scholarly journals PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder

2021 ◽  
Vol 10 (8) ◽  
pp. 1758
Author(s):  
Ji Soo Lee ◽  
Emma M. O’Connell ◽  
Pal Pacher ◽  
Falk W. Lohoff
Keyword(s):  
Alcohol Use ◽  
Therapeutic Target ◽  
Alcohol Use Disorder ◽  
Inflammatory Responses ◽  
Density Lipoprotein ◽  
Organ Damage ◽  
Brain Inflammation ◽  
Organ Injury ◽  
Chronic Alcohol ◽  
Novel Therapeutic

Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to control or stop alcohol intake and is associated with organ damage including alcohol-associated liver disease (ALD) and progressive neurodegeneration. The etiology of AUD is complex, but organ injury due to chronic alcohol use can be partially attributed to systemic and local inflammation along the gut-liver-brain axis. Excessive alcohol use can result in translocation of bacterial products into circulation, increased expression of pro-inflammatory cytokines, and activation of immune cells, including macrophages and/or microglia in the liver and brain. One potential mediator of this alcohol-induced inflammation is proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is primarily known for its regulation of plasma low-density lipoprotein cholesterol but has more recently been shown to influence inflammatory responses in the liver and brain. In rodent and post-mortem brain studies, chronic alcohol use altered methylation of the PCSK9 gene and increased expression of PCSK9 in the liver and cerebral spinal fluid. Additionally, PCSK9 inhibition in a rat model of ALD attenuated liver inflammation and steatosis. PCSK9 may play an important role in alcohol-induced pathologies along the gut-liver-brain axis and may be a novel therapeutic target for AUD-related liver and brain inflammation.

scholarly journals Probenecid Reduces Alcohol Drinking in Rodents. Is Pannexin1 a Novel Therapeutic Target for Alcohol Use Disorder?

2019 ◽  
Vol 54 (5) ◽  
pp. 497-502 ◽  
Author(s):  
Brendan J Tunstall ◽  
Irene Lorrai ◽  
Sam A McConnell ◽  
Katrina L Gazo ◽  
Lia J Zallar ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Therapeutic Target ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Drug Repositioning ◽  
Organic Anion ◽  
Self Administration ◽  
Saccharin Intake ◽  
Anion Transporter ◽  
Novel Therapeutic

Abstract Aims The development of novel and more effective medications for alcohol use disorder (AUD) is an important unmet medical need. Drug repositioning or repurposing is an appealing strategy to bring new therapies to the clinic because it greatly reduces the overall costs of drug development and expedites the availability of treatments to those who need them. Probenecid, p-(di-n-propylsulfamyl)-benzoic acid, is a drug used clinically to treat hyperuricemia and gout due to its activity as an inhibitor of the kidneys’ organic anion transporter that reclaims uric acid from urine. Probenecid also inhibits pannexin1 channels that are involved in purinergic neurotransmission and inflammation, which have been implicated in alcohol’s effects and motivation for alcohol. Therefore, we tested the effects of probenecid on alcohol intake in rodents. Methods We tested the effects of probenecid on operant oral alcohol self-administration in alcohol-dependent rats during acute withdrawal as well as in nondependent rats and in the drinking-in-the-dark (DID) paradigm of binge-like drinking in mice. Results Probenecid reduced alcohol intake in both dependent and nondependent rats and in the DID paradigm in mice without affecting water or saccharin intake, indicating that probenecid’s effect was selective for alcohol and not the result of a general reduction in reward. Conclusions These results raise the possibility that pannexin1 is a novel therapeutic target for the treatment of AUD. The clinical use of probenecid has been found to be generally safe, suggesting that it can be a candidate for drug repositioning for the treatment of AUD.

scholarly journals Magnesium Metabolism in Chronic Alcohol-Use Disorder: Meta-Analysis and Systematic Review

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1959
Author(s):  
Flora O. Vanoni ◽  
Gregorio P. Milani ◽  
Carlo Agostoni ◽  
Giorgio Treglia ◽  
Pietro B. Faré ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Meta Analysis ◽  
Final Analysis ◽  
Magnesium Content ◽  
Chronic Alcohol ◽  
Renal Handling ◽  
Intracellular Magnesium ◽  
Magnesium Depletion ◽  
Statistical Heterogeneity

Chronic alcohol-use disorder has been imputed as a possible cause of dietary magnesium depletion. The purpose of this study was to assess the prevalence of hypomagnesemia in chronic alcohol-use disorder, and to provide information on intracellular magnesium and on its renal handling. We carried out a structured literature search up to November 2020, which returned 2719 potentially relevant records. After excluding non-significant records, 25 were retained for the final analysis. The meta-analysis disclosed that both total and ionized circulating magnesium are markedly reduced in chronic alcohol-use disorder. The funnel plot and the Egger’s test did not disclose significant publication bias. The I2-test demonstrated significant statistical heterogeneity between studies. We also found that the skeletal muscle magnesium content is reduced and the kidney’s normal response to hypomagnesemia is blunted. In conclusion, magnesium depletion is common in chronic alcohol-use disorder. Furthermore, the kidney plays a crucial role in the development of magnesium depletion.

scholarly journals Different aspects of impulsivity in chronic alcohol use disorder with and without comorbid problem gambling

