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Silici S, Demiray S, Okan A, Ertuğrul S, Alizada S, Doğanyiğit Z. Effects of short- and long-term use of propolis extracts on liver and kidney in rats. Food Sci Nutr 2024; 12:5538-5547. [PMID: 39139938 PMCID: PMC11317695 DOI: 10.1002/fsn3.4199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 08/15/2024] Open
Abstract
Propolis is widely used as a supplementary food product for its health benefits. The aim of this study was to determine the effects of commercial propolis extracts on the liver and kidney. Propolis extracts (250 mg/kgbw/day) were administered orally to adult male Wistar albino rats in solvents of ethanol, propylene glycol, water, and olive oil. Liver enzyme levels were determined biochemically in blood samples, and histopathological examinations were performed on the liver. Damage rate in both kidney tissue in the propolis-ethanol extract group increased significantly compared with the other groups after 30 and 90 days of application (p < .05). According to the results, ethanol, used as a common solvent in propolis products, may adversely affect the liver in long-term use. The data indicate that propolis-olive oil extract may be an essential alternative due to its effective and reliable properties.
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Affiliation(s)
- Sibel Silici
- Department of Agricultural Biotechnology, Faculty of Agriculture, Nutral TherapyErciyes UniversityKayseriTurkey
| | - Sevim Demiray
- Department of Agricultural Biotechnology, Faculty of Agriculture, Nutral TherapyErciyes UniversityKayseriTurkey
| | - Aslı Okan
- Department of Histology and Embryology, Faculty of MedicineYozgat Bozok UniversityYozgatTurkey
| | - Sena Ertuğrul
- Gulhane Medical FacultyUniversity of Health SciencesAnkaraTurkey
| | - Sahar Alizada
- Cerrahpasa Medical FacultyIstanbul University‐CerrahpasaIstanbulTurkey
| | - Züleyha Doğanyiğit
- Department of Histology and Embryology, Faculty of MedicineYozgat Bozok UniversityYozgatTurkey
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2
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Dumitru A, Matei E, Cozaru GC, Chisoi A, Alexandrescu L, Popescu RC, Butcaru MP, Dumitru E, Rugină S, Tocia C. Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis. Int J Mol Sci 2024; 25:2472. [PMID: 38473721 DOI: 10.3390/ijms25052472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.
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Affiliation(s)
- Andrei Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Luana Alexandrescu
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Răzvan Cătălin Popescu
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Mihaela Pundiche Butcaru
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Eugen Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Sorin Rugină
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Cristina Tocia
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
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Rastovic U, Bozzano SF, Riva A, Simoni-Nieves A, Harris N, Miquel R, Lackner C, Zen Y, Zamalloa A, Menon K, Heaton N, Chokshi S, Palma E. Human Precision-Cut Liver Slices: A Potential Platform to Study Alcohol-Related Liver Disease. Int J Mol Sci 2023; 25:150. [PMID: 38203321 PMCID: PMC10778645 DOI: 10.3390/ijms25010150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Alcohol-related liver disease (ALD) encompasses a range of pathological conditions that are complex to study at the clinical and preclinical levels. Despite the global burden of ALD, there is a lack of effective treatments, and mortality is high. One of the reasons for the unsuccessful development of novel therapies is that experimental studies are hindered by the challenge of recapitulating this multifactorial disorder in vitro, including the contributions of hepatotoxicity, impaired lipid metabolism, fibrosis and inflammatory cytokine storm, which are critical drivers in the pathogenesis of ALD in patients and primary targets for drug development. Here, we present the unique characteristics of the culture of human precision-cut liver slices (PCLS) to replicate key disease processes in ALD. PCLS were prepared from human liver specimens and treated with ethanol alone or in combination with fatty acids and lipopolysaccharide (FA + LPS) for up to 5 days to induce hepatotoxic, inflammatory and fibrotic events associated with ALD. Alcohol insult induced hepatocyte death which was more pronounced with the addition of FA + LPS. This mixture showed a significant increase in the cytokines conventionally associated with the prototypical inflammatory response observed in severe ALD, and interestingly, alcohol alone exhibited a different effect. Profibrogenic activation was also observed in the slices and investigated in the context of slice preparation. These results support the versatility of this organotypic model to study different pathways involved in alcohol-induced liver damage and ALD progression and highlight the applicability of the PCLS for drug discovery, confirming their relevance as a bridge between preclinical and clinical studies.
