-
Alcoholism, Clinical and Experimental... Sep 2019Alcohol intake increases the risk of developing colon cancer. Circadian disruption promotes alcohol's effect on colon carcinogenesis through unknown mechanisms....
BACKGROUND
Alcohol intake increases the risk of developing colon cancer. Circadian disruption promotes alcohol's effect on colon carcinogenesis through unknown mechanisms. Alcohol's metabolites induce DNA damage, an early step in carcinogenesis. We assessed the effect of time of alcohol consumption on markers of tissue damage in the colonic epithelium.
METHODS
Mice were treated by alcohol or phosphate-buffered saline (PBS), at 4-hour intervals for 3 days, and their colons were analyzed for (i) proliferation (Ki67) and antiapoptosis (Bcl-2) markers, (ii) DNA damage (γ-H2AX), and (iii) the major acetaldehyde (AcH)-DNA adduct, N -ethylidene-dG. To model circadian disruption, mice were shifted once weekly for 12 h and then were sacrificed at 4-hour intervals. Samples of mice with a dysfunctional molecular clock were analyzed. The dynamics of DNA damage repair from AcH treatment as well as role of xeroderma pigmentosum, complementation group A (XPA) in their repair were studied in vitro.
RESULTS
Proliferation and survival of colonic epithelium have daily rhythmicity. Alcohol induced colonic epithelium proliferation in a time-dependent manner, with a stronger effect during the light/rest period. Alcohol-associated DNA damage also occurred more when alcohol was given at light. Levels of DNA adduct did not vary by time, suggesting rather lower repair efficiency during the light versus dark. XPA gene expression, a key excision repair gene, was time-dependent, peaking at the beginning of the dark. XPA knockout colon epithelial cells were inefficient in repair of the DNA damage induced by alcohol's metabolite.
CONCLUSIONS
Time of day of alcohol intake may be an important determinant of colon tissue damage and carcinogenicity.
Topics: Animals; Central Nervous System Depressants; Circadian Rhythm; Colon; DNA Damage; Ethanol; Intestinal Mucosa; Male; Mice, Inbred C57BL; Time Factors; Xeroderma Pigmentosum Group A Protein
PubMed: 31237690
DOI: 10.1111/acer.14141 -
Alcoholism, Clinical and Experimental... Dec 2022The N-methyl-D-aspartate receptor (NMDAR) is a major molecular target of alcohol action in the central nervous system, yet many aspects of alcohol's modulation of the...
BACKGROUND
The N-methyl-D-aspartate receptor (NMDAR) is a major molecular target of alcohol action in the central nervous system, yet many aspects of alcohol's modulation of the activity of this ion channel remain unclear. We and others have shown that ethanol inhibition of NMDAR involves alterations in gating, especially a reduction in mean open time. However, a full description of ethanol's effects on NMDAR kinetics, including fitting them to a kinetic model, has not been reported.
METHODS
To determine ethanol's effects on NMDAR kinetics, we used steady-state single-channel recording in outside-out patches from HEK-293 cells transfected with recombinant GluN1/GluN2A or GluN1/GluN2B NMDAR subunits. Very low glutamate concentrations were used to isolate individual activations of the receptor.
RESULTS
In both subunit types, ethanol, at approximate whole-cell IC values (156 mM, GluN2A; 150 mM, GluN2B), reduced open probability (p ) by approximately 50% and decreased mean open time without changing the frequency of opening. Open and shut time distributions exhibited two and five components, respectively; ethanol selectively decreased the time constant and relative proportion of the longer open time component. In the GluN2A subunit, ethanol increased the time constants of all but the longest shut time components, whereas in the GluN2B subunit, shut times were unchanged by ethanol. Fitting of bursts of openings (representing individual activations of the receptor) to the gating portion of a kinetic model revealed that ethanol altered two rates: the rate associated with activation of the GluN2A or GluN2B subunit, and the rate associated with the closing of the longer of the two open states.
CONCLUSIONS
These results demonstrate that ethanol selectively alters individual kinetic rates and thus appears to selectively affect distinct conformational transitions involved in NMDAR gating.
Topics: Humans; Receptors, N-Methyl-D-Aspartate; Ethanol; Ion Channel Gating; HEK293 Cells; Glutamic Acid
PubMed: 36305341
DOI: 10.1111/acer.14965 -
Alcohol (Fayetteville, N.Y.) Jun 2020While ethanol-paired stimuli are frequently postulated to increase drinking motivation and thus increase ethanol responding and precipitate relapse, no study has...