PLoS ONE ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. e0227645 ◽  
Author(s):  
Ildikó Kovács ◽  
Ildikó Demeter ◽  
Zoltán Janka ◽  
Zsolt Demetrovics ◽  
Aniko Maraz ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Problem Gambling ◽  
Alcohol Use Disorder ◽  
Chronic Alcohol

scholarly journals The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis

2018 ◽  
Vol 314 (5) ◽  
pp. F788-F797
Author(s):  
Jonathan M. Street ◽  
Erik H. Koritzinsky ◽  
Tiffany R. Bellomo ◽  
Xuzhen Hu ◽  
Peter S. T. Yuen ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Cumulative Effect ◽  
Organ Damage ◽  
Tubuloglomerular Feedback ◽  
Organ Injury ◽  
Sodium Reabsorption ◽  
Wild Type

Sepsis and acute kidney injury (AKI) synergistically increase morbidity and mortality in the ICU. How sepsis reduces glomerular filtration rate (GFR) and causes AKI is poorly understood; one proposed mechanism includes tubuloglomerular feedback (TGF). When sodium reabsorption by the proximal tubules is reduced in normal animals, the macula densa senses increased luminal sodium chloride, and then adenosine-1a receptor (A1aR) signaling triggers tubuloglomerular feedback, reducing GFR through afferent arteriole vasoconstriction. We measured GFR and systemic hemodynamics early during cecal ligation and puncture-induced sepsis in wild-type and A1aR-knockout mice. A miniaturized fluorometer was attached to the back of each mouse and recorded the clearance of FITC-sinistrin via transcutaneous fluorescence to monitor GFR. Clinical organ injury markers and cytokines were measured and hemodynamics monitored using implantable transducer telemetry devices. In wild-type mice, GFR was stable within 1 h after surgery, declined by 43% in the next hour, and then fell to less than 10% of baseline after 2 h and 45 min. In contrast, in A1aR-knockout mice GFR was 37% below baseline immediately after surgery and then gradually declined over 4 h. A1aR-knockout mice had similar organ injury and inflammatory responses, albeit with lower heart rate. We conclude that transcutaneous fluorescence can accurately monitor GFR and detect changes rapidly during sepsis. Tubuloglomerular feedback plays a complex role in sepsis; initially, TGF helps maintain GFR in the 1st hour, and over the subsequent 3 h, TGF causes GFR to plummet. By 18 h, TGF has no cumulative effect on renal or extrarenal organ damage.

scholarly journals Is training in creative writing a feasible treatment adjunct for clients suffering from chronic alcohol-use disorder?

2017 ◽  
Vol 34 (4) ◽  
pp. 299-313 ◽  
Author(s):  
Rikke Hellum ◽  
Stine Jensen ◽  
Anette Nielsen
Keyword(s):  
Alcohol Use ◽  
Creative Writing ◽  
Alcohol Use Disorder ◽  
Brain Activity ◽  
Chronic Alcohol ◽  
Care Providers ◽  
Self Confidence ◽  
Writing Course ◽  
Mental Problems ◽  
Treatment Centre

Introduction: If and how various ways of expressing oneself creatively might help heal and resolve mental problems is a question that has been discussed for decades. Creative writing is typically used as an add-on to traditional therapy rather than being an integrated part of the therapy. There is a lack of research into the effect of implementing creative writing as an add-on to therapy for alcohol dependence. The aim of this study was to introduce creative writing to chronic alcohol-dependent clients. Method: A creative writing course was held as a pilot study with six workshops each lasting two hours. Six clients recruited from a harm reduction unit in a Danish alcohol treatment centre and suffering from chronic alcohol-use disorder participated in the workshops. The workshops were led by two professional authors experienced in teaching creative writing. At the end we conducted three interviews: one with the clients, one with the therapist and one with the authors. The interviews were analysed with a focus on the clients’ perspective. Findings: In the analysis, we found that writing can give the clients a lower self-esteem, make them fear failure, and it can be too private. We also found that writing can increase the clients’ self-confidence and unity in the group, give them new nuances of life, stimulate their brain, give zest for life, and improve relations between clients and care providers. Further, we identified a few points of importance to be added to the organization of the workshops. Conclusion: We found that clients suffering from alcohol-use disorder participating in creative writing profited from increased self-confidence, a sense of unity, were better able to appreciate the nuances of life, experienced stimulating brain activity, had more zest for life, and that the intervention improved relations between clients and care providers.

scholarly journals Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage

2009 ◽  
Vol 33 (2) ◽  
pp. 98-104 ◽  
Author(s):  
Heiko Funke-Kaiser ◽  
Frank S Zollmann ◽  
Jan H Schefe ◽  
Thomas Unger
Keyword(s):  
Signal Transduction ◽  
Therapeutic Target ◽  
Organ Damage ◽  
End Organ Damage ◽  
Novel Therapeutic

scholarly journals Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Blood ◽  
2015 ◽  
Vol 126 (15) ◽  
pp. 1844-1855 ◽  
Author(s):  
Paritha I. Arumugam ◽  
Eric S. Mullins ◽  
Shiva Kumar Shanmukhappa ◽  
Brett P. Monia ◽  
Anastacia Loberg ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Target ◽  
Organ Damage ◽  
Disease Outcome ◽  
Cell Disease ◽  
Spontaneous Bleeding ◽  
End Organ Damage ◽  
Key Points ◽  
Novel Therapeutic

Key PointsReduced prothrombin improves survival and ameliorates inflammation and end-organ damage without spontaneous bleeding in sickle cell mice. An individual procoagulant, prothrombin, represents a novel therapeutic target that can improve sickle cell disease outcome.

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