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Drug Metabolism Reviews Nov 2019This article summarizes recent experimental and epidemiological data on the toxic and beneficial effects of ethanol and its metabolites (acetaldehyde), and focuses on... (Review)
Review
This article summarizes recent experimental and epidemiological data on the toxic and beneficial effects of ethanol and its metabolites (acetaldehyde), and focuses on their immunomodulatory effects. The section dealing with the toxic effects of alcohol focuses on its chronic toxicity (liver disorders, carcinogenic effects, cardiovascular disorders, neuropsychic disorders, addiction and withdrawal syndrome, hematologic disorders, reprotoxicity, osteoporosis) although acute toxicity is considered. The role of oxidative metabolism of ethanol by alcohol dehydrogenase, cytochrome P450 2E1, and aldehyde dehydrogenase, as well as the impact of genetic polymorphism in its physiopathology are also highlighted. The section dealing with the beneficial effects of low to moderate alcohol consumption (on cardiovascular system, diabetes, the nervous system and sensory organs, autoimmune diseases, and rheumatology) highlights the importance of anti-inflammatory and immunomodulatory effects in these observations. This knowledge, enriched by a focus on the immunomodulatory effects of ethanol and its metabolites, in particular on the NLRP3 inflammasome pathway, might facilitate the development of treatments that can reduce ethanol's harmful effects or accentuate its beneficial effects.
Topics: Alcohol Drinking; Alcoholism; Animals; Ethanol; Humans; Immunologic Factors
PubMed: 31646907
DOI: 10.1080/03602532.2019.1679169 -
Journal of Clinical and Experimental... 2022Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes... (Review)
Review
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
PubMed: 36340300
DOI: 10.1016/j.jceh.2022.05.004 -
Journal of Translational Medicine May 2023Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the... (Review)
Review
Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the leading cause of chronic liver disease. Many metabolic enzymes, including alcohol dehydrogenases such as ADH, CYP2E1, and CATacetaldehyde dehydrogenases ALDHsand nonoxidative metabolizing enzymes such as SULT, UGT, and FAEES, are involved in the metabolism of ethanol, the main component in alcoholic beverages. Ethanol consumption changes the functional or expression profiles of various regulatory factors, such as kinases, transcription factors, and microRNAs. Therefore, the underlying mechanisms of ALD are complex, involving inflammation, mitochondrial damage, endoplasmic reticulum stress, nitrification, and oxidative stress. Moreover, recent evidence has demonstrated that the gut-liver axis plays a critical role in ALD pathogenesis. For example, ethanol damages the intestinal barrier, resulting in the release of endotoxins and alterations in intestinal flora content and bile acid metabolism. However, ALD therapies show low effectiveness. Therefore, this review summarizes ethanol metabolism pathways and highly influential pathogenic mechanisms and regulatory factors involved in ALD pathology with the aim of new therapeutic insights.
Topics: Humans; Liver Diseases, Alcoholic; Liver; Ethanol; Alcoholism; Alcohol Dehydrogenase
PubMed: 37143126
DOI: 10.1186/s12967-023-04166-8 -
European Review For Medical and... Sep 2020Acute alcohol intoxication is actually a common admission cause in the Emergency Department and represents an increasing public health burden, in particular among... (Review)
Review
OBJECTIVE
Acute alcohol intoxication is actually a common admission cause in the Emergency Department and represents an increasing public health burden, in particular among adolescents. It involves possible and significant illness and injury, which can quickly get worse and may need to be managed in the emergency room.
MATERIALS AND METHODS
We conducted a narrative review of the literature regarding the effectiveness of first aid role of the Emergency Department setting.