While ethanol-paired stimuli are frequently postulated to increase drinking motivation and thus increase ethanol responding and precipitate relapse, no study has demonstrated increases in ethanol-reinforced responding following presentation of an ethanol-paired stimulus that had not previously been part of a contingent relationship. Previous studies have shown that food-paired stimuli can increase food responding that is at low rates and increase food consumption in food-sated rats. In Experiment 1, we show that an ethanol-paired stimulus can increase ethanol responding that is at low levels late in the experimental session, presumably due to satiation. However, these increases may have resulted from either associative or non-associative mechanisms. In Experiment 2, we compared the effects of an ethanol-paired stimulus to those of the same stimulus in a Truly-Random-Control group. In a Truly-Random-Control, the stimulus and ethanol each are presented on independent random schedules, and thus any differences between the effects of the stimulus in the experimental and control groups is likely attributable to the association between the stimulus and ethanol. The stimulus increased ethanol-reinforced responding in both the experimental and control groups, but these increases were greater in the experimental than the control group. Thus, both stimulus-change and the pairing of the stimulus with ethanol may result in increases in ethanol-reinforced responding.
Topics: Alcohol Drinking; Animals; Conditioning, Operant; Ethanol; Extinction, Psychological; Male; Rats; Rats, Inbred Lew; Reinforcement, Psychology; Self Administration
PubMed: 31689483
DOI: 10.1016/j.alcohol.2019.10.007 -
Biochemistry Apr 2010We used CD and UV resonance Raman spectroscopy to study the impact of alcohols on the conformational equilibria and relative Gibbs free energy landscapes along the...
We used CD and UV resonance Raman spectroscopy to study the impact of alcohols on the conformational equilibria and relative Gibbs free energy landscapes along the Ramachandran Psi-coordinate of a mainly poly-Ala peptide, AP with an AAAAA(AAARA)(3)A sequence. 2,2,2-Trifluoroethanol (TFE) most stabilizes the alpha-helix-like conformations, followed by ethanol, methanol, and pure water. The pi-bulge conformation is stabilized more than the alpha-helix, while the 3(10)-helix is destabilized due to the alcohol-increased hydrophobicity. Turns are also stabilized by alcohols. We also found that while TFE induces more alpha-helices, it favors multiple, shorter helix segments.
Topics: Alcohols; Amino Acid Sequence; Circular Dichroism; Ethanol; Indicators and Reagents; Methanol; Models, Molecular; Peptides; Protein Conformation; Spectrophotometry, Ultraviolet; Spectrum Analysis, Raman; Thermodynamics; Water
PubMed: 20225890
DOI: 10.1021/bi100176a -
New Anti-Prelog Stereospecific Whole-Cell Biocatalyst for Asymmetric Reduction of Prochiral Ketones.Molecules (Basel, Switzerland) Feb 2023The biocatalytic asymmetric reduction of prochiral ketones for the production of enantiopure alcohols is highly desirable due to its inherent advantages over chemical...
The biocatalytic asymmetric reduction of prochiral ketones for the production of enantiopure alcohols is highly desirable due to its inherent advantages over chemical methods. In this study, a new bacterial strain capable of transforming ketones to corresponding alcohols with high activity and excellent enantioselectivity was discovered in a soil sample. The strain was subsequently identified as TQ-2 based on its physiological characteristics and 16S rDNA sequence analysis. Under optimized reaction conditions, the resting cells of TQ-2 converted acetophenone to enantioenriched ()-1-phenylethanol with 99% enantiometric excess following anti-Prelog's rule, which is scarce in biocatalytic ketone reduction. The optimum temperature for the cells was 30 °C, and considerable catalytic activity was observed over a broad pH range from 5.0 to 9.0. The cells showed enhanced catalytic activity in the presence of 15% () glycerol as a co-substrate. The catalytic activity can also be substantially improved by adding Ca or K ions. Moreover, the TQ-2 cell was highly active in reducing several structurally diverse ketones and aldehydes to form corresponding alcohols with good to excellent conversion. Our study provides a versatile whole-cell biocatalyst that can be used in the asymmetric reduction of ketones for the production of chiral alcohol, thereby expanding the biocatalytic toolbox for potential practical applications.
Topics: Ketones; Oxidation-Reduction; Alcohols; Biocatalysis; Ethanol; Glycerol; Stereoisomerism
PubMed: 36771091
DOI: 10.3390/molecules28031422 -
The Journal of International Medical... 2007A number of studies from different countries and several large-scale meta-analyses have reported reduced coronary heart disease rates among those regularly consuming... (Review)
Review
A number of studies from different countries and several large-scale meta-analyses have reported reduced coronary heart disease rates among those regularly consuming mild to moderate amounts of alcohol compared with those abstaining from alcohol. In contrast, various studies have also reported that heavy alcohol consumption promotes the progression of atherosclerosis and that binge drinking might trigger embolic stroke and acute myocardial infarction. We discuss the association between alcohol consumption and acute myocardial infarction on the basis of evidence from literature published recently. Alcohol consumption has both favourable and unfavourable effects on metabolism, lipid profile, blood coagulation and fibrinolysis, blood pressure and vascular tone depending on the amount of alcohol consumed and the way that it is drunk (i.e. drinking habits). We conclude that it is extremely important to warn people of the risks associated with binge drinking and to encourage them to remain within the recommended safe limits for alcohol consumption.
