Redox Regulation in Alcoholic Liver Disease

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 11057

Special Issue Editors


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Guest Editor
Division of Rheumatology, Hospital Universitario de Canarias, 38320 Tenerife, Spain
Interests: rheumatoid arthritis; rheumatology; arthritis; systemic inflammatory diseases with liver involvement; musculoskeletal disease

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Guest Editor
Internal Medicine Department, Universidad de La Laguna, Hospital Universitario de Canarias, 38320 Santa Cruz de Tenerife, Spain
Interests: liver disease; alcoholic hepatitis; liver injury; alcohol; alcohol and disease
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Special Issue Information

Dear Colleagues,

Oxygen is a double edged sword for life. It is a key element for optimal energy production (e.g., aerobic glycolysis, tricarboxylic acid cycle, oxidative phosphorylation), but also a toxic compound, involved in the generation of reactive oxygen species (ROS) able to damage DNA, proteins, and lipids, and also in the formation of reactive nitrogen species (RNS).  Oxidative damage activates proinflammatory cytokines production, and, together with RNS, ROS damage mitochondrial enzymatic chain. Mitochondrial damage and proinflammatory cytokines amplify the deleterious effects of ROS, creating a harmful positive feed-back loop, ultimately leading to cell death. Also, lipid peroxidation promotes ferroptosis, another important pathway involved in cell injury, and oxidative damage to histone proteins and/or DNA may lead to altered gene expression.  As a defense against the toxic effects of oxygen, several enzymatic pathways (e.g, superoxide dismutases) developed, since probably very early in the evolution of life. Together with other non-enzymatic compounds, such as urate, bilirubin, several vitamins, and reduced glutathione, and with enzymes involved in the maintenance of cell function and DNA repair during oxidative injury, antioxidants are usually in homeostatic balance with oxidative damage. However, chronic exposure to ethanol, by many mechanisms, may alter this delicate equilibrium, leading to accumulation of ROS and to ongoing disease, not only in the liver but also affecting other organs, especially those with highest oxygen consumption, such as muscle, heart and brain.

Despite intensive research in this field many aspects are still poorly understood, including for instance the role of ferroptosis, or that of the acetaldehyde/advanced glycation end-products on oxidative damage, the relation of epigenetic changes induced by alcoholism, among many others, so studies devoted to shed light on any of the still obscure aspects of the mechanisms and consequences of altered redox equilibrium in alcoholic liver disease are strongly welcome.

Contributions need not be limited to the fields mentioned in the keywords. We look forward to your contribution.

Dr. Iván Ferraz-Amaro
Dr. María Candelaria Martín-González
Guest Editors

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Keywords

  • alcoholism
  • alcoholic liver disease
  • reactive oxygen species
  • reactive nitrogen species
  • oxidative damage
  • lipid peroxidation
  • proinflammatory cytokines
  • ferroptosis
  • advanced glycation end-products
  • epigenetic changes
  • altered redox equilibrium

Published Papers (5 papers)