RESULTS
This review included eighteen studies about alcohol intoxication management in the Emergency Department; most of all highlights the emerging phenomenon in Europe and around the world of acute alcohol intoxication management in first aid. The treatment of acute alcohol intoxication depends on general clinical conditions of the patient, vital signs, hemodynamic stability, cognitive state, alcohol-related complications, which are closely related to the blood alcohol concentration. At the same time, symptoms could be extremely variable due to individual differences in alcohol metabolism. In case of mild-moderate intoxication (blood alcohol concentration < 1 g/L), no drugs are necessary. In case of severe intoxication (blood alcohol concentration > 1 g/L), it is necessary to support with intravenous fluids, treat hypoglycemia, hypotension, hypothermia and electrolyte imbalance, administer complex B and C vitamins and accelerate alcohol elimination from blood with metadoxine. Unlike adults, adolescents are more exposed to the toxic effect of alcohol (because of their immature hepatic alcohol dehydrogenase activity), and then, acute alcohol-related complications are more frequent and dangerous in young people than in adult population. In many cases, patients affected by acute alcohol intoxication referring to an Emergency Department have mild-moderate transitory symptoms that do not require the use of drugs; they can benefit from a clinical observation, with a clinical course often completed within 24 hours with a favorable outcome. Clinical observation with vital signs control is necessary also to evaluate the possible development of the alcohol withdrawal syndrome (that involves a specific treatment) and to evaluate also possible pathological complications of the organism, above all acute liver damage.
CONCLUSIONS
Patients affected by acute alcohol intoxication are the best candidates to apply the rules of the Temporary Observation Unit in the Emergency Department, because of a clinical course often completed within 24 hours, a favorable outcome and without the need for hospitalization. In many cases, hospitalization could be not necessary, but the patient affected by Alcohol Use Disorder must be referred to an Alcohol Addiction Unit for the follow-up, to reduce the risk of alcohol relapse and complications related to alcohol abuse, and financial costs of hospitalization.
Topics: Alcoholic Intoxication; Blood Alcohol Content; Emergency Service, Hospital; First Aid; Hospitalization; Humans
PubMed: 32965003
DOI: 10.26355/eurrev_202009_22859 -
Cancers Feb 2023Malignant melanoma is the deadliest form of skin cancer. Despite significant efforts in sun protection education, melanoma incidence is still rising globally, drawing... (Review)
Review
Malignant melanoma is the deadliest form of skin cancer. Despite significant efforts in sun protection education, melanoma incidence is still rising globally, drawing attention to other socioenvironmental risk factors for melanoma. Ethanol and acetaldehyde (AcAH) are ubiquitous in our diets, medicines, alcoholic beverages, and the environment. In the liver, ethanol is primarily oxidized to AcAH, a toxic intermediate capable of inducing tumors by forming adducts with proteins and DNA. Once in the blood, ethanol and AcAH can reach the skin. Although, like the liver, the skin has metabolic mechanisms to detoxify ethanol and AcAH, the risk of ethanol/AcAH-associated skin diseases increases when the metabolic enzymes become dysfunctional in the skin. This review highlights the evidence linking cutaneous ethanol metabolism and melanoma. We summarize various sources of skin ethanol and AcAH and describe how the reduced activity of each alcohol metabolizing enzyme affects the sensitivity threshold to ethanol/AcAH toxicity. Data from the Gene Expression Omnibus database also show that three ethanol metabolizing enzymes (alcohol dehydrogenase 1B, P450 2E1, and catalase) and an AcAH metabolizing enzyme (aldehyde dehydrogenase 2) are significantly reduced in melanoma tissues.
