scholarly journals Transcriptomics identifies STAT3 as a key regulator of hippocampal gene expression and anhedonia during withdrawal from chronic alcohol exposure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wei-Yang Chen ◽  
Hu Chen ◽  
Kana Hamada ◽  
Eleonora Gatta ◽  
Ying Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alcohol Drinking ◽  
Alcohol Withdrawal ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Alcohol Exposure ◽  
Immune Gene ◽  
Chronic Alcohol ◽  
Chronic Alcohol Exposure

AbstractAlcohol use disorder (AUD) is highly comorbid with depression. Withdrawal from chronic alcohol drinking results in depression and understanding brain molecular mechanisms that drive withdrawal-related depression is important for finding new drug targets to treat these comorbid conditions. Here, we performed RNA sequencing of the rat hippocampus during withdrawal from chronic alcohol drinking to discover key signaling pathways involved in alcohol withdrawal-related depressive-like behavior. Data were analyzed by weighted gene co-expression network analysis to identify several modules of co-expressed genes that could have a common underlying regulatory mechanism. One of the hub, or highly interconnected, genes in module 1 that increased during alcohol withdrawal was the transcription factor, signal transducer and activator of transcription 3 (Stat3), a known regulator of immune gene expression. Total and phosphorylated (p)STAT3 protein levels were also increased in the hippocampus during withdrawal after chronic alcohol exposure. Further, pSTAT3 binding was enriched at the module 1 genes Gfap, Tnfrsf1a, and Socs3 during alcohol withdrawal. Notably, pSTAT3 and its target genes were elevated in the postmortem hippocampus of human subjects with AUD when compared with control subjects. To determine the behavioral relevance of STAT3 activation during alcohol withdrawal, we treated rats with the STAT3 inhibitor stattic and tested for sucrose preference as a measure of anhedonia. STAT3 inhibition alleviated alcohol withdrawal-induced anhedonia. These results demonstrate activation of STAT3 signaling in the hippocampus during alcohol withdrawal in rats and in human AUD subjects, and suggest that STAT3 could be a therapeutic target for reducing comorbid AUD and depression.

scholarly journals Integrative In Silico and In Vitro Transcriptomics Analysis Revealed Gene Expression Changes and Oncogenic Features of Normal Cholangiocytes after Chronic Alcohol Exposure

2019 ◽  
Vol 20 (23) ◽  
pp. 5987
Author(s):  
Suthipong Chujan ◽  
Tawit Suriyo ◽  
Jutamaad Satayavivad
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Molecular Mechanisms ◽  
Function Analysis ◽  
Alcohol Exposure ◽  
Gene Expression Omnibus ◽  
Regulation Of Transcription ◽  
Chronic Alcohol ◽  
Chronic Alcohol Exposure

Cholangiocarcinoma (CCA) is a malignant tumor originating from cholangiocyte. Prolonged alcohol consumption has been suggested as a possible risk factor for CCA, but there is no information about alcohol’s mechanisms in cholangiocyte. This study was designed to investigate global transcriptional alterations through RNA-sequencing by using chronic alcohol exposure (20 mM for 2 months) in normal human cholangiocyte MMNK-1 cells. To observe the association of alcohol induced CCA pathogenesis, we combined differentially expressed genes (DEGs) with computational bioinformatics of CCA by using publicly gene expression omnibus (GEO) datasets. For biological function analysis, Gene ontology (GO) analysis showed biological process and molecular function related to regulation of transcription from RNA polymerase II promoter, while cellular component linked to the nucleoplasm. KEGG pathway presented pathways in cancer that were significantly enriched. From KEGG result, we further examined the oncogenic features resulting in chronic alcohol exposure, enhanced proliferation, and migration through CCND-1 and MMP-2 up-regulation, respectively. Finally, combined DEGs were validated in clinical data including TCGA and immunohistochemistry from HPA database, demonstrating that FOS up-regulation was related to CCA pathogenesis. This study is the first providing more information and molecular mechanisms about global transcriptome alterations and oncogenic enhancement of chronic alcohol exposure in normal cholangiocytes.

scholarly journals Chronic alcohol exposure induced gene expression changes in the zebrafish brain

2011 ◽  
Vol 216 (1) ◽  
pp. 66-76 ◽  
Author(s):  
Yi Pan ◽  
Mo Kaiguo ◽  
Zak Razak ◽  
J. Timothy Westwood ◽  
Robert Gerlai
Keyword(s):  
Gene Expression ◽  
Alcohol Exposure ◽  
Chronic Alcohol ◽  
Zebrafish Brain ◽  
Chronic Alcohol Exposure

