scholarly journals Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

2019 ◽  
Author(s):  
Audrey E. Padula ◽  
Jennifer A. Rinker ◽  
Fauzan Khan ◽  
Marcelo F. Lopez ◽  
Megan K. Mulligan ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Alcohol Use Disorder ◽  
Genetic Factors ◽  
Bioinformatics Analysis ◽  
Ethanol Exposure ◽  
Ethanol Drinking ◽  
Chronic Intermittent Ethanol ◽  
Marble Burying ◽  
Positive Modulator ◽  
High Comorbidity

AbstractAnxiety and mood disorders are often comorbid with alcohol use disorder (AUD) and are considered critical in the development, maintenance, and reinstatement of alcohol dependence and harmful alcohol-seeking behaviors. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy ethanol drinking and anxiety-related behaviors. We used a model of stress-induced escalation of drinking in ethanol dependent C57BL/6J mice to measure anxiety-like behaviors on the marble burying and novelty-suppressed feeding task (NSFT) during abstinence. In order to identify novel pharmacogenetic targets that may lead to more effective treatment, a targeted bioinformatics analysis was used to quantify the expression of K+ channel genes in the amygdala that covary with anxiety-related phenotypes in the well phenotyped and fully sequenced family of BXD strains. A pharmacological approach was used to validate the key bioinformatics finding in ethanol-dependent, stressed C57BL/6J mice during the NSFT. Amygdalar expression of Kcnn3 correlated significantly with just over 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors in this family. Kcnn3 expression in the amygdala correlated negatively with binge-like and voluntary ethanol drinking. C57BL/6J mice treated with chronic intermittent ethanol exposure and repeated swim stress consumed more ethanol in their home cages and showed hypophagia on the NSFT during prolonged abstinence. Pharmacologically targeting KCNN3 protein with the KCa2 channel positive modulator 1-EBIO decreased ethanol drinking and reduced latency to approach food during the NSFT in ethanol-dependent, stressed mice. Collectively these validation studies provide central nervous system mechanistic links into to the covariance of stress, anxiety, and AUD in the BXD strains. Further this analytical approach is effective in defining targets for treating alcohol dependence and comorbid mood and anxiety disorders.

scholarly journals Bioinformatics Analysis of Allele Frequencies and Expression Patterns of ACE2, TMPRSS2 and FURIN in Different Populations and Susceptibility to SARS-CoV-2

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1041
Author(s):  
Mohammad Tarek ◽  
Hana Abdelzaher ◽  
Firas Kobeissy ◽  
Hassan A. N. El-Fawal ◽  
Mohammed M. Salama ◽  
...  
Keyword(s):  
Immune Response ◽  
Genetic Factors ◽  
Bioinformatics Analysis ◽  
Expression Patterns ◽  
Spike Protein ◽  
Target Cells ◽  
Health Crisis ◽  
Expression Levels ◽  
Different Populations ◽  
Shed Light

The virus responsible for the COVID-19 global health crisis, SARS-CoV-2, has been shown to utilize the ACE2 protein as an entry point to its target cells. The virus has been shown to rely on the actions of TMPRSS2 (a serine protease), as well as FURIN (a peptidase), for the critical priming of its spike protein. It has been postulated that variations in the sequence and expression of SARS-CoV-2’s receptor (ACE2) and the two priming proteases (TMPRSS2 and FURIN) may be critical in contributing to SARS-CoV-2 infectivity. This study aims to examine the different expression levels of FURIN in various tissues and age ranges in light of ACE2 and TMPRSS2 expression levels using the LungMAP database. Furthermore, we retrieved expression quantitative trait loci (eQTLs) of the three genes and their annotation. We analyzed the frequency of the retrieved variants in data from various populations and compared it to the Egyptian population. We highlight FURIN’s potential interplay with the immune response to SARS-CoV-2 and showcase a myriad of variants of the three genes that are differentially expressed across populations. Our findings provide insights into potential genetic factors that impact SARS-CoV-2 infectivity in different populations and shed light on the varying expression patterns of FURIN.

