Alcohol-Associated Tissue Injury: Current Views on Pathophysiological Mechanisms

Annual Review of Physiology, Journal Year: 2022, Volume and Issue: 84(1), P. 87 - 112

Published: Feb. 10, 2022

At-risk alcohol use is a major contributor to the global health care burden and leads preventable deaths diseases including addiction, alcoholic liver disease, cardiovascular diabetes, traumatic injuries, gastrointestinal diseases, cancers, fetal syndrome. Excessive frequent consumption has increasingly been linked alcohol-associated tissue injury pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal vitro models elucidated salient mechanisms involved alcohol-induced injury. In some cases, these pathophysiological are shared across The alcohol- metabolite–mediated include oxidative stress, inflammation immunometabolic dysregulation, gut leak dysbiosis, cell death, extracellular matrix remodeling, endoplasmic reticulum mitochondrial dysfunction, epigenomic modifications. These complex interrelated, determining interplay among them will make it possible identify how they synergistically or additively interact cause alcohol-mediated multiorgan this article, we review current understanding of

Language: Английский

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Linking environmental risk factors with epigenetic mechanisms in Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Aug. 25, 2023

Abstract Sporadic Parkinson’s disease (PD) is a progressive neurodegenerative disease, with complex risk structure thought to be influenced by interactions between genetic variants and environmental exposures, although the full aetiology unknown. Environmental factors, including pesticides, have been reported increase of developing disease. Growing evidence suggests epigenetic changes are key mechanisms which these factors act upon gene regulation, in disease-relevant cell types. We present systematic review critically appraising summarising current body relationship PD inform future research this area. Epigenetic studies relevant animal models yielded promising results, however, humans just emerging. While published currently relatively limited, importance field for elucidation molecular pathogenesis opens clear avenues research. Carefully designed epidemiological carried out patients hold great potential uncover regulatory mechanisms. Therefore, advance burgeoning field, we recommend broadening scope investigations include more increasing sample sizes, focusing on types, recruiting diverse cohorts.

Language: Английский

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Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

Addiction Biology, Journal Year: 2021, Volume and Issue: 26(6)

Published: Feb. 3, 2021

Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there heritable component, the etiology of AUD complex can involve environmental exposures like trauma be associated with many different patterns alcohol consumption. Epigenetic modifications, which mediate influence genetic variants variables on gene expression, have emerged as an important area research. Over past decade, number studies investigating DNA methylation, form epigenetic modification, has grown rapidly. Yet we are still far from understanding how methylation contributes or reflects aspects AUD. In this paper, reviewed discussed field evolved. We found that global candidate did not produce replicable results. To assess whether findings epigenome-wide association (EWAS) were replicated, aggregated significant across identified 184 genes 15 ontological pathways differentially methylated in at least two four three studies. These repeatedly enrichment immune processes, line recent developments suggesting system may altered Finally, current limitations make recommendations design future resolve outstanding questions.

Language: Английский

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the central nervous system

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105155 - 105155

Published: April 3, 2023

Language: Английский

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Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(3), P. 1754 - 1764

Published: Dec. 2, 2021

Abstract Alcohol misuse is common in many societies worldwide and associated with extensive morbidity mortality, often leading to alcohol use disorders (AUD) alcohol-related end-organ damage. The underlying mechanisms contributing the development of AUD are largely unknown; however, growing evidence suggests that consumption strongly alterations DNA methylation. Identification alcohol-associated methylomic variation might provide novel insights into pathophysiology treatment targets for AUD. Here we performed largest single-cohort epigenome-wide association study (EWAS) date ( N = 8161) cross-validated findings populations relevant endophenotypes, as well animal models. Results showed 2504 CpGs significantly (Bonferroni p value < 6.8 × 10 −8 ) five probes located SLC7A11 7.75 −108 , JDP2 1.44 −56 GAS5 2.71 −47 TRA2B 3.54 −42 ), SLC43A1 1.18 −40 ). Genes annotated CpG sites implicated liver brain function, cellular response diseases, including hypertension Alzheimer’s disease. Two-sample Mendelian randomization confirmed causal relationship on risk (inverse variance weighted (IVW) 5.37 −09 A methylation-based predictor was able discriminate cases two independent cohorts 6.32 −38 5.41 −14 top EWAS probe cg06690548, cystine/glutamate transporter SLC7A11, replicated an cohort control participants 615) strong hypomethylation −17 Decreased methylation at this consistently clinical measures increased heavy drinking days −4 function enzymes (GGT 1.03 −21 ALT 1.29 −6 AST 1.97 )) individuals Postmortem analyses documented expression frontal cortex models marked liver, suggesting a mechanism by which leads hypomethylation-induced overexpression SLC7A11. Taken together, our discovery sample subsequent validation suggest role abnormal glutamate signaling mediated Our data intriguing given prominent important target therapeutic intervention.

