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Redox Biology May 2024Elevated fasting ethanol levels in peripheral blood frequently found in metabolic dysfunction-associated steatohepatitis (MASLD) patients even in the absence of alcohol...
Elevated fasting ethanol levels in peripheral blood frequently found in metabolic dysfunction-associated steatohepatitis (MASLD) patients even in the absence of alcohol consumption are discussed to contribute to disease development. To test the hypothesis that besides an enhanced gastrointestinal synthesis a diminished alcohol elimination through alcohol dehydrogenase (ADH) may also be critical herein, we determined fasting ethanol levels and ADH activity in livers and blood of MASLD patients and in wild-type ± anti-TNFα antibody (infliximab) treated and TNFα mice fed a MASLD-inducing diet. Blood ethanol levels were significantly higher in patients and wild-type mice with MASLD while relative ADH activity in blood and liver tissue was significantly lower compared to controls. Both alterations were significantly attenuated in MASLD diet-fed TNFα mice and wild-type mice treated with infliximab. Moreover, alcohol elimination was significantly impaired in mice with MASLD. In in vitro models, TNFα but not IL-1β or IL-6 significantly decreased ADH activity. Our data suggest that elevated ethanol levels in MASLD patients are related to TNFα-dependent impairments of ADH activity.
Topics: Mice; Humans; Animals; Alcohol Dehydrogenase; Tumor Necrosis Factor-alpha; Infliximab; Ethanol; Fatty Liver; Alcohol Drinking
PubMed: 38493749
DOI: 10.1016/j.redox.2024.103121 -
PloS One 2024Glycerol dehydrogenase (GDH) catalyzes glycerol oxidation to dihydroxyacetone in a NAD+-dependent manner. As an initiator of the oxidative pathway of glycerol...
Glycerol dehydrogenase (GDH) catalyzes glycerol oxidation to dihydroxyacetone in a NAD+-dependent manner. As an initiator of the oxidative pathway of glycerol metabolism, a variety of functional and structural studies of GDH have been conducted previously. Structural studies revealed intriguing features of GDH, like the flexible β-hairpin and its significance. Another commonly reported structural feature is the enzyme's octameric oligomerization, though its structural details and functional significance remained unclear. Here, with a newly reported GDH structure, complexed with both NAD+ and glycerol, we analyzed the octamerization of GDH. Structural analyses revealed that octamerization reduces the structural dynamics of the N-domain, which contributes to more consistently maintaining a distance required for catalysis between the cofactor and substrate. This suggests that octamerization may play a key role in increasing the likelihood of the enzyme reaction by maintaining the ligands in an appropriate configuration for catalysis. These findings expand our understanding of the structure of GDH and its relation to the enzyme's activity.
Topics: NAD; Glycerol; Sugar Alcohol Dehydrogenases; Oxidation-Reduction; Glutamate Dehydrogenase
PubMed: 38483875
DOI: 10.1371/journal.pone.0300541 -
International Journal of Molecular... Feb 2024Prenatal alcohol exposure (PAE) and prenatal stress (PS) are highly prevalent conditions known to affect fetal programming of the hypothalamic-pituitary-adrenal (HPA)...
Prenatal alcohol exposure (PAE) and prenatal stress (PS) are highly prevalent conditions known to affect fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this study were to assess the effect of light PAE, PS, and PAE-PS interaction on fetal HPA axis activity assessed via placental and umbilical cord blood biomarkers. Participants of the ENRICH-2 cohort were recruited during the second trimester and classified into the PAE and unexposed control groups. PS was assessed by the Perceived Stress Scale. Placental tissue was collected promptly after delivery; gene and protein analysis for 11-HSD1, 11-HSD2, and pCRH were conducted by qPCR and ELISA, respectively. Umbilical cord blood was analyzed for cortisone and cortisol. Pearson correlation and multivariable linear regression examined the association of PAE and PS with HPA axis biomarkers. Mean alcohol consumption in the PAE group was ~2 drinks/week. Higher PS was observed in the PAE group ( < 0.01). In multivariable modeling, PS was associated with pCRH gene expression ( = 0.006, < 0.01), while PAE was associated with 11-HSD2 protein expression ( = 0.56, < 0.01). A significant alcohol-by-stress interaction was observed with respect to 11-HSD2 protein expression ( < 0.01). Results indicate that PAE and PS may independently and in combination affect fetal programming of the HPA axis.