Chronic alcohol exposure alters transcription broadly in a key integrative brain nucleus for homeostasis: the nucleus tractus solitarius

2006 ◽  
Vol 24 (1) ◽  
pp. 45-58 ◽  
Author(s):  
Maria Yolanda Covarrubias ◽  
Rishi L. Khan ◽  
Rajanikanth Vadigepalli ◽  
Jan B. Hoek ◽  
James S. Schwaber
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Differentially Expressed Genes ◽  
Nucleus Tractus Solitarius ◽  
Expression Patterns ◽  
Alcohol Exposure ◽  
Differentially Expressed ◽  
Chronic Alcohol ◽  
Brain Nucleus ◽  
Chronic Alcohol Exposure

Chronic exposure to alcohol modifies physiological processes in the brain, and the severe symptoms resulting from sudden removal of alcohol from the diet indicate that these modifications are functionally important. We investigated the gene expression patterns in response to chronic alcohol exposure (21–28 wk) in the rat nucleus tractus solitarius (NTS), a brain nucleus with a key integrative role in homeostasis and cardiorespiratory function. Using methods and an experimental design optimized for detecting transcriptional changes less than twofold, we found 575 differentially expressed genes. We tested these genes for significant associations with physiological functions and signaling pathways using Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, respectively. Chronic alcohol exposure resulted in significant NTS gene regulation related to the general processes of synaptic transmission, intracellular signaling, and cation transport as well as specific neuronal functions including plasticity and seizure behavior that could be related to alcohol withdrawal symptoms. The differentially expressed genes were also significantly enriched for enzymes of lipid metabolism, glucose metabolism, oxidative phosphorylation, MAP kinase signaling, and calcium signaling pathways from KEGG. Intriguingly, many of the genes we found to be differentially expressed in the NTS are known to be involved in alcohol-induced oxidative stress and/or cell death. The study provides evidence of very extensive alterations of physiological gene expression in the NTS in the adapted state to chronic alcohol exposure.

scholarly journals Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

2021 ◽  
Vol 11 (9) ◽  
pp. 1149
Author(s):  
Brent R. Kisby ◽  
Sean P. Farris ◽  
Michelle M. McManus ◽  
Florence P. Varodayan ◽  
Marisa Roberto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Alcohol Dependence ◽  
Functional Groups ◽  
Molecular Mechanisms ◽  
Alcohol Exposure ◽  
Cell Types ◽  
Behavioral Changes ◽  
Molecular Pathways ◽  
Chronic Alcohol

Alcohol dependence is associated with adverse consequences of alcohol (ethanol) use and is evident in most severe cases of alcohol use disorder (AUD). The central nucleus of the amygdala (CeA) plays a critical role in the development of alcohol dependence and escalation of alcohol consumption in dependent subjects. Molecular mechanisms underlying the CeA-driven behavioral changes are not well understood. Here, we examined the effects of alcohol on global gene expression in the CeA using a chronic intermittent ethanol (CIE) vapor model in rats and RNA sequencing (RNA-Seq). The CIE procedure resulted in robust changes in CeA gene expression during intoxication, as the number of differentially expressed genes (DEGs) was significantly greater than those expected by chance. Over-representation analysis of cell types, functional groups and molecular pathways revealed biological categories potentially important for the development of alcohol dependence in our model. Genes specific for astrocytes, myelinating oligodendrocytes, and endothelial cells were over-represented in the DEG category, suggesting that these cell types were particularly affected by the CIE procedure. The majority of the over-represented functional groups and molecular pathways were directly related to the functions of glial and endothelial cells, including extracellular matrix (ECM) organization, myelination, and the regulation of innate immune response. A coordinated regulation of several ECM metalloproteinases (e.g., Mmp2; Mmp14), their substrates (e.g., multiple collagen genes and myelin basic protein; Mbp), and a metalloproteinase inhibitor, Reck, suggests a specific mechanism for ECM re-organization in response to chronic alcohol, which may modulate neuronal activity and result in behavioral changes, such as an escalation of alcohol drinking. Our results highlight the importance of glial and endothelial cells in the effects of chronic alcohol exposure on the CeA, and demonstrate further insight into the molecular mechanisms of alcohol dependence in rats. These molecular targets may be used in future studies to develop therapeutics to treat AUD.

