scholarly journals Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients

2015 ◽  
Vol 22 (2) ◽  
pp. 59-69 ◽  
Author(s):  
Mani Haschemi Nassab ◽  
Mathias Rhein ◽  
Lars Hagemeier ◽  
Marius Kaeser ◽  
Marc Muschler ◽  
...  
Keyword(s):  
Protein Expression ◽  
Alcohol Dependence ◽  
Promoter Region ◽  
Promoter Polymorphism ◽  
Aldehyde Dehydrogenase 2 ◽  
Protein Levels ◽  
Epigenetic Effects ◽  
Carcinogenic Metabolite ◽  
Low Alcohol ◽  
Alcohol Dependent

Acetaldehyde, the carcinogenic metabolite of ethanol known to provoke aversive symptoms of alcohol consumption, is predominantly eliminated by aldehyde dehydrogenase 2 (ALDH2). Reduced ALDH2 activity correlates with low alcohol tolerance and low risk for alcohol dependence. The ALDH2 promoter polymorphism rs886205 (A>G) is associated with decreased promoter activity, but a molecular mechanism and allele-dependent ALDH2 protein expression has not been described yet. On the basis of allele-dependent epigenetic effects, we analyzed the rs886205 genotype, methylation rates of cytosine-phosphatidyl-guanine (CpG)-sites within a regulatory promoter region and ALDH2 protein levels in 82 alcohol-dependent patients during a 2-week withdrawal and compared them to 34 matched controls. Patients without the G-allele of rs886205 showed higher methylation of the promoter region than controls and readily adapted epigenetically as well as on protein level during withdrawal, while patients with the G-allele displayed retarded methylation readjustment and no change in ALDH2 protein levels. Our data provide novel insights into an unknown genetic-epigenetic interaction, revealing impaired ALDH2 protein expression in patients with the G-allele of rs886205. Additionally, we checked for an association between rs886205 and protection against alcohol dependence and found a trend association between the G-allele and protection against alcohol dependence that needs replication in a larger Caucasian cohort.

scholarly journals PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1425
Author(s):  
Alena Shmakova ◽  
Mark Frost ◽  
Michael Batie ◽  
Niall S. Kenneth ◽  
Sonia Rocha
Keyword(s):  
Protein Expression ◽  
Cellular Response ◽  
Transcriptional Activity ◽  
Mrna Translation ◽  
Protein Translation ◽  
Signalling Pathways ◽  
Independent Function ◽  
Protein Levels ◽  
Associated Proteins ◽  
Core Components

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

scholarly journals Influences of Histone Stoichiometry on the Target Site Preference of Retrotransposons Ty1 and Ty2 in Saccharomyces cerevisiae

Genetics ◽  
1996 ◽  
Vol 142 (3) ◽  
pp. 761-776 ◽  
Author(s):  
Lori A Rinckel ◽  
David J Garfinkel
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Promoter Region ◽  
Target Site ◽  
Site Preference ◽  
Wild Type ◽  
Histone Proteins ◽  
Protein Levels ◽  
In The Wild ◽  
Type Strains ◽  
Orientation Bias

Abstract In Saccharomyces cerevisiae, the target site specificity of the retrotransposon Ty1 appears to involve the Ty integration complex recognizing chromatin structures. To determine whether changes in chromatin structure affect Ty1 and Ty2 target site preference, we analyzed Ty transposition at the CAN1 locus in mutants containing altered levels of histone proteins. A Δhta1-htb1 mutant with decreased levels of H2A and H2B histone proteins showed a pattern of Ty1 and Ty2 insertions at CAN1 that was significantly different from that of both the wild-type and a Δhta2-htb2 mutant, which does not have altered histone protein levels. Altered levels of H2A and H2B proteins disrupted a dramatic orientation bias in the CAN1 promoter region. In the wild-type strains, few Ty1 and Ty2 insertions in the promoter region were oriented opposite to the direction of CAN1 transcription. In the Δhta1-htb1 background, however, numerous Ty1 and Ty2 insertions were in the opposite orientation clustered within the TATA region. This altered insertion pattern does not appear to be due to a bias caused by selecting canavanine resistant isolates in the different HTA1-HTB1 backgrounds. Our results suggest that reduced levels of histone proteins alter Ty target site preference and disrupt an asymmetric Ty insertion pattern.

Comorbidity among alcohol and tobacco dependent patients

2011 ◽  
Vol 26 (S2) ◽  
pp. 132-132
Author(s):  
A. Zoghlami ◽  
D. Blauensteiner ◽  
O. Scheibenbogen ◽  
S. Zadro-Jäger ◽  
M. Musalek
Keyword(s):  
Alcohol Dependence ◽  
Inpatient Treatment ◽  
Preliminary Analysis ◽  
Psychiatric Comorbidity ◽  
Icd 10 ◽  
Withdrawal Therapy ◽  
Clinically Significant ◽  
Drug Use Disorder ◽  
Group Allocation ◽  
Alcohol Dependent

IntroductionPsychiatric concomitant diseases are common with alcohol and tobacco dependent patients. Few studies have compared comorbidities between alcohol dependent smokers and non-smokers.AimsThe aim of this study is to examine the pattern of psychiatric comorbidity among alcohol dependent smokers in an inpatient alcohol therapy unit.Material and methodAfter successfully completing withdrawal therapy, subjects between the ages of 18–65 years who meet the ICD 10 criteria for alcohol dependence and no criteria for other drug use disorder except smoking, and who were participating in an inpatient treatment program for alcohol dependence at Anton Proksch Institut were included.ResultsThis is a preliminary analysis of the survey. In total 81 patients could be examined. 53.1% of the interviewed subjects were female and 46.9% male. The explored samples age ranged from 21–66 years.74.1% of the questioned subjects were smokers, 60% of these patients smoked more than 20 cigarettes per day.Preliminary analysis shows that smoking alcohol dependent patients present a higher comorbidity rate than non-smokers but above all they show a tendency to increased anxiety disorders. Within the population of smokers 48.3% suffer from an anxiety disorder, 48.3% from depression and dysthymia, 12.1% from manic and hypomanic disorder and 5.2% from psychosis. These differences are not clinically significant. This can be explained by the small number of the sample and by the group allocation.ConclusionAlcohol addicted patients exhibit heightened psychiatric comorbidity. Smoking alcohol dependents are more frequently affected and have a disposition to psychiatric disorders.

scholarly journals Resveratrol Stimulates Cortisol Biosynthesis by Activating SIRT-Dependent Deacetylation of P450scc

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3258-3268 ◽  
Author(s):  
Donghui Li ◽  
Eric B. Dammer ◽  
Marion B. Sewer
Keyword(s):  
Protein Expression ◽  
Fold Increase ◽  
Pyridine Nucleotide ◽  
Nucleotide Metabolism ◽  
Side Chain ◽  
Mitochondrial Enzyme ◽  
Adrenocortical Cells ◽  
Protein Levels ◽  
Chain Cleavage ◽  
Cleavage Enzyme

In the human adrenal cortex, cortisol is synthesized from cholesterol by members of the cytochrome P450 superfamily and hydroxysteroid dehydrogenases. Both the first and last steps of cortisol biosynthesis occur in mitochondria. Based on our previous findings that activation of ACTH signaling changes the ratio of nicotinamide adenine dinucleotide (NAD) phosphate to reduced NAD phosphate in adrenocortical cells, we hypothesized that pyridine nucleotide metabolism may regulate the activity of the mitochondrial NAD+-dependent sirtuin (SIRT) deacetylases. We show that resveratrol increases the protein expression and half-life of P450 side chain cleavage enzyme (P450scc). The effects of resveratrol on P450scc protein levels and acetylation status are dependent on SIRT3 and SIRT5 expression. Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis. Finally, resveratrol also increases the protein expression of P450 11β, another mitochondrial enzyme required for cortisol biosynthesis. Collectively, this study identifies a role for NAD+-dependent SIRT deacetylase activity in regulating the expression of mitochondrial steroidogenic P450.

scholarly journals The efficacy of iCBT added to treatment as usual for alcohol dependent patients in Primary Care: study protocol for a randomized controlled trial.