Topics: Blood Coagulation; Ethanol; Fibrinolysis; Humans; Myocardial Infarction
PubMed: 17408054
DOI: 10.1177/147323000703500104 -
Gut Microbes Nov 2020Many patients with alcohol use disorder (AUD) consume alcohol chronically and in large amounts that alter intestinal microbiota, damage the gastrointestinal tract, and...
Many patients with alcohol use disorder (AUD) consume alcohol chronically and in large amounts that alter intestinal microbiota, damage the gastrointestinal tract, and thereby injure other organs via malabsorption and intestinal inflammation. We hypothesized that alcohol consumption and subsequent abstinence would change the gut microbiome in adults admitted to a treatment program. Stool and oral specimens, diet data, gastrointestinal assessment scores, anxiety, depression measures and drinking amounts were collected longitudinally for up to 4 weeks in 22 newly abstinent inpatients with AUD who were dichotomized as less heavy drinkers (LHD, <10 drinks/d) and very heavy drinkers (VHD, 10 or more drinks/d). Next-generation 16 S rRNA gene sequencing was performed to measure the gut and oral microbiome at up to ten time points/subject and LHD and VHD were compared for change in principal components, Shannon diversity index and specific genera. The first three principal components explained 46.7% of the variance in gut microbiome diversity across time and all study subjects, indicating the change in gut microbiome following abstinence. The first time point was an outlier in three-dimensional principal component space versus all other time points. The gut microbiota in LHD and VHD were significantly dissimilar in change from day 1 to day 5 ( = .03) and from day 1 to week 3 ( = .02). The VHD drinking group displayed greater change from baseline. The Shannon diversity index of the gut microbiome changed significantly during abstinence in five participants. In both groups, the Shannon diversity was lower in the oral microbiome than gut. Ten total genera were shared between oral and stool in the AUD participants. These data were compared with healthy controls from the Human Microbiome Project to investigate the concept of a core microbiome. Rapid changes in gut microbiome following abstinence from alcohol suggest resilience of the gut microbiome in AUD and reflects the benefits of refraining from the highest levels of alcohol and potential benefits of abstinence.
Topics: Adult; Alcohol Abstinence; Alcohol Drinking; Ethanol; Feces; Female; Gastrointestinal Microbiome; Humans; Longitudinal Studies; Male; Microbiota; Middle Aged
PubMed: 32615913
DOI: 10.1080/19490976.2020.1758010 -
Brain, Behavior, and Immunity Jun 2011Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor... (Review)
Review
Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of α1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration.
Topics: Alcohols; Animals; Ethanol; Hypothalamo-Hypophyseal System; Neurons; Pituitary-Adrenal System; Rats
PubMed: 21300146
DOI: 10.1016/j.bbi.2011.01.016 -
Forensic Toxicology Jan 2023Methyl-2-(1-(4-fluorobutyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (4F-MDMB-BINACA) is a newly emerging synthetic cannabinoid receptor agonists (SCRA) first...
PURPOSE
Methyl-2-(1-(4-fluorobutyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (4F-MDMB-BINACA) is a newly emerging synthetic cannabinoid receptor agonists (SCRA) first described in 2018 in both Europe and the United States. Two fatal cases are reported caused by simultaneous consumption of 4F-MDMB-BINACA and ethanol.
METHODS
The victims were brothers who were both found deceased after consuming 4F-MDMB-BINACA and ethanol. Post-mortem toxicological analyses of blood and urine were carried out by supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) and headspace gas chromatography with flame ionization detection (HS-GC-FID).
RESULTS
The concentration of 4F-MDMB-BINACA in the postmortem blood was 2.50 and 2.34 ng/mL, and blood alcohol concentration was 2.11 and 2.49 g/L, respectively.
CONCLUSION
According to the reported cases and reviews of the scientific literature, concurrent ethanol consumption should amplify the toxicity of SCRAs. The threshold SCRA concentration for fatal overdose can be estimated ng/mL level (0.37-4.1 ng/mL according to the reported cases) in cases in which 1.5-2.5 g/L of ethanol is present in the blood.
Topics: Male; Humans; United States; Cannabinoids; Tandem Mass Spectrometry; Illicit Drugs; Gas Chromatography-Mass Spectrometry; Ethanol; Blood Alcohol Content; Cannabinoid Receptor Agonists
PubMed: 36652056
DOI: 10.1007/s11419-022-00632-y -
Alcohol Research & Health : the Journal... 2006Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the... (Review)
Review
Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement- and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaldehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaldehyde modulates, rather than mediates, some of alcohol's effects.
Topics: Acetaldehyde; Alcohol Drinking; Behavior; Behavior, Addictive; Brain; Catalase; Ethanol; Humans
PubMed: 17718404
DOI: No ID Found