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  1. Article: Chronic alcohol consumption and COVID-19 infection risk: A narrative review.

    Friske, Marion M / Spanagel, Rainer

    Alcohol (Hanover, York County, Pa.)

    2023  Volume 47, Issue 4, Page(s) 629–639

    Abstract: During the COVID-19 pandemic, many potential risk groups have been identified, such as those with obesity, diabetes, preexisting organ injuries, and several other conditions. Smoking is the most reported substance use disorder linked to increased COVID- ... ...

    Abstract During the COVID-19 pandemic, many potential risk groups have been identified, such as those with obesity, diabetes, preexisting organ injuries, and several other conditions. Smoking is the most reported substance use disorder linked to increased COVID-19 hospitalization rate and disease severity. In relation to smoking, we discuss the impairment of the innate and the adaptive immune systems as being among the main potential reasons for increased COVID-19 infection risk and severity. Chronic alcohol consumption and alcohol use disorder (AUD) also have a negative impact on the immune system, but when it comes to COVID-19 risk, they produce diverse outcomes. Some studies provide evidence that chronic alcohol consumption and AUD increase the risk of COVID-19 infection and severe disease progression, while others report reduced hospitalization and death rates. In this review, we summarize the current state of epidemiological and molecular data concerning alcohol consumption and AUD as risk factors for COVID-19 infection, hospitalization, and mortality.
    MeSH term(s) Humans ; COVID-19/epidemiology ; Alcoholism/epidemiology ; Pandemics ; Alcohol Drinking/adverse effects ; Alcohol Drinking/epidemiology ; Risk Factors
    Language English
    Publishing date 2023-02-27
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    DOI 10.1111/acer.15041
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Chronic alcohol intake regulates expression of SARS-CoV2 infection-relevant genes in an organ-specific manner.

    Friske, Marion M / Giannone, Francesco / Senger, Mona / Seitz, Robin / Hansson, Anita C / Spanagel, Rainer

    Alcohol (Hanover, York County, Pa.)

    2023  Volume 47, Issue 1, Page(s) 76–86

    Abstract: Background: Chronic alcohol consumption and alcohol use disorder have a tremendous impact on the patient's psychological and physiological health. There is evidence that chronic alcohol consumption influences SARS-CoV2 infection risk, but so far, the ... ...

    Abstract Background: Chronic alcohol consumption and alcohol use disorder have a tremendous impact on the patient's psychological and physiological health. There is evidence that chronic alcohol consumption influences SARS-CoV2 infection risk, but so far, the molecular mechanism underlying such an effect is unknown.
    Methods: We generated the expression data of SARS-CoV2 infection-relevant genes (Ace2, Tmprss2, and Mas) in different organs in rat models of chronic alcohol exposure and alcohol dependence. Ace2 and Tmprss2 represent the virus entry point, whereas Mas activates the anti-inflammatory response once the cells are infected.
    Results: Across three different chronic alcohol test conditions, we found a consistent upregulation of Ace2 gene expression in the lung, which has been shown to be the most affected organ in COVID-19 patients. Other organs such as liver, ileum, kidney, heart, and brain also showed upregulation of Ace2 and Mas gene expression but less consistently across the different animal models, while Tmprss2 expression was unaffected in all conditions.
    Conclusions: We conclude that alcohol-induced upregulation of Ace2 gene expression can lead to an elevated stochastic probability of virus entry into cells and may thus confer a molecular risk for SARS-CoV2 infection.
    MeSH term(s) Rats ; Animals ; COVID-19 ; Angiotensin-Converting Enzyme 2 ; RNA, Viral ; SARS-CoV-2 ; Alcohol Drinking
    Chemical Substances Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; RNA, Viral
    Language English
    Publishing date 2023-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    DOI 10.1111/acer.14981
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  3. Article ; Online: Chronic alcohol intake regulates expression of SARS-CoV2 infection-relevant genes in an organ-specific manner

    Friske, Marion M / Giannone, Francesco / Senger, Mona / Seitz, Robin / Hansson, Anita C / Spanagel, Rainer

    bioRxiv

    Abstract: Chronic alcohol consumption and alcohol use disorder (AUD) have a tremendous impact on the patients psychological and physiological health. There is some evidence that chronic alcohol consumption influences SARS-CoV2 infection risk, but the molecular ... ...

    Abstract Chronic alcohol consumption and alcohol use disorder (AUD) have a tremendous impact on the patients psychological and physiological health. There is some evidence that chronic alcohol consumption influences SARS-CoV2 infection risk, but the molecular mechanism is unknown. Here, we generated expression data of SARS-CoV2 infection relevant genes (Ace2, Tmprss2 and Mas) in different organs in rat models of chronic alcohol exposure and alcohol dependence. ACE2 and TMPRSS2 represent the virus entry point whereas Mas is activating the anti-inflammatory response once the cells are infected. Across three different chronic alcohol test conditions, we found a consistent up-regulation of Ace2 in the lung, which is the most affected organ in Covid-19 patients. Other organs such as liver, ileum, kidney, heart, and the brain showed also up-regulation of Ace2 and Mas but in a less consistent manner across the different animal models, while Tmprss2 was unaffected in all conditions. We suggest that alcohol-induced upregulation of Ace2 can lead to an elevated stochastic probability of cellular virus entry and may thus confer a molecular risk factor for a SARS-CoV2 infection.
    Keywords covid19
    Language English
    Publishing date 2022-02-02
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.02.01.478685
    Database COVID19

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  4. Article: DNA methylation in cocaine use disorder-An epigenome-wide approach in the human prefrontal cortex.