Topics: Humans; Pregnancy; Female; Placenta; Hypothalamo-Hypophyseal System; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Stress, Psychological; Prenatal Exposure Delayed Effects; Pituitary-Adrenal System; Fetal Development; Fetal Diseases; Biomarkers; Psychological Tests; Self Report
PubMed: 38473937
DOI: 10.3390/ijms25052690 -
Foods (Basel, Switzerland) Feb 2024The aim of this study was to obtain egg-derived peptides with facilitating alcohol metabolism (EPs) by enzymolysis, to identify their structures, and screen small...
The aim of this study was to obtain egg-derived peptides with facilitating alcohol metabolism (EPs) by enzymolysis, to identify their structures, and screen small polypeptides with higher activity by molecular docking. The optimum conditions for preparing EPs with facilitating alcohol metabolism were obtained by a single factor experiment, adding 2% Protamex and performing enzymolysis for 3 h with a liquid-material ratio of 35:1. The dose-response relationship experiment showed that 800 mg/kg·bw EPs played a better role in facilitating alcohol metabolism. EPs contained 40% hydrophobic amino acids (HAA), including 9.24% Leu. Eighty-four peptides were identified by HPLC-MS/MS and four peptides with potential activation of alcohol dehydrogenase were further selected by molecular docking. The tetrapeptide Trp-Ile-Val-Asp (WIVD) with the highest binding energy reached -7.16 kcal/mol. These findings suggest that egg is a good source for the preparation of peptides with facilitating alcohol metabolism activity.
PubMed: 38472859
DOI: 10.3390/foods13050745 -
Nanomaterials (Basel, Switzerland) Feb 2024The modern global trend toward sustainable processes that meet the requirements of "green chemistry" provides new opportunities for the broad application of highly...
The modern global trend toward sustainable processes that meet the requirements of "green chemistry" provides new opportunities for the broad application of highly active, selective, and specific enzymatic reactions. However, the effective application of enzymes in industrial processes requires the development of systems for the remote regulation of their activity triggered by external physical stimuli, one of which is a low-frequency magnetic field (LFMF). Magnetic nanoparticles (MNPs) transform the energy of an LFMF into mechanical forces and deformations applied to enzyme molecules on the surfaces of MNPs. Here, we demonstrate the up- and down-regulation of two biotechnologically important enzymes, yeast alcohol dehydrogenase (YADH) and soybean formate dehydrogenase (FDH), in aggregates with gold-covered magnetic nanoparticles (GCMNPs) triggered by an LFMF. Two types of aggregates, "dimeric" (with the enzyme attached to several GCMNPs simultaneously), with YADH or FDH, and "monomeric" (the enzyme attached to only one GCMNP), with FDH, were synthesized. Depending on the aggregate type ("dimeric" or "monomeric"), LFMF treatment led to a decrease (down-regulation) or an increase (up-regulation) in enzyme activity. For "dimeric" aggregates, we observed 67 ± 9% and 47 ± 7% decreases in enzyme activity under LFMF exposure for YADH and FDH, respectively. Moreover, in the case of YADH, varying the enzyme or the cross-linking agent concentration led to different magnitudes of the LFMF effect, which was more significant at lower enzyme and higher cross-linking agent concentrations. Different responses to LFMF exposure depending on cofactor presence were also demonstrated. This effect might result from a varying cofactor binding efficiency to enzymes. For the "monomeric" aggregates with FDH, the LFMF treatment caused a significant increase in enzyme activity; the magnitude of this effect depended on the cofactor type: we observed up to 40% enzyme up-regulation in the case of NADP, while almost no effect was observed in the case of NAD.
PubMed: 38470742
DOI: 10.3390/nano14050411 -
Frontiers in Cellular and Infection... 2024Stingless bees, a social corbiculate bee member, play a crucial role in providing pollination services. Despite their importance, the structure of their microbiome,...
Stingless bees, a social corbiculate bee member, play a crucial role in providing pollination services. Despite their importance, the structure of their microbiome, particularly the fungal communities, remains poorly understood. This study presents an initial characterization of the fungal community associated with two Thai commercial stingless bee species, (Smith) and (Schwarz) from Chiang Mai, Thailand. Utilizing ITS amplicon sequencing, we identified distinct fungal microbiomes in these two species. Notably, fungi from the phyla Ascomycota, Basidiomycota, Mucoromycota, Mortierellomycota, and Rozellomycota were present. The most dominant genera, which varied significantly between species, included and . Additionally, several key enzymes associated with energy metabolism, structural strength, and host defense reactions, such as adenosine triphosphatase, alcohol dehydrogenase, -glucosidase, chitinase, and peptidylprolyl isomerase, were predicted. Our findings not only augment the limited knowledge of the fungal microbiome in Thai commercial stingless bees but also provide insights for their sustainable management through understanding their microbiome.
Topics: Bees; Animals; Mycobiome; Thailand; Microbiota
PubMed: 38469352
DOI: 10.3389/fcimb.2024.1367010 -
Tremor and Other Hyperkinetic Movements... 2024L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by pathogenic variants in the gene which encodes...
BACKGROUND
L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by pathogenic variants in the gene which encodes mitochondrial 2-hydroxyglutarate dehydrogenase. Here, we report a case of L2HGA in a Mexican-Mayan patient with a homozygous mutation at gene and clinical response to vitamin supplements and levocarnitine.
CASE REPORT
A 17-year-old, right-handed female patient with long-term history of seizures, developmental delay and ataxia was referred to a movement disorders specialist for the evaluation of tremor. Her brain MRI showed typical findings of L2HGA. The diagnosis was corroborated with elevated levels of 2-hydroxyglutaric acid in urine and genetic test which revealed a homozygous genetic known variant c.569C>T in exon 5 of gene. She was treated with levocarnitine and vitamin supplements, showing improvement in tremor and gait.
DISCUSSION
To our knowledge this is the first report of a Mexican patient with L2HGA. This case adds information about a rare condition in a different ethnic group and supports the findings of other authors which encountered symptomatic improvement with the use of flavin adenine dinucleotide (and its precursor riboflavin), and levocarnitine.
HIGHLIGHTS
We report the first case of Mexican-Mayan patient with L2HGA showing a missense homozygous mutation in gene, and improvement of symptoms with vitamin supplements and levocarnitine.
Topics: Humans; Female; Adolescent; Carnitine; Tremor; Mutation; Vitamins; Alcohol Oxidoreductases; Brain Diseases, Metabolic, Inborn
PubMed: 38464914
DOI: 10.5334/tohm.854 -
Environmental Health and Preventive... 2024Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the...
BACKGROUND
Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the toll was relatively low in East Asia. A genetic polymorphism unique to East Asians, Aldehyde dehydrogenase 2 rs671, has been reported to confer protection against infections.
METHOD
We retrospectively investigated the association between the surrogate marker of the rs671 variant, the skin flushing phenomenon after alcohol consumption, and the timing of COVID-19 incidence using a web-based survey tool to test any protective effects of rs671 against COVID-19.
RESULTS
A total of 807 valid responses were received from 362 non-flushers and 445 flushers. During the 42 months, from 12/1/2019 to 5/31/2023, 40.6% of non-flushers and 35.7% of flushers experienced COVID-19. Flushers tended to have a later onset (Spearman's partial rank correlation test, p = 0.057, adjusted for sex and age). Similarly, 2.5% of non-flushers and 0.5% of flushers were hospitalized because of COVID-19. Survival analysis estimated lower risks of COVID-19 and associated hospitalization among flushers (p = 0.03 and <0.01, respectively; generalized Wilcoxon test). With the Cox proportional hazards model covering 21 months till 8/31/2021, when approximately half of the Japanese population had received two doses of COVID-19 vaccine, the hazard ratio (95% confidence interval) of COVID-19 incidence was estimated to be 0.21 (0.10-0.46) for flusher versus non-flusher, with adjustment for sex, age, steroid use, and area of residence.
CONCLUSIONS
Our study suggests an association between the flushing phenomenon after drinking and a decreased risk of COVID-19 morbidity and hospitalization, suggesting that the rs671 variant is a protective factor. This study provides valuable information for infection control and helps understand the unique constitutional diversity of East Asians.
Topics: Humans; Retrospective Studies; Alcohol Drinking; Japan; Protective Factors; COVID-19 Vaccines; COVID-19; Flushing; Internet; Aldehyde Dehydrogenase, Mitochondrial
PubMed: 38462476
DOI: 10.1265/ehpm.23-00361 -
ACS Catalysis Mar 2024The unmatched chemo-, regio-, and stereoselectivity of enzymes renders them powerful catalysts in the synthesis of chiral active pharmaceutical ingredients (APIs)....
The unmatched chemo-, regio-, and stereoselectivity of enzymes renders them powerful catalysts in the synthesis of chiral active pharmaceutical ingredients (APIs). Inspired by the discovery route toward the LPA-antagonist BMS-986278, access to the API building block (1,3)-3-hydroxycyclohexanecarbonitrile was envisaged using an ene reductase (ER) and alcohol dehydrogenase (ADH) to set both stereocenters. Starting from the commercially available cyclohexene-1-nitrile, a C-H oxyfunctionalization step was required to introduce the ketone functional group, yet several chemical allylic oxidation strategies proved unsuccessful. Enzymatic strategies for allylic oxidation are underdeveloped, with few examples on selected substrates with cytochrome P450s and unspecific peroxygenases (UPOs). In this case, UPOs were found to catalyze the desired allylic oxidation with high chemo- and regioselectivity, at substrate loadings of up to 200 mM, without the addition of organic cosolvents, thus enabling the subsequent ER and ADH steps in a three-step one-pot cascade. UPOs even displayed unreported enantioselective oxyfunctionalization and overoxidation of the substituted cyclohexene. After screening of enzyme panels, the final product was obtained at titers of 85% with 97% and 99% , with a substrate loading of 50 mM, the ER being the limiting step. This synthetic approach provides the first example of a three-step, one-pot UPO-ER-ADH cascade and highlights the potential for UPOs to catalyze diverse enantioselective allylic hydroxylations and oxidations that are otherwise difficult to achieve.
PubMed: 38449536
DOI: 10.1021/acscatal.4c00177 -
Medical Microbiology and Immunology Mar 2024Multidrug-resistant clinical isolates of Moraxella catarrhalis have emerged, increasing the demand for the identification of new treatment and prevention strategies. A...
Multidrug-resistant clinical isolates of Moraxella catarrhalis have emerged, increasing the demand for the identification of new treatment and prevention strategies. A thorough understanding of how M. catarrhalis can establish an infection and respond to different stressors encountered in the host is crucial for new drug-target identification. Formaldehyde is a highly cytotoxic compound that can be produced endogenously as a by-product of metabolism and exogenously from environmental sources. Pathways responsible for formaldehyde detoxification are thus essential and are found in all domains of life. The current work investigated the role of the system consisting of the S-hydroxymethyl alcohol dehydrogenase (AdhC), a Zn-dependent class III alcohol dehydrogenase, and the S-formyl glutathione hydrolase (FghA) in the formaldehyde detoxification process in M. catarrhalis. Bioinformatics showed that the components of the system are conserved across the species and are highly similar to those of Streptococcus pneumoniae, which share the same biological niche. Isogenic mutants were constructed to study the function of the system in M. catarrhalis. A single fghA knockout mutant did not confer sensitivity to formaldehyde, while the adhC-fghA double mutant is formaldehyde-sensitive. In addition, both mutants were significantly cleared in a murine pulmonary model of infection as compared to the wild type, demonstrating the system's importance for this pathogen's virulence. The respective phenotypes were reversed upon the genetic complementation of the mutants. To date, this is the first study investigating the role of the AdhC-FghA system in formaldehyde detoxification and pathogenesis of M. catarrhalis.
Topics: Animals; Mice; Moraxella catarrhalis; Streptococcus pneumoniae; Formaldehyde; Glutathione; Hydrolases
PubMed: 38448747
DOI: 10.1007/s00430-024-00785-0