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Research

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16 pages, 2734 KiB  
Article
Predominantly Pro-Inflammatory Phenotype with Mixed M1/M2 Polarization of Peripheral Blood Classical Monocytes and Monocyte-Derived Macrophages among Patients with Excessive Ethanol Intake
by María Fernández-Regueras, Cristina Carbonell, Daniel Salete-Granado, Juan-Luis García, Marcos Gragera, María-Ángeles Pérez-Nieto, Francisco-Javier Morán-Plata, Andrea Mayado, Jorge-Luis Torres, Luis-Antonio Corchete, Ricardo Usategui-Martín, Elena Bueno-Martínez, Maura Rojas-Pirela, Guadalupe Sabio, Rogelio González-Sarmiento, Alberto Orfao, Francisco-Javier Laso, Julia Almeida and Miguel Marcos
Antioxidants 2023, 12(9), 1708; https://doi.org/10.3390/antiox12091708 - 01 Sep 2023
Cited by 2 | Viewed by 1781
Abstract
Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD). We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers [...] Read more.
Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD). We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers (EADs). PB samples from 20 EADs and 22 healthy controls were collected for isolation of CD14+ monocytes and short-term culture with LPS/IFNγ, IL4/IL13, or without stimulation. These conditions were also used to polarize MDMs into M1, M2, or M0 phenotypes. Cytokine production was assessed in the blood and culture supernatants. M1/M2-related markers were analyzed using mRNA expression and surface marker detection. Additionally, the miRNA profile of CD14+ monocytes was analyzed. PB samples from EADs exhibited increased levels of pro-inflammatory cytokines. Following short-term culture, unstimulated blood samples from EADs showed higher levels of soluble TNF-α and IL-8, whereas monocytes expressed increased levels of surface TNF-α and elevated mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase. MDMs from EADs showed higher levels of TNF-α and CD206 surface markers and increased IL-10 production. LPS/IFNγ induced higher mRNA expression of Nrf2 only in the controls. miRNA analysis revealed a distinctive miRNA profile that is potentially associated with liver carcinogenesis and ALD through inflammation and oxidative stress. This study confirms the predominantly pro-inflammatory profile of PB monocytes among EADs and suggests immune exhaustion features in MDMs. Full article
(This article belongs to the Special Issue Redox Regulation in Alcoholic Liver Disease)
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17 pages, 2216 KiB  
Article
Mediterranean Diet Improves Plasma Biomarkers Related to Oxidative Stress and Inflammatory Process in Patients with Non-Alcoholic Fatty Liver Disease
by Maria Magdalena Quetglas-Llabrés, Margalida Monserrat-Mesquida, Cristina Bouzas, Isabel Llompart, David Mateos, Miguel Casares, Lucía Ugarriza, J. Alfredo Martínez, Josep A. Tur and Antoni Sureda
Antioxidants 2023, 12(4), 833; https://doi.org/10.3390/antiox12040833 - 29 Mar 2023
Cited by 5 | Viewed by 1935
Abstract
Non-alcoholic fatty liver disease (NAFLD) shows liver fat depots without alcohol consumption. NAFLD does not have specific drug therapies, with a healthy lifestyle and weight loss being the main approaches to prevent and treat NAFLD. The aim was to assess the antioxidant and [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) shows liver fat depots without alcohol consumption. NAFLD does not have specific drug therapies, with a healthy lifestyle and weight loss being the main approaches to prevent and treat NAFLD. The aim was to assess the antioxidant and pro-inflammatory state in patients with NAFLD after 12-month-lifestyle intervention depending on the change in adherence to a Mediterranean diet (AMD). Antioxidant and inflammatory biomarkers were measured in 67 adults (aged 40–60 years old) diagnosed with NAFLD. Anthropometric parameters and dietary intake were measured by a validated semi-quantitative 143-item food frequency questionnaire. The nutritional intervention improved anthropometric and biochemical parameters after a 12-month follow-up. However, decreases in alanine aminotransferase (ALT) and C reactive protein (CRP) were higher in participants with high AMD, which also showed higher improvement in physical fitness (Chester step test) and intrahepatic fat contents. The intervention reduced plasma levels of malondialdehyde, myeloperoxidase, zonulin, and omentin, and increased resolvin D1 (RvD1), whereas the decrease in leptin, ectodysplasin-A (EDA), cytokeratin-18 (CK-18), interleukin-1ra (IL-1ra) and endotoxin was only significant in participants with higher AMD. The current study showed that a one-year nutritional intervention improved main NAFLD features such as body mass index, IFC, liver enzymes, and prooxidant and proinflammatory status. There was also a decrease in the concentration of plasmatic endotoxin, suggesting an improvement in intestinal permeability. These health benefits were more evident in participants that improved AMD to a greater extent. The trial was registered at ClinicalTrials.gov with registry number NCT04442620. Full article
(This article belongs to the Special Issue Redox Regulation in Alcoholic Liver Disease)
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14 pages, 2740 KiB  
Article
DMF-Activated Nrf2 Ameliorates Palmitic Acid Toxicity While Potentiates Ferroptosis Mediated Cell Death: Protective Role of the NO-Donor S-Nitroso-N-Acetylcysteine
by Diana Abu-Halaka, Adi Shpaizer, Haim Zeigerman, Joseph Kanner and Oren Tirosh
Antioxidants 2023, 12(2), 512; https://doi.org/10.3390/antiox12020512 - 17 Feb 2023
Cited by 3 | Viewed by 2509
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that can develop into an aggressive form called nonalcoholic steatohepatitis (NASH), which ultimately progresses to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure. Currently, the deterioration of NAFLD is attributed to [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that can develop into an aggressive form called nonalcoholic steatohepatitis (NASH), which ultimately progresses to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure. Currently, the deterioration of NAFLD is attributed to specific lipid toxicity which could be due to lipotoxicity and/or ferroptosis. In the current study, we evaluated the involvement of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf-2), which is a main activator of phase II metabolism in the two types of lipid-induced toxicity in hepatocytes, lipotoxicity by saturated fatty acids, and in ferroptosis, and the effect of NO donor treatment. AML12 cells were exposed to 600 μM palmitic acid to induce lipotoxicity or treated with 20 μM erastin or 5 μM RSL3 for ferroptosis. In SFA-lipotoxicity, pretreatment with the Nrf2 activator dimethyl fumarate (DMF) managed to ameliorate the cells and the oxidative stress level while aggravating ferroptosis due to emptying the thiol pool. On the other hand, the nitric oxide (NO)-donor, S-nitroso-N-acetylcysteine (NAC-SNO) proved to be effective in the prevention of hepatocytes ferroptosis. Full article
(This article belongs to the Special Issue Redox Regulation in Alcoholic Liver Disease)
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Review

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18 pages, 1176 KiB  
Review
The Role of Oxidative Inactivation of Phosphatase PTEN and TCPTP in Fatty Liver Disease
by Thang Nguyen Huu, Jiyoung Park, Ying Zhang, Hien Duong Thanh, Iha Park, Jin Myung Choi, Hyun Joong Yoon, Sang Chul Park, Hyun Ae Woo and Seung-Rock Lee
Antioxidants 2023, 12(1), 120; https://doi.org/10.3390/antiox12010120 - 03 Jan 2023
Cited by 4 | Viewed by 2101
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent worldwide. Despite the different etiologies, their spectra and histological feature are similar, from simple steatosis to more advanced stages such as steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Studies including [...] Read more.
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent worldwide. Despite the different etiologies, their spectra and histological feature are similar, from simple steatosis to more advanced stages such as steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Studies including peroxiredoxin knockout models revealed that oxidative stress is crucial in these diseases, which present as consequences of redox imbalance. Protein tyrosine phosphatases (PTPs) are a superfamily of enzymes that are major targets of reactive oxygen species (ROS) because of an oxidation-susceptible nucleophilic cysteine in their active site. Herein, we review the oxidative inactivation of two tumor suppressor PTPs, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and T-cell protein tyrosine phosphatase (TCPTP), and their contribution to the pathogenicity of ALD and NAFLD, respectively. This review might provide a better understanding of the pathogenic mechanisms of these diseases and help develop new therapeutic strategies to treat fatty liver disease. Full article
(This article belongs to the Special Issue Redox Regulation in Alcoholic Liver Disease)
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Other

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31 pages, 1318 KiB  
Systematic Review
Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications
by Daniel Salete-Granado, Cristina Carbonell, David Puertas-Miranda, Víctor-José Vega-Rodríguez, Marina García-Macia, Ana Belén Herrero and Miguel Marcos
Antioxidants 2023, 12(7), 1425; https://doi.org/10.3390/antiox12071425 - 14 Jul 2023
Cited by 3 | Viewed by 2029
Abstract
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and [...] Read more.
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ–organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies. Full article
(This article belongs to the Special Issue Redox Regulation in Alcoholic Liver Disease)
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