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Affiliation(s)
- Una Rastovic
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Sergio Francesco Bozzano
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Antonio Riva
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Arturo Simoni-Nieves
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Nicola Harris
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Rosa Miquel
- Institute of Liver Studies, King’s College London, London WC2R 2LS, UK
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Yoh Zen
- Institute of Liver Studies, King’s College London, London WC2R 2LS, UK
| | - Ane Zamalloa
- Institute of Liver Studies, King’s College London, London WC2R 2LS, UK
| | - Krishna Menon
- Institute of Liver Studies, King’s College London, London WC2R 2LS, UK
| | - Nigel Heaton
- Institute of Liver Studies, King’s College London, London WC2R 2LS, UK
| | - Shilpa Chokshi
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
| | - Elena Palma
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK
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Han J, Lee C, Hur J, Jung Y. Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease. Cells 2022; 12:22. [PMID: 36611816 PMCID: PMC9818513 DOI: 10.3390/cells12010022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD.
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Affiliation(s)
- Jinsol Han
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Chanbin Lee
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Jin Hur
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
- PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
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Brandão-Bezerra L, Aparecida da Rosa A, Figueiredo de Oliveira RM, Neves RH, Corrêa CL, Machado-Silva JR. Impact of acute schistosomiasis mansoni and long-term ethanol intake on mouse liver pathology. Exp Parasitol 2022; 242:108388. [PMID: 36174706 DOI: 10.1016/j.exppara.2022.108388] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 09/08/2022] [Accepted: 09/21/2022] [Indexed: 11/26/2022]
Abstract
While the effect of ethanol and schistosomiasis mansoni on liver injury has been well-documented, the influence of comorbidity on liver pathology remains unclear. To address this gap, schistosomiasis-infected mice were given one daily dose of 18% ethanol for 28 consecutive days, from day 35 post-infection. Mice were assigned to four groups: A. control; B. uninfected/ethanol gavage; C. infected; and D. infected/ethanol gavage. At day 64 post-infection, mice were euthanized by CO2 asphyxiation, livers were excised, fixed in 10% buffered formalin, paraffin embedded and cut into 5 μm sections. These were stained with hematoxylin and eosin (HE), Lennert's Giemsa and picrosirius red (for polarization microscopy) to assess histopathological and stereological changes. Group B showed alcoholic liver disease (ALD), including microsteatosis, hepatocyte karyopyknosis, karyorrhexis, karyolysis, increased frequency of Kupffer cells, hydropic degeneration of hepatocyte, thickened plasma membrane and binucleated hepatocytes. Infected mice showed typical exudative and exudative-productive hepatic granulomas, and destruction of the adjacent hepatic parenchyma, resulting in necrotic tissue and periovular leukocyte infiltrate. Group D showed hyperemia (parenchymal panlobular lesions), and liquefactive necrosis in hepatic abscess area. There was also reduced liver collagen deposition (-76%; p = 0.0001) and reduced microsteatosis (-80%, p = 0.0079) compared to group C and group B, respectively. In conclusion, comorbidity exacerbated liver damage.
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Affiliation(s)
- Luciana Brandão-Bezerra
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Aline Aparecida da Rosa
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Regina Maria Figueiredo de Oliveira
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Renata Heisler Neves
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Christiane Leal Corrêa
- Department of Pathology and Laboratories, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Brazil. Medical College, Estácio de Sá University, Rio de Janeiro, Brazil
| | - José Roberto Machado-Silva
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil.