Language: Английский

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Epigenome-wide association study of alcohol use disorder in five brain regions

Neuropsychopharmacology, Journal Year: 2021, Volume and Issue: 47(4), P. 832 - 839

Published: Nov. 13, 2021

Alcohol use disorder (AUD) is closely linked to the brain regions forming neurocircuitry of addiction. Postmortem human tissue enables direct study molecular pathomechanisms AUD. This aims identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls 58) using a brain-region-specific approach, in which sample sizes ranged 46 94. Samples anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), putamen (PUT) were investigated. levels determined Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses carried out differentially methylated CpG-sites each region. Weighted correlation network analysis (WGCNA), gene-set, GWAS-enrichment performed. Two associated CN, 18 VS (q < 0.05). No epigenome-wide significant found BA9, ACC, or PUT. Differentially case-/control status 0.05) CN 6), 18), ACC 1). In VS, WGCNA-module showing strongest was enriched for immune-related pathways. first analyze methylation differences multiple consists largest date. Several novel implicated identified, providing basis explore epigenetic correlates

Language: Английский

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Additive Effects of Stress and Alcohol Exposure on Accelerated Epigenetic Aging in Alcohol Use Disorder

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 93(4), P. 331 - 341

Published: July 16, 2022

BackgroundStress contributes to premature aging and susceptibility alcohol use disorder (AUD), AUD itself is a factor in aging; however, the interrelationships of stress, AUD, are poorly understood.MethodsWe constructed composite score stress from 13 stress-related outcomes discovery cohort 317 individuals with control subjects. We then developed novel methylation (MS stress) as proxy comprising 211 CpGs selected using penalized regression model. The effects MS on health epigenetic were assessed sample 615 patients subjects clocks DNA methylation–based telomere length. Statistical analysis an additive model for consumption alcohol) was conducted. Results replicated 2 independent cohorts (Generation Scotland, N = 7028 Grady Trauma Project, 795).ResultsComposite strongly associated heavy consumption, trauma experience, age acceleration (EAA), shortened length AUD. Together, additively showed strong stepwise increases EAA. Replication analyses robust association between EAA Generation Scotland Project cohorts.ConclusionsA methylation-derived tracking exposure various phenotypes Stress have aging, offering new insights into pathophysiology and, potentially, other aspects gene dysregulation this disorder.

Language: Английский

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Post-translational modifications of histone and non-histone proteins in epigenetic regulation and translational applications in alcohol-associated liver disease: Challenges and research opportunities

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 251, P. 108547 - 108547

Published: Oct. 13, 2023

Language: Английский

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Genetics of Substance Use Disorders

Oxford University Press eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 621 - 634

Published: Jan. 1, 2025

Abstract Substance use disorders (SUDs) are influenced by genes, environment, and gene × environment interactions, leading to different levels kinds of vulnerability. Some genes substance specific, including that mediate drug metabolism or receptor binding. Others nonspecific, influencing reward, stress resiliency, executive function, thus pleiotropic, cross-transmission comorbidity SUDs other disorders. Genome-wide association studies have revealed many SUD some in known pathways addiction. Most functional loci unknown, but polygenic scores accounting for an increasing fraction genetic liability. The identification rare uncommon variants with roles is expanding, being “private” certain populations, underscoring the need increase diversity studies. Together multiomic data transcriptome epigenome, genomic identifying new generating novel targets treatment prevention.

Language: Английский

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Allele-specific methylation of SSTR4 associated with aging and cognitive functions in patients with schizophrenia

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(2), P. e0303038 - e0303038

Published: Feb. 5, 2025

The co-occurrence of alcohol use disorder (AUD) and schizophrenia is prevalent, with a rate 33.7%. Previous research has suggested genetic epigenetic overlap between these two disorders. SSTR4 , member the somatostatin receptor family, implicated in various neurological psychiatric conditions, including cognitive function, AUD, schizophrenia. However, role genetic-epigenetic interactions involving patients remains unexplored. In this study, we conducted an integration publicly available datasets identified allele-specific methylation patterns SSTR4. Additionally, pinpointed several variants (rs17691954, rs11464356, rs3109190, rs145879288) that influence pace aging functions (rs705935) through their quantitative trait loci effects on CpG sites within .

Language: Английский

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