PubMed: 36831600
DOI: 10.3390/cancers15041258 -
Ageing Research Reviews Jan 2022The primordial small gaseous molecules, such as: NO, CO, HS and formaldehyde (FA) are present in the brains. Whether FA as well as the other molecules participates in... (Review)
Review
The primordial small gaseous molecules, such as: NO, CO, HS and formaldehyde (FA) are present in the brains. Whether FA as well as the other molecules participates in brain functions is unclear. Recently, its pathophysiological functions have been investigated. Notably, under physiological conditions, learning activity induces a transient generation of hippocampal FA, which promotes memory formation by enhancing N-methyl-D-aspartate (NMDA)-currents. However, ageing leads to FA accumulation in brain for the dysregulation of FA metabolism; and excessive FA directly impairs memory by inhibiting NMDA-receptor. Especially, in Alzheimer's disease (AD), amyloid-beta (Aβ) accelerates FA accumulation by inactivating alcohol dehydrogenase-5; in turn, FA promotes Aβ oligomerization, fibrillation and tau hyperphosphorylation. Hence, there is a vicious circle encompassing Aβ assembly and FA generation. Even worse, FA induces Aβ deposition in the extracellular space (ECS), which blocks the medicines (dissolved in the interstitial fluid) flowing into the damaged neurons in the deep cortex. However, phototherapy destroys Aβ deposits in the ECS and restores ISF flow. Coenzyme Q10, which scavenges FA, was shown to ameliorate Aβ-induced AD pathological phenotypes, thus suggesting a causative relation between FA toxicity and AD. These findings suggest that the combination of these two methods is a promising strategy for treating AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Formaldehyde; Humans; Respiratory Hypersensitivity
PubMed: 34798299
DOI: 10.1016/j.arr.2021.101512 -
The Journal of Organic Chemistry Aug 2023We report on novel chemoenzymatic routes toward tenofovir using low-cost starting materials and commercial or homemade enzyme preparations as biocatalysts. The...
We report on novel chemoenzymatic routes toward tenofovir using low-cost starting materials and commercial or homemade enzyme preparations as biocatalysts. The biocatalytic key step was accomplished either via stereoselective reduction using an alcohol dehydrogenase or via kinetic resolution using a lipase. By employing a suspension of immobilized lipase from (Amano PS-IM) in a mixture of vinyl acetate and toluene, the desired ()-ester (99% ee) was obtained on a 500 mg scale (60 mM) in 47% yield. Alternatively, stereoselective reduction of 1-(6-chloro-9-purin-9-yl) propan-2-one (84 mg, 100 mM) catalyzed by lyophilized cells harboring recombinant alcohol dehydrogenase (ADH) from (/Lk-ADH Prince) allowed one to reach quantitative conversion, 86% yield and excellent optical purity (>99% ee) of the corresponding ()-alcohol. The key ()-intermediate was transformed into tenofovir through "one-pot" aminolysis-hydrolysis of ()-acetate in NH-saturated methanol, alkylation of the resulting ()-alcohol with tosylated diethyl(hydroxymethyl) phosphonate, and bromotrimethylsilane (TMSBr)-mediated cleavage of the formed phosphonate ester into the free phosphonic acid. The elaborated enzymatic strategy could be applicable in the asymmetric synthesis of tenofovir prodrug derivatives, including 5'-disoproxil fumarate (TDF, Viread) and 5'-alafenamide (TAF, Vemlidy). The molecular basis of the stereoselectivity of the employed ADHs was revealed by molecular docking studies.
Topics: Tenofovir; Alcohol Dehydrogenase; Escherichia coli; Molecular Docking Simulation; Alanine; Organophosphonates; Lipase; Anti-HIV Agents
PubMed: 37467462
DOI: 10.1021/acs.joc.3c01005 -
Current Biology : CB Mar 2023Several molecules can extend healthspan and lifespan across organisms. However, most are upstream signaling hubs or transcription factors orchestrating complex...
Several molecules can extend healthspan and lifespan across organisms. However, most are upstream signaling hubs or transcription factors orchestrating complex anti-aging programs. Therefore, these molecules point to but do not reveal the fundamental mechanisms driving longevity. Instead, downstream effectors that are necessary and sufficient to promote longevity across conditions or organisms may reveal the fundamental anti-aging drivers. Toward this goal, we searched for effectors acting downstream of the transcription factor EB (TFEB), known as HLH-30 in C. elegans, because TFEB/HLH-30 is necessary across anti-aging interventions and its overexpression is sufficient to extend C. elegans lifespan and reduce biomarkers of aging in mammals including humans. As a result, we present an alcohol-dehydrogenase-mediated anti-aging response (AMAR) that is essential for C. elegans longevity driven by HLH-30 overexpression, caloric restriction, mTOR inhibition, and insulin-signaling deficiency. The sole overexpression of ADH-1 is sufficient to activate AMAR, which extends healthspan and lifespan by reducing the levels of glycerol-an age-associated and aging-promoting alcohol. Adh1 overexpression is also sufficient to promote longevity in yeast, and adh-1 orthologs are induced in calorically restricted mice and humans, hinting at ADH-1 acting as an anti-aging effector across phyla.