Early Alcohol Withdrawal Reverses the Abnormal Levels of proBDNF/mBDNF and their Receptors

2021 ◽  
Author(s):  
Li Zhou ◽  
Jing Xiong ◽  
Chang-qing Gao ◽  
Jian-jun Bao ◽  
Xin-Fu Zhou
Keyword(s):  
Serum Level ◽  
Alcohol Dependence ◽  
Alcohol Withdrawal ◽  
Neurotrophic Factor ◽  
Ethanol Exposure ◽  
Enzyme Linked Immunosorbent Assay ◽  
Western Blots ◽  
Time Points ◽  
Protein Levels ◽  
Chronic Ethanol Exposure

Abstract ObjectiveProlonged excessive ethanol intake impairs learning, memory and also causes brain atrophy. Brain-derived neurotrophic factor (BDNF) plays pivotal roles in the pathology of alcohol dependence. Our previous work found that chronic ethanol exposure altered the metabolism of BDNF, leading to the imbalance of proBDNF and mature BDNF (mBDNF). In this study, we hypothesized that early alcohol withdrawal would reverse the abnormal levels of proBDNF, mBDNF and their receptors.Method30 male alcohol dependence patients were recruited. Peripheral blood was sampled from all the subjects before and one week after alcohol withdrawal. The lymphocyte protein levels of proBDNF, p75NTR, sortilin and TrkB were analyzed by western blots and the serum level of mBDNF and TrkB was assayed by sandwich enzyme-linked immunosorbent assay (ELISA) at two different time points. ResultsThe levels of mBDNF and its receptor (TrkB) increased, oppositely the levels of proBDNF and its receptors (p75NTR and sortilin) decreased one week after alcohol withdrawal. ConclusionsEarly alcohol withdrawal reversed the abnormal levels of proBDNF, mBDNF and their receptors. The shift levels of proBDNF and mBDNF were both taken in the pathology of alcohol withdrawal.

Unhealthy Alcohol Use

2019 ◽  
Author(s):  
Stephen R Holt ◽  
Joseph H. Donroe
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Genetic Factors ◽  
Physical And Mental Health ◽  
Unhealthy Alcohol Use ◽  
Unhealthy Alcohol ◽  
Societal Norms ◽  
High Prevalence ◽  
Excessive Alcohol

Unhealthy alcohol use refers to a spectrum of alcohol consumption ranging from at-risk drinking to alcohol use disorder. It is associated with both a high cost to society and to individuals. Globally, alcohol is a leading cause of death and disability, and despite the high prevalence of unhealthy alcohol use, diagnosis, and treatment of alcohol use disorder remains disproportionately low. Risk for unhealthy alcohol use and alcohol related harms is multifactorial and includes genetic factors, gender, age, socioeconomic status, cultural and societal norms, and policies regulating alcohol consumption among others. Excessive alcohol use is associated with a myriad of poor physical and mental health outcomes, and screening for unhealthy alcohol use is universally recommended and effective. This review contains 1 figures, 2 tables, and 76 references.  Key Words: addiction, alcohol, cancer, diagnosis, drinking, liver disease, screening, stigma, use disorderImportant Advances

scholarly journals Effects of chronic intermittent ethanol exposure and withdrawal on neuroblastoma cell transcriptome

Alcohol ◽  
2020 ◽  
Vol 85 ◽  
pp. 119-126
Author(s):  
Jeanette N. McClintick ◽  
Kriti Thapa ◽  
Yunlong Liu ◽  
Xiaoling Xuei ◽  
Howard J. Edenberg
Keyword(s):  
Neuroblastoma Cell ◽  
Ethanol Exposure ◽  
Chronic Intermittent Ethanol ◽  
Cell Transcriptome ◽  
Chronic Intermittent Ethanol Exposure

scholarly journals Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder

2020 ◽  
Vol 6 (1) ◽  
pp. 47-66 ◽  
Author(s):  
Ignatius Alvarez Cooper ◽  
Kate Beecher ◽  
Fatemeh Chehrehasa ◽  
Arnauld Belmer ◽  
Selena E. Bartlett
Keyword(s):  
Alcohol Use ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Alcohol Use Disorder ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Neuroimmune System ◽  
Inflammatory Status ◽  
The Brain ◽  
Necrosis Factor

Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF’s effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF’s essential involvement in alcohol’s effect on neurogenesis. Overall, defining TNF’s role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF’s effects within the brain.

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