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Cells May 2024Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and -knockout (KO) mice are more susceptible to...
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and -knockout (KO) mice are more susceptible to alcohol-induced tissue damage. However, the underlying mechanisms behind ALDH2-related gut-associated brain damage remain unclear. Age-matched young female -KO and C57BL/6J wild-type (WT) mice were gavaged with binge alcohol (4 g/kg/dose, three doses) or dextrose (control) at 12 h intervals. Tissues and sera were collected 1 h after the last ethanol dose and evaluated by histological and biochemical analyses of the gut and hippocampus and their extracts. For the mechanistic study, mouse neuroblast Neuro2A cells were exposed to ethanol with or without an Aldh2 inhibitor (Daidzin). Binge alcohol decreased intestinal tight/adherens junction proteins but increased oxidative stress-mediated post-translational modifications (PTMs) and enterocyte apoptosis, leading to elevated gut leakiness and endotoxemia in -KO mice compared to corresponding WT mice. Alcohol-exposed -KO mice also showed higher levels of hippocampal brain injury, oxidative stress-related PTMs, and neuronal apoptosis than the WT mice. Additionally, alcohol exposure reduced Neuro2A cell viability with elevated oxidative stress-related PTMs and apoptosis, all of which were exacerbated by Aldh2 inhibition. Our results show for the first time that ALDH2 plays a protective role in binge alcohol-induced brain injury partly through the gut-brain axis, suggesting that ALDH2 is a potential target for attenuating alcohol-induced tissue injury.
Topics: Animals; Aldehyde Dehydrogenase, Mitochondrial; Mice, Knockout; Mice; Mice, Inbred C57BL; Binge Drinking; Brain Injuries; Ethanol; Female; Apoptosis; Oxidative Stress; Hippocampus; Mitochondria
PubMed: 38891060
DOI: 10.3390/cells13110927 -
Science Advances Jan 2024An East Asian-specific variant on ( rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide... (Meta-Analysis)
Meta-Analysis
An East Asian-specific variant on ( rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (, , and ) in wild-type homozygotes and six (, , , , , and ) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (, , , and ) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.
Topics: Humans; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Alcohol Drinking; Genotype; Aldehyde Dehydrogenase, Mitochondrial; Esophageal Neoplasms; Genetic Predisposition to Disease; East Asian People
PubMed: 38277453
DOI: 10.1126/sciadv.ade2780 -
Bioscience, Biotechnology, and... Apr 2024Gluconobacter strains perform incomplete oxidation of various sugars and alcohols, employing regio- and stereoselective membrane-bound dehydrogenases oriented toward the... (Review)
Review
Gluconobacter strains perform incomplete oxidation of various sugars and alcohols, employing regio- and stereoselective membrane-bound dehydrogenases oriented toward the periplasmic space. This oxidative fermentation process is utilized industrially. The ketogluconate production pathway, characteristic of these strains, begins with the conversion of d-glucose to d-gluconate, which then diverges and splits into 2 pathways producing 5-keto-d-gluconate and 2-keto-d-gluconate and subsequently 2,5-diketo-d-gluconate. These transformations are facilitated by membrane-bound d-glucose dehydrogenase, glycerol dehydrogenase, d-gluconate dehydrogenase, and 2-keto-d-gluconate dehydrogenase. The variance in end products across Gluconobacter strains stems from the diversity of enzymes and their activities. This review synthesizes biochemical and genetic knowledge with biotechnological applications, highlighting recent advances in metabolic engineering and the development of an efficient production process focusing on enzymes relevant to the ketogluconate production pathway in Gluconobacter strains.
Topics: Gluconates; Gluconobacter; Biotechnology; Fermentation; Metabolic Engineering; Glucose; Glucose 1-Dehydrogenase; Sugar Alcohol Dehydrogenases
PubMed: 38323387
DOI: 10.1093/bbb/zbae013 -
International Journal of Molecular... Aug 2023Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ)...
Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ species-small oligomers, large oligomers, insoluble fibrils, and monomers-were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ oligomers induced a concentration- and time-dependent increase in intracellular Ca and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca nor viability was significantly affected by larger Aβ species or monomers. In addition, the small Aβ oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy.
Topics: Rats; Animals; Amyloid beta-Peptides; Microglia; Reactive Oxygen Species; Alzheimer Disease; Peptide Fragments; Receptors, N-Methyl-D-Aspartate
PubMed: 37569690
DOI: 10.3390/ijms241512315 -
Plants (Basel, Switzerland) Aug 2023Kiwifruit ( spp.) is susceptible to waterlogging stress. Although abundant wild germplasm resources exist among plants for improving the waterlogging tolerance of...
Kiwifruit ( spp.) is susceptible to waterlogging stress. Although abundant wild germplasm resources exist among plants for improving the waterlogging tolerance of kiwifruit cultivars, the underlying mechanisms remain largely unknown. Here, a comparative study was undertaken using one wild germplasm, Maorenshen ( Dunn, MRS), and one cultivar, Miliang-1 ( var. (A.Chev.) A.Chev. cv. Miliang-1, ML). Under stress, the ML plantlets were seriously damaged with wilted chlorotic leaves and blackened rotten roots, whereas the symptoms of injury in the MRS plantlets were much fewer, along with higher photosynthetic rates, chlorophyll fluorescence characteristics and root activity under stress conditions. However, neither aerenchyma in the root nor adventitious roots appeared in both germplasms upon stress exposure. The activities of pyruvate decarboxylase (PDC) and alcohol dehydrogenase (ADH), as well as their transcript levels, were constitutively higher in MRS than those in ML under both normal and stress conditions. Waterlogging stress significantly enhanced the PDC and ADH enzyme activities in both germplasms, which were 60.8% and 22.4% higher in the MRS roots than those in the ML roots under waterlogging stress, respectively. Moreover, MRS displayed higher activities of antioxidant enzymes, including SOD, CAT, and APX, as well as DPPH-radical scavenging ability, and decreased HO and MDA accumulation under both normal and stress conditions. Our findings suggest that the waterlogging tolerance of the wild germplasm was associated with high PDC and ADH, as well as antioxidant ability.
PubMed: 37571025
DOI: 10.3390/plants12152872 -
Journal of Dental Sciences Oct 2023Tobacco and alcohol are the well-known carcinogenic agents of oral cavity health. The purpose of this study was to investigate the scientometric characteristics of...
BACKGROUND/PURPOSE
Tobacco and alcohol are the well-known carcinogenic agents of oral cavity health. The purpose of this study was to investigate the scientometric characteristics of alcohol and tobacco use and oral health.
MATERIALS AND METHODS
The papers on alcohol and tobacco use and oral cavity were published since 1885 and 1895, respectively. All the eligible papers were retrieved on March 20, 2023 from the Scopus database.
RESULTS
There are 2529 and 1545 papers on tobacco smoking and alcohol drinking and oral cavity in the Scopus database, respectively. Based on the frequency of keywords in all included papers, both smoking and drinking are involved in mouth neoplasms, oral cancer, leukoplakia, and periodontal diseases. In the papers on tobacco and alcohol use and oral cavity, the same research keywords confirm tobacco and alcohol use associate with oral cancer risk possibly through influencing genetics and gene and protein expression. For the distinctive keywords, nicotine, smoking cessation, and electronic cigarette are unique keywords of tobacco use. Acetaldehyde, alcohol dehydrogenase, and alcohol metabolism are unique ones of alcohol use.
CONCLUSION
This study for the first time reports the scientometric characteristics of tobacco and alcohol use and oral health, which might aid healthcare authorities to promote tobacco and alcohol control measures focused on the necessities of their population.
PubMed: 37799876
DOI: 10.1016/j.jds.2023.05.016 -
Pharmacogenomics Aug 2023As the most distressing complication of sickle cell disease (SCD), pain is marked by considerable heterogenicity. In this study we explored the potential association of...
As the most distressing complication of sickle cell disease (SCD), pain is marked by considerable heterogenicity. In this study we explored the potential association of alcohol dehydrogenase 7 gene () polymorphism rs971074 with sickle cell pain. We analyzed clinical phenotypes and the rs971074 single-nucleotide polymorphism in by MassARRAY-iPlex analysis in a cohort of SCD patients. The synonymous rs971074 was significantly associated with both acute and chronic pain in SCD. Patients with the minor T allele(s) recorded significantly more crisis episodes and severe chronic pain symptoms. Our study has identified the rs971074 minor T allele as a genetic biomarker potentially influencing acute and chronic pain. These findings may ultimately help inform strategies to develop precision pain therapies in SCD.
Topics: Humans; Alcohol Dehydrogenase; Anemia, Sickle Cell; Chronic Pain; Phenotype; Polymorphism, Single Nucleotide
PubMed: 37712142
DOI: 10.2217/pgs-2023-0084 -
Drug and Alcohol Dependence Apr 2024National survey data suggest Asian Americans (AA) are less likely to consume alcohol and develop AUD than Americans in other groups. However, it is common for AA to be...
BACKGROUND
National survey data suggest Asian Americans (AA) are less likely to consume alcohol and develop AUD than Americans in other groups. However, it is common for AA to be born outside of the US and carry gene variants that alter alcohol metabolism, both of which can lead to lower levels of alcohol involvement. The current study examined differences in alcohol use and AUD between AA and other groups before and after controlling for birth location and gene variants.
DESIGN
Past year alcohol measures were examined from adults 18+ (N=22,848) in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III before and after controlling for birth location (inside or outside of the US) and gene variants (ALDH2*2 and ADH1B*2/ADH1B*3). Gender gaps in alcohol measures also were assessed.
RESULTS
Before adjustments, AA were less likely than White Americans to drink in the previous year (OR=0.50, 95% CI 0.41-0.62), binge (OR=0.68, 95% CI 0.52-0.88), engage in frequent heavy drinking (OR=0.55, 95% CI 0.42-0.73), and reach criteria for AUD (OR=0.71, 95% CI 0.53-0.94). After controlling for birth location and gene variants, AA remained less likely to drink in the past year (OR=0.54, 95% CI 0.41-0.70) but all other differences disappeared. Gender gaps were only observed for AA born outside of the US, highlighting the importance of experience rather than racial category per se.
CONCLUSIONS
Findings indicate that heterogeneity among AA leads to spurious generalizations regarding alcohol use and AUD and challenge the model minority myth.
Topics: Adult; Humans; Alcohol Dehydrogenase; Alcohol Drinking; Alcoholism; Aldehyde Dehydrogenase, Mitochondrial; Asian; Ethanol; White
PubMed: 38402754
DOI: 10.1016/j.drugalcdep.2024.111120 -
American Journal of Physiology.... May 2024Fatty acid oxidation (FAO) releases the energy stored in fat to maintain basic biological processes. Dehydrogenation is a major way to oxidize fatty acids, which needs... (Review)
Review
Fatty acid oxidation (FAO) releases the energy stored in fat to maintain basic biological processes. Dehydrogenation is a major way to oxidize fatty acids, which needs NAD to accept the released H from fatty acids and form NADH, which increases the ratio of NADH/NAD and consequently inhibits FAO leading to the deposition of fat in the liver, which is termed fatty liver or steatosis. Consumption of alcohol (ethanol) initiates simple steatosis that progresses to alcoholic steatohepatitis, which constitutes a spectrum of liver disorders called alcohol-associated liver disease (ALD). ALD is linked to ethanol metabolism. Ethanol is metabolized by alcohol dehydrogenase (ADH), microsomal ethanol oxidation system (MEOS), mainly cytochrome P450 2E1 (CYP2E1), and catalase. ADH also requires NAD to accept the released H from ethanol. Thus, ethanol metabolism by ADH leads to increased ratio of NADH/NAD, which inhibits FAO and induces steatosis. CYP2E1 directly consumes reducing equivalent NADPH to oxidize ethanol, which generates reactive oxygen species (ROS) that lead to cellular injury. Catalase is mainly present in peroxisomes, where very long-chain fatty acids and branched-chain fatty acids are oxidized, and the resultant short-chain fatty acids will be further oxidized in mitochondria. Peroxisomal FAO generates hydrogen peroxide (HO), which is locally decomposed by catalase. When ethanol is present, catalase uses HO to oxidize ethanol. In this review, we introduce FAO (including α-, β-, and ω-oxidation) and ethanol metabolism (by ADH, CYP2E1, and catalase) followed by the interaction between FAO and ethanol metabolism in the liver and its pathophysiological significance.
Topics: Humans; Catalase; NAD; Cytochrome P-450 CYP2E1; Hydrogen Peroxide; Fatty Liver; Ethanol; Liver Diseases, Alcoholic; Fatty Acids
PubMed: 38573193
DOI: 10.1152/ajpgi.00281.2023 -
Molecular Pharmaceutics Aug 2023The use of -butyl alcohol for the lyophilization of pharmaceuticals has seen an uptick over the past years. Its advantages include increased solubility of hydrophobic...
The use of -butyl alcohol for the lyophilization of pharmaceuticals has seen an uptick over the past years. Its advantages include increased solubility of hydrophobic drugs, enhanced product stability, shorter reconstitution time, and decreased processing time. While the mechanisms of protein stabilization exerted by cryo- and lyo-protectants are well known when water is the solvent of choice, little is known for organic solvents. This work investigates the interactions between two model proteins, namely, lactate dehydrogenase and myoglobin, and various excipients (mannitol, sucrose, 2-hydroxypropyl-β-cyclodextrin and Tween 80) in the presence of -butyl alcohol. We thermally characterized mixtures of these components by differential scanning calorimetry and freeze-drying microscopy. We also spectroscopically evaluated the protein recovery after freezing and freeze-drying. We additionally performed molecular dynamics simulations to elucidate the interactions in ternary mixtures of the herein-investigated excipients, -butyl alcohol and the proteins. Both experiments and simulations revealed that -butyl alcohol had a detrimental impact on the recovery of the two investigated proteins, and no combination of excipients yielded a satisfactory recovery when the organic solvent was present within the formulation. Simulations suggested that the denaturing effect of -butyl alcohol was related to its propensity to accumulate in the proximity of the peptide surface, especially near positively charged residues.
Topics: tert-Butyl Alcohol; Excipients; Molecular Dynamics Simulation; Biological Products; Solvents; Proteins; Freeze Drying; Calorimetry, Differential Scanning
PubMed: 37435823
DOI: 10.1021/acs.molpharmaceut.3c00125