Aldehyde-Induced DNA and Protein Adducts as Biomarker Tools for Alcohol Use Disorder

Heymann, Helen; Gardner, Adriana M.; Gross, Eric R.

doi:10.1016/j.molmed.2017.12.003

Cited by 48 publications

(41 citation statements)

References 86 publications

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“…The enhanced activation of macrophages following CHD can be hypothesised to occur via two different mechanisms. First, the oxidative stress induced by ethanol or its metabolites (acetyl-CoA) and acetaldehyde adducts can exert a significant impact on cellular transcriptional profiles [60,61]. Specifically, these molecules can serve as cofactors and substrates within signalling pathways that result in epigenetic changes via histone modifications [62], potentially altering chromatin accessibility and regulating gene expression.…”

Section: Discussionmentioning

confidence: 99%

Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

et al. 2019

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Background Chronic heavy alcohol drinking (CHD) leads to significant organ damage, increased susceptibility to infections, and delayed wound healing. These adverse outcomes are believed to be mediated by alterations in the function of myeloid cells; however, the mechanisms underlying these changes are poorly understood. Methods We determined the impact of CHD on the phenotype of splenic macrophages using flow cytometry. Changes in functional responses to LPS were measured using luminex and RNA-Seq. Finally, alterations in chromatin accessibility were uncovered using ATAC-Seq. Findings A history of CHD led to increased frequency of splenic macrophages that exhibited a heightened activation state at resting. Additionally, splenic macrophages from CHD animals generated a larger inflammatory response to LPS, both at protein and gene expression levels. Finally, CHD resulted in increased levels of H3K4me3, a histone mark of active promoters, as well as chromatin accessibility at promoters and intergenic regions that regulate inflammatory responses. Interpretation These findings suggest that a history of CHD alters the immune fitness of tissue-resident macrophages via epigenetic mechanisms. Fund National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH) - R24AA019431, U01 AA13641, U01 AA13510, R21AA021947, and R21AA025839.

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Section: Discussionmentioning

confidence: 99%

Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

et al. 2019

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“…No gold standard is yet available, and commonly applied biochemical markers are far from ideal with respect to their discriminatory power, as indicated by AUC values ranging from 0.21 to 0.67 [29]. While new approaches, including protein markers [29], DNA methylation patterns [57], aldehyde-induced DNA, and protein adducts [58], and even neuroimaging [59,60] enhance the detection of heavy drinkers, there is still room for improvement, for example, by utilizing novel biomarkers or by developing of a composite score for excessive alcohol use screening [61]. In our study population, S-ASM activity alone did not perform better than any of the analyzed markers (Table 2, AUC = 0.77 compared to AUC ≥ 0.80 for conventional biomarkers in our cohort), and it also did not appear to be beneficial when this information was added to a combined model.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Acid Sphingomyelinase Activity Is Associated with Biomarkers and Phenotypes of Alcohol Use and Dependence in Patients and Healthy Controls

Mühle

Weinland

Gulbins

et al. 2018

IJMS

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By catalyzing the hydrolysis of sphingomyelin into ceramide, acid sphingomyelinase (ASM) changes the local composition of the plasma membrane with effects on receptor-mediated signaling. Altered enzyme activities have been noted in common human diseases, including alcohol dependence. However, the underlying mechanisms remain largely unresolved. Blood samples were collected from early-abstinent alcohol-dependent in-patients (n[♂] = 113, n[♀] = 87) and matched healthy controls (n[♂] = 133, n[♀] = 107), and analyzed for routine blood parameters and serum ASM activity. We confirmed increased secretory ASM activities in alcohol-dependent patients compared to healthy control subjects, which decreased slightly during detoxification. ASM activity correlated positively with blood alcohol concentration, withdrawal severity, biomarkers of alcohol dependence (liver enzyme activities of gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase; homocysteine, carbohydrate-deficient transferrin; mean corpuscular volume, and creatine kinase). ASM activity correlated negatively with leukocyte and thrombocyte counts. ASM and gamma-glutamyl transferase were also associated in healthy subjects. Most effects were similar for males and females with different strengths. We describe previously unreported associations between ASM activity and markers of liver damage and myelosuppression. Further research should investigate whether this relationship is causal, or whether these parameters are part of a common pathway in order to gain insights into underlying mechanisms and develop clinical applications.

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“…However, treatment with an antioxidant can halt AA-AGE adduct formation, supporting the idea that AA-AGE adducts can be generated from a Schiff base product similar to AA adducts and AGEs. [189][190][191][192][193][194][195][196][197][198] AA-DNA adducts ↓ DNA integrity and neuronal viability ↓ represses DNA repair enzymes/system ↑ genetic instability and DNA mutations ↑ correlated with AUD 53,192,197,198 AA [214][215][216][217][218][219][220][221][222][223][224][225][226][227][228][229][230] ↑ CYP2E1, oxidative stress, AFLD, and advanced ALD [203][204][205][206][207][208][209][210][211][212][213] AA-AGE adducts ↑ RAGE expression ↑ ROS and oxidative stress ↑ hepatic fatty degeneration and steatosis ↑ hepatocyte ballooning, apoptosis, and steatosis ↑ ALD and AFLD 215,231 Lung soluble RAGE (+HMGB1) ↑ lung inflammation…”

Section: Age-alcohol-adduct Formations (Fig 1)mentioning

confidence: 99%

“…AA-protein adducts are widely present in the brains of alcohol-exposed rodents or people with alcohol use disorder (AUD) [189][190][191][192] . After alcohol consumption, AAprotein adducts are rapidly produced in the cerebral cortex primarily with mitochondrial proteins and localized in the white matter, deep layers of the frontal cortex, and molecular layer of the cerebellum 188,189,191 .…”

Section: Age-alcohol-adduct Formations (Fig 1)mentioning

confidence: 99%

Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury

et al. 2021

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Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer. Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE–alcohol–adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.

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Aldehyde-Induced DNA and Protein Adducts as Biomarker Tools for Alcohol Use Disorder

Cited by 48 publications

References 86 publications

Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

Peripheral Acid Sphingomyelinase Activity Is Associated with Biomarkers and Phenotypes of Alcohol Use and Dependence in Patients and Healthy Controls

Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury

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