    Poisel, Eric / Zillich, Lea / Streit, Fabian / Frank, Josef / Friske, Marion M / Foo, Jerome C / Mechawar, Naguib / Turecki, Gustavo / Hansson, Anita C / Nöthen, Markus M / Rietschel, Marcella / Spanagel, Rainer / Witt, Stephanie H

    Frontiers in psychiatry

    2023  Volume 14, Page(s) 1075250

    Abstract: Background: Cocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized ...

    Abstract Background: Cocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue.
    Methods: We investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of Brodmann area 9 (BA9). A total of
    Results: While no cytosine-phosphate-guanine (CpG) site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified
    Conclusion: Results from our study highlight that CUD is associated with epigenome-wide differences in DNAm levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex (PFC). Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.
    Language English
    Publishing date 2023-02-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564218-2
    ISSN 1664-0640
    ISSN 1664-0640
    DOI 10.3389/fpsyt.2023.1075250
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  5. Article: Epigenetic Signatures of Smoking in Five Brain Regions.

    Zillich, Lea / Poisel, Eric / Streit, Fabian / Frank, Josef / Fries, Gabriel R / Foo, Jerome C / Friske, Marion M / Sirignano, Lea / Hansson, Anita C / Nöthen, Markus M / Witt, Stephanie H / Walss-Bass, Consuelo / Spanagel, Rainer / Rietschel, Marcella

    Journal of personalized medicine

    2022  Volume 12, Issue 4

    Abstract: 1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which ... ...

    Abstract (1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (
    Language English
    Publishing date 2022-04-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662248-8
    ISSN 2075-4426
    ISSN 2075-4426
    DOI 10.3390/jpm12040566
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  6. Article ; Online: Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum.

    Zillich, Lea / Poisel, Eric / Frank, Josef / Foo, Jerome C / Friske, Marion M / Streit, Fabian / Sirignano, Lea / Heilmann-Heimbach, Stefanie / Heimbach, André / Hoffmann, Per / Degenhardt, Franziska / Hansson, Anita C / Bakalkin, Georgy / Nöthen, Markus M / Rietschel, Marcella / Spanagel, Rainer / Witt, Stephanie H

    Translational psychiatry

    2022  Volume 12, Issue 1, Page(s) 190

    Abstract: Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed ( ...

    Abstract Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR < 0.05), but not the ventral striatum of AUD cases. In the VS, DE genes at FDR < 0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD.
    MeSH term(s) Alcohol Drinking/genetics ; Alcoholism/genetics ; DNA ; Humans ; Inflammation ; Ventral Striatum
    Chemical Substances DNA (9007-49-2)
    Language English
    Publishing date 2022-05-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2609311-X
    ISSN 2158-3188 ; 2158-3188
    ISSN (online) 2158-3188
    ISSN 2158-3188
    DOI 10.1038/s41398-022-01959-1
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  7. Article ; Online: Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.

    Zillich, Lea / Cetin, Metin / Hummel, Elisabeth M / Poisel, Eric / Fries, Gabriel R / Frank, Josef / Streit, Fabian / Foo, Jerome C / Sirignano, Lea / Friske, Marion M / Lenz, Bernd / Hoffmann, Sabine / Adorjan, Kristina / Kiefer, Falk / Bakalkin, Georgy / Hansson, Anita C / Lohoff, Falk W / Kärkkäinen, Olli / Kok, Eloise /
    Karhunen, Pekka J / Sutherland, Greg T / Walss-Bass, Consuelo / Spanagel, Rainer / Rietschel, Marcella / Moser, Dirk A / Witt, Stephanie H

    Alcohol, clinical & experimental research

    2024  Volume 48, Issue 2, Page(s) 250–259

    Abstract: Background: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD ... ...

    Abstract Background: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken.
    Methods: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates.
    Results: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain.
    Conclusions: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.
    Language English
    Publishing date 2024-01-26
    Publishing country United States
    Document type Journal Article
    ISSN 2993-7175
    ISSN (online) 2993-7175
    DOI 10.1111/acer.15241
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  8. Article ; Online: Epigenome-wide association study of alcohol use disorder in five brain regions.

    Zillich, Lea / Frank, Josef / Streit, Fabian / Friske, Marion M / Foo, Jerome C / Sirignano, Lea / Heilmann-Heimbach, Stefanie / Dukal, Helene / Degenhardt, Franziska / Hoffmann, Per / Hansson, Anita C / Nöthen, Markus M / Rietschel, Marcella / Spanagel, Rainer / Witt, Stephanie H

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2021  Volume 47, Issue 4, Page(s) 832–839

    Abstract: Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by ... ...

    Abstract Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < 0.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < 0.05) were found in the CN (n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.
    MeSH term(s) Alcohol Drinking ; Alcoholism/genetics ; Brain ; DNA Methylation ; Epigenesis, Genetic ; Epigenome ; Genome-Wide Association Study ; Humans
    Language English
    Publishing date 2021-11-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/s41386-021-01228-7
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