8 h of exposure. This longer exposure to ethanol also resulted in the regulation of genes involved in cilia function, which is consistent with an important role for the effects of ethanol on cilia in the deleterious effects of chronic ethanol consumption in humans. Finally, we found that food deprivation for an 8-h period induced gene expression changes that were somewhat ameliorated by the presence of ethanol, supporting previous observations that worms can use ethanol as a calorie source.

Fenofibrate (a PPAR-α Agonist) Administered During Ethanol Withdrawal Reverts Ethanol-Induced Astrogliosis and Restores the Levels of Glutamate Transporter in Ethanol-Administered Adolescent Rats

High-ethanol intake induces a neuroinflammatory response, which has been proposed as responsible for the maintenance of chronic ethanol consumption. Neuroinflammation decreases glutamate transporter (GLT-1) expression, increasing levels of glutamate that trigger dopamine release at the corticolimbic reward areas, driving long-term drinking behavior. The activation of peroxisome proliferator-activated receptor alpha (PPARα) by fibrates inhibits neuroinflammation, in models other than ethanol consumption. However, the effect of fibrates on ethanol-induced neuroinflammation has not yet been studied. We previously reported that the administration of fenofibrate to ethanol-drinking rats decreased ethanol consumption. Here, we studied whether fenofibrate effects are related to a decrease in ethanol-induced neuroinflammation and to the normalization of the levels of GLT-1. Rats were administered ethanol on alternate days for 4 weeks (2 g/kg/day). After ethanol withdrawal, fenofibrate was administered for 14 days (50 mg/kg/day) and the levels of glial fibrillary acidic protein (GFAP), phosphorylated NF-κB-inhibitory protein (pIκBα) and GLT-1, were quantified in the prefrontal cortex, hippocampus, and hypothalamus. Ethanol treatment increased the levels of GFAP in the hippocampus and hypothalamus, indicating a clear astrocytic activation. Similarly, ethanol increased the levels of pIκBα in the three areas. The administration of fenofibrate decreased the expression of GFAP and pIκBα in the three areas. These results indicate that fenofibrate reverts both astrogliosis and NF-κB activation. Finally, ethanol decreased GLT-1 expression in the prefrontal cortex and hippocampus. Fenofibrate normalized the levels of GLT-1 in both areas, suggesting that its effect in reducing ethanol consumption could be due to the normalization of glutamatergic tone.