Topics: Humans; Animals; Mice; Longevity; Caenorhabditis elegans; Alcohol Dehydrogenase; Caenorhabditis elegans Proteins; Aging; Mammals; Basic Helix-Loop-Helix Transcription Factors
PubMed: 36805847
DOI: 10.1016/j.cub.2023.01.059 -
Journal of Hepatology Aug 2021Liver sinusoidal endothelial cell (LSEC) dysfunction has been reported in alcohol-related liver disease, yet it is not known whether LSECs metabolize alcohol. Thus, we...
BACKGROUND & AIMS
Liver sinusoidal endothelial cell (LSEC) dysfunction has been reported in alcohol-related liver disease, yet it is not known whether LSECs metabolize alcohol. Thus, we investigated this, as well as the mechanisms of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury.
METHODS
Primary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs via adeno-associated virus (AAV)-mediated gene delivery to decrease heat shock protein 90 (Hsp90) acetylation in ethanol-fed mice.
RESULTS
LSECs expressed CYP2E1 and alcohol dehydrogenase 1 (ADH1) and metabolized alcohol. Ethanol induced CYP2E1 in LSECs, but not ADH1. Alcohol metabolism by CYP2E1 increased Hsp90 acetylation and decreased its interaction with endothelial nitric oxide synthase (eNOS) leading to a decrease in nitric oxide (NO) production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyperacetylation mutant decreased NO production. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. AAV8-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90's interaction with eNOS and ameliorated alcohol-induced liver injury in mice.
CONCLUSION
Restoring LSEC function is important for ameliorating alcohol-induced liver injury. To this end, blocking acetylation of Hsp90 specifically in LSECs via AAV-mediated gene delivery has the potential to be a new therapeutic strategy.
LAY SUMMARY
Alcohol metabolism in liver sinusoidal endothelial cells (LSECs) and the mechanism of alcohol-induced LSEC dysfunction are largely unknown. Herein, we demonstrate that LSECs can metabolize alcohol. We also uncover a mechanism by which alcohol induces LSEC dysfunction and liver injury, and we identify a potential therapeutic strategy to prevent this.
Topics: Acetylation; Adult; Alcohol Drinking; Analysis of Variance; Animals; Endothelial Cells; HSP90 Heat-Shock Proteins; Humans; Liver Diseases, Alcoholic; Mice; Rats
PubMed: 33675874
DOI: 10.1016/j.jhep.2021.02.028 -
Antioxidants (Basel, Switzerland) Jul 2022Alcohol use disorder (AUD) is a highly prevalent, comorbid, and disabling disorder. The underlying mechanism of ethanol neurotoxicity and the involvement of oxidative... (Review)
Review
Alcohol use disorder (AUD) is a highly prevalent, comorbid, and disabling disorder. The underlying mechanism of ethanol neurotoxicity and the involvement of oxidative stress is still not fully elucidated. However, ethanol metabolism has been associated with increased oxidative stress through alcohol dehydrogenase, the microsomal ethanol oxidation system, and catalase metabolic pathways. We searched the PubMed and genome-wide association studies (GWAS) catalog databases to review the literature systematically and summarized the findings focusing on AUD and alcohol abstinence in relation to oxidative stress. In addition, we reviewed the ClinicalTrials.gov resource of the US National Library of Medicine to identify all ongoing and completed clinical trials that include therapeutic interventions based on antioxidants. The retrieved clinical and preclinical studies show that oxidative stress impacts AUD through genetics, alcohol metabolism, inflammation, and neurodegeneration.
PubMed: 35883865
DOI: 10.3390/antiox11071374