2019 ◽  
Author(s):  
Karin Hyland ◽  
Anders Hammarberg ◽  
Erik Hedman-Lagerlöf ◽  
Magnus Johansson ◽  
Sven Andreasson
Keyword(s):  
Primary Care ◽  
Randomized Controlled Trial ◽  
Alcohol Dependence ◽  
Controlled Trial ◽  
Alcohol Problems ◽  
Primary Study ◽  
Mixed Effect ◽  
Treatment As Usual ◽  
Randomized Controlled ◽  
Alcohol Dependent

Abstract Introduction Alcohol dependence is a common disorder with a continuum regarding severity. Most alcohol dependent persons have a moderate level of dependence and live under socially orderly conditions. Treatment seeking in this group is low, mainly due to stigma and because treatment options are seen as unappealing. Alcohol is a relevant topic to discuss in many primary care (PC) consultations and PC is less stigmatizing to visit compared to addiction care units for people with alcohol problems. General practitioners (GP) hesitate to engage in treating alcohol problems due to time constraints and lack of knowledge. Screening and brief interventions are effective for high consumers but there are few studies on dependence. Methods This is a two-group, parallel, randomized controlled trial (RCT). The aim is to study whether an Internet based Cognitive Behavioral Treatment (iCBT) when added to treatment as usual (TAU) is more effective than TAU only for alcohol dependence in PC. 260 adults with alcohol dependence will be included. Participants are randomized to iCBT and TAU or TAU only. The primary study outcome is alcohol consumption in grams per week and heavy drinking days. Secondary outcomes include alcohol related problem severity, number of diagnostic criteria for alcohol dependence, depression and anxiety symptoms, health related quality of life and biochemical markers for high consumption and liver pathology. Data will be analyzed using mixed-effect models. Discussion Internet based interventions are attractive to and have been shown to reach people with alcohol problems. Yet there are no studies investigating the efficacy of internet treatment of alcohol dependence in PC. In this study we hypothesize that iCBT when added to TAU will improve treatment outcome for alcohol dependence in PC, compared to TAU only. If effective, iCBT can be distributed to the public to a low cost for a stakeholder and has the opportunity to reduce both short term and long-term public health costs. Trial registration: ISRCTN69957414. Retrospectively registered 07/06/2018. http://www.isrctn.com/ISRCTN69957414

scholarly journals Cortical Glutamate and GABA Changes During Early Abstinence in Alcohol Dependence and Their Associations With Benzodiazepine Medication

2021 ◽  
Vol 12 ◽  
Author(s):  
Guoying Wang ◽  
Wolfgang Weber-Fahr ◽  
Ulrich Frischknecht ◽  
Derik Hermann ◽  
Falk Kiefer ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Alcohol Withdrawal ◽  
Withdrawal Symptoms ◽  
Internal Quality ◽  
Treatment Seeking ◽  
Withdrawal Period ◽  
Cross Sectional ◽  
Longitudinal Changes ◽  
Single Voxel ◽  
Alcohol Dependent

In this report, we present cross-sectional and longitudinal findings from single-voxel MEGA-PRESS MRS of GABA as well as Glu, and Glu + glutamine (Glx) concentrations in the ACC of treatment-seeking alcohol-dependent patients (ADPs) during detoxification (first 2 weeks of abstinence). The focus of this study was to examine whether the amount of benzodiazepine administered to treat withdrawal symptoms was associated with longitudinal changes in Glu, Glx, and GABA. The tNAA levels served as an internal quality reference; in agreement with the vast majority of previous reports, these levels were initially decreased and normalized during the course of abstinence in ADPs. Our results on Glu and Glx support hyperglutamatergic functioning during alcohol withdrawal, by showing higher ACC Glu and Glx levels on the first day of detoxification in ADPs. Withdrawal severity is reflected in cumulative benzodiazepine requirements throughout the withdrawal period. The importance of withdrawal severity for the study of GABA and Glu changes in early abstinence is emphasized by the benzodiazepine-dependent Glu, Glx, and GABA changes observed during the course of abstinence.

scholarly journals Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics

2021 ◽  
Vol 22 (23) ◽  
pp. 12791
Author(s):  
Alexia Grangeon ◽  
Valérie Clermont ◽  
Azemi Barama ◽  
Fleur Gaudette ◽  
Jacques Turgeon ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Small Intestine ◽  
Protein Expression ◽  
Mrna Levels ◽  
Targeted Proteomics ◽  
Tissue Samples ◽  
Human Organ ◽  
Expression Levels ◽  
Protein Levels ◽  
Human Small Intestine

The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 (p = 0.004) and CYP2C19 (p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 (p = 0.001) increased, and a trend was observed for CYP3A5 (p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum (p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum (p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.

scholarly journals A Prospective Comparison of Bipolar I and II Subjects With and Without Comorbid Alcohol Dependence From the COGA Dataset

2020 ◽  
Vol 11 ◽  
Author(s):  
Ulrich W. Preuss ◽  
M. N. Hesselbrock ◽  
V. M. Hesselbrock
Keyword(s):  
Bipolar Disorder ◽  
Alcohol Use ◽  
Alcohol Dependence ◽  
Collaborative Study ◽  
Structured Interviews ◽  
Prospective Comparison ◽  
Bipolar Ii ◽  
Bipolar Patients ◽  
Alcohol Dependent

Objective: Comorbidity of alcohol use disorders in bipolar subjects is high as indicated by epidemiological and clinical studies. Though a more severe course of bipolar disorder in subjects with comorbid alcohol dependence has been reported, fewer studies considered the longitudinal course of alcohol dependence in bipolar subjects and the prospective course of comorbid bipolar II subjects. Beside baseline analysis, longitudinal data of the COGA (Collaborative Study on Genetics in Alcoholism) were used to evaluate the course of bipolar I and II disordered subjects with and without comorbid alcohol dependence over more than 5 years of follow-up.Methods: Characteristics of bipolar disorder, alcohol dependence and comorbid psychiatric disorders were assessed using semi-structured interviews (SSAGA) at baseline and at a 5-year follow-up. Two hundred twenty-eight bipolar I and II patients were subdivided into groups with and without comorbid alcohol dependence.Results: Of the 152 bipolar I and 76 bipolar II patients, 172 (75, 4%) had a comorbid diagnosis of alcohol dependence. Bipolar I patients with alcohol dependence, in particular women, had a more severe course of bipolar disorder, worse social functioning and more suicidal behavior than all other groups of subjects during the 5-year follow-up. In contrast, alcohol dependence improved significantly in both comorbid bipolar I and II individuals during this time.Conclusions: A 5-year prospective evaluation of bipolar patients with and without alcohol dependence confirmed previous investigations suggesting a more severe course of bipolar disorder in comorbid bipolar I individuals, whereas bipolar II individuals were less severely impaired by comorbid alcohol use disorder. While severity of alcohol dependence improved during this time in comorbid alcohol-dependent bipolar I patients, the unfavorable outcome for these individuals might be due to the higher comorbidity with personality and other substance use disorders which, together with alcohol dependence, eventually lead to poorer symptomatic and functional clinical outcomes.

scholarly journals EGFR DNA Methylation Correlates With EGFR Expression, Immune Cell Infiltration, and Overall Survival in Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhanyu Xu ◽  
Fanglu Qin ◽  
Liqiang Yuan ◽  
Jiangbo Wei ◽  
Yu Sun ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Methylation Level ◽  
Promoter Region ◽  
Body Region ◽  
Gene Body ◽  
Immune Infiltration ◽  
Cpg Sites ◽  
Gene Body Region

BackgroundThe epidermal growth factor receptor (EGFR) is a primary target of molecular targeted therapy for lung adenocarcinoma (LUAD). The mechanisms that lead to epigenetic abnormalities of EGFR in LUAD are still unclear. The purpose of our study was to evaluate the abnormal methylation of EGFR CpG sites as potential biomarkers for LUAD.MethodsTo assess the differentially methylation CpG sites of EGFR in LUAD, we used an integrative study of Illumina HumanMethylation450K and RNA-seq data from The Cancer Genome Atlas (TCGA). We evaluated and compared EGFR multiple-omics data to explore the role of CpG sites located in EGFR promoter regions and gene body regions and the association with transcripts, protein expression levels, mutations, and somatic copy number variation. We calculated the correlation coefficients between CpG sites of EGFR and immune infiltration fraction (by MCPcounter and ESTIMATE) and immune-related pathways in LUAD. Finally, we validated the differential methylation of clinically and prognostically relevant CpG sites using quantitative methylation-specific PCR (qMSP).ResultsWe found that the methylation level of many EGFR CpGs in the promoter region was negatively correlated with the transcription level, protein expression, and SCNV, while the methylation at the gene body region was positively correlated with these features. The methylation level of EGFR CpGs in the promoter region was positively correlated with the level of immune infiltration and IFN-γ signature, while the opposite was found for methylation of the gene body region. The qMSP results showed that cg02316066 had a high methylation level, while cg02166842 had a low methylation level in LUAD. There was a high degree of co-methylation between cg02316066 and cg03046247.ConclusionOur data indicate that EGFR is an epigenetic regulator in LUAD acting through DNA methylation. Our research provides a theoretical basis for the further detection of EGFR DNA methylation as a predictive biomarker for LUAD survival and immunotherapy.

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