scholarly journals Mechanisms of chronic alcohol exposure-induced aggressiveness in cellular model of HCC and recovery after alcohol withdrawal

2021 ◽  
Author(s):  
Constance Marié ◽  
Gregory Fouquet ◽  
Rabbind Singh Amrathlal ◽  
Nicolas Jankovsky ◽  
Hicham Bouhlal ◽  
...  
Keyword(s):  
Liver Disease ◽  
Cancer Progression ◽  
Alcohol Withdrawal ◽  
Alcohol Exposure ◽  
Epidemiological Studies ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Chronic Alcohol ◽  
Chronic Alcohol Exposure ◽  
Related Liver Disease

Abstract Alcohol-related liver disease is the most prevalent chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. However, the knowledge on mechanisms by which alcohol consumption leads to cancer progression and its aggressiveness is limited. Better understanding of the clinical features and the mechanisms of alcohol-induced HCC are of critical importance for prevention and the development of novel treatments.Early stage Huh-7 and advanced SNU449 liver cancer cell lines were subjected to Chronic Alcohol Exposure (CAE), at different doses for 6 months followed by one-month alcohol withdrawal period. ADH activity and ALDH expression were much lower in SNU449 compared with Huh-7 cells and at the 270mM dose, CAE decreased cell viability by about 50% and 80%, respectively in Huh-7 and SNU449 cells but induced mortality only in Huh-7 cells. Thus, Huh-7 may be more vulnerable to ethanol toxicity because of the higher levels of acetaldehyde. CAE induced a dose-dependent increase in cell migration and invasion and also in the expression of Cancer Stem Cells markers (CD133, CD44, CD90). CAE in Huh-7 cells selectively activated ERK1/2 and inhibited GSK3β signaling pathways. Most of the changes induced by CAE were reversed after alcohol withdrawal. Interestingly we confirmed the increase in CD133 mRNA levels in the tumoral tissue of patients with ethanol-related HCC compared to other HCC etiologies.Our results may explain the benefits observed in epidemiological studies showing a significant increase of overall survival in abstinent compared with non-abstinent patients.

scholarly journals Mechanisms involved in the inhibitory effect of chronic alcohol exposure on pancreatic acinar thiamin uptake

2014 ◽  
Vol 306 (7) ◽  
pp. G631-G639 ◽  
Author(s):  
Padmanabhan Srinivasan ◽  
Veedamali S. Subramanian ◽  
Hamid M. Said
Keyword(s):  
Molecular Mechanisms ◽  
Alcohol Exposure ◽  
Regulatory Elements ◽  
Inhibitory Effect ◽  
Pancreatic Acinar Cells ◽  
Chronic Alcohol ◽  
Sp1 Transcription Factor ◽  
Chronic Alcohol Exposure

Pancreatic acinar cells (PAC) obtain thiamin from the circulation via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and THTR-2; products of SLC19A2 and SLC19A3, respectively). Chronic alcohol exposure of PAC inhibits thiamin uptake, and, on the basis of in vitro studies, this inhibition appears to be transcriptionally mediated. The aim of this study was to confirm the involvement of a transcriptional mechanism in mediating the chronic alcohol effect in in vivo settings and to delineate the molecular mechanisms involved. Using transgenic mice carrying full-length SLC19A2 and SLC19A3 promoters, we found that chronic alcohol feeding led to a significant reduction in the activity of SLC19A2 and SLC19A3 promoters (as well as in thiamin uptake and expression of THTR-1 and -2). Similar findings were seen in 266-6 cells chronically exposed to alcohol in vitro. In the latter studies, the alcohol inhibitory effect was found to be mediated via the minimal SLC19A2 and SLC19A3 promoters and involved the cis-regulatory elements stimulating protein 1 (SP1)/gut-enriched Kruppel-like factor and SP1-GG-box and SP1/GC, respectively. Chronic alcohol exposure of PAC also led to a significant reduction in the expression of the SP1 transcription factor, which upon correction (via expression) led to the prevention of alcohol inhibitory effects on not only the activity of SLC19A2 and SLC19A3 promoters but also on the expression of THTR-1 and -2 mRNA and thiamin uptake. These results demonstrate that the inhibitory effect of chronic alcohol exposure on physiological/molecular parameters of thiamin uptake by PAC is mediated via specific cis-regulatory elements in SLC19A2 and SLC19A3 minimal promoters.

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