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6
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Sadasivam N, Kim YJ, Radhakrishnan K, Kim DK. Oxidative Stress, Genomic Integrity, and Liver Diseases. Molecules 2022; 27:3159. [PMID: 35630636 PMCID: PMC9147071 DOI: 10.3390/molecules27103159] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 02/04/2023] Open
Abstract
Excess reactive oxygen species production and free radical formation can lead to oxidative stress that can damage cells, tissues, and organs. Cellular oxidative stress is defined as the imbalance between ROS production and antioxidants. This imbalance can lead to malfunction or structure modification of major cellular molecules such as lipids, proteins, and DNAs. During oxidative stress conditions, DNA and protein structure modifications can lead to various diseases. Various antioxidant-specific gene expression and signal transduction pathways are activated during oxidative stress to maintain homeostasis and to protect organs from oxidative injury and damage. The liver is more vulnerable to oxidative conditions than other organs. Antioxidants, antioxidant-specific enzymes, and the regulation of the antioxidant responsive element (ARE) genes can act against chronic oxidative stress in the liver. ARE-mediated genes can act as the target site for averting/preventing liver diseases caused by oxidative stress. Identification of these ARE genes as markers will enable the early detection of liver diseases caused by oxidative conditions and help develop new therapeutic interventions. This literature review is focused on antioxidant-specific gene expression upon oxidative stress, the factors responsible for hepatic oxidative stress, liver response to redox signaling, oxidative stress and redox signaling in various liver diseases, and future aspects.
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Affiliation(s)
- Nanthini Sadasivam
- Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea; (N.S.); (Y.-J.K.)
| | - Yu-Ji Kim
- Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea; (N.S.); (Y.-J.K.)
| | - Kamalakannan Radhakrishnan
- Clinical Vaccine R&D Center, Department of Microbiology, Combinatorial Tumor Immunotherapy MRC, Medical School, Chonnam National University, Gwangju 58128, Korea
| | - Don-Kyu Kim
- Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, Korea; (N.S.); (Y.-J.K.)
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Park H, Lee E, Kim Y, Jung HY, Kim KM, Kwon O. Metabolic Profiling Analysis Reveals the Potential Contribution of Barley Sprouts against Oxidative Stress and Related Liver Cell Damage in Habitual Alcohol Drinkers. Antioxidants (Basel) 2021; 10:antiox10030459. [PMID: 33804285 PMCID: PMC8000388 DOI: 10.3390/antiox10030459] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic excessive alcohol consumption is associated with multiple liver defects, such as steatosis and cirrhosis, mainly attributable to excessive reactive oxygen species (ROS) production. Barley sprouts (Hordeum vulgare L.) contain high levels of polyphenols that may serve as potential antioxidants. This study aimed to investigate whether barley sprouts extract powder (BSE) relieves alcohol-induced oxidative stress and related hepatic damages in habitual alcohol drinkers with fatty liver. In a 12-week randomized controlled trial with two arms (placebo or 480 mg/day BSE; n = 76), we measured clinical markers and metabolites at the baseline and endpoint to understand the complex molecular mechanisms. BSE supplementation reduced the magnitude of ROS generation and lipid peroxidation and improved the glutathione antioxidant system. Subsequent metabolomic analysis identified alterations in glutathione metabolism, amino acid metabolism, and fatty acid synthesis pathways, confirming the role of BSE in glutathione-related lipid metabolism. Finally, the unsupervised machine learning algorithm indicated that subjects with lower glutathione reductase at the baseline were responders for liver fat content, and those with higher fatigue and lipid oxidation were responders for γ-glutamyl transferase. These findings suggest that BSE administration may protect against hepatic injury by reducing oxidative stress and changing the metabolism in habitual alcohol drinkers with fatty liver.
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Affiliation(s)
- Hyerin Park
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea; (H.P.); (Y.K.); (H.Y.J.)
| | - Eunok Lee
- Department of Nutritional Science and Food Management, Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Korea;
| | - Yunsoo Kim
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea; (H.P.); (Y.K.); (H.Y.J.)
| | - Hye Yoon Jung
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea; (H.P.); (Y.K.); (H.Y.J.)
| | - Kwang-Min Kim
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon 16449, Korea;
| | - Oran Kwon
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea; (H.P.); (Y.K.); (H.Y.J.)
- Department of Nutritional Science and Food Management, Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Korea;
- Correspondence: ; Tel./Fax: +82-2-3277-6860
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Rungratanawanich W, Qu Y, Wang X, Essa MM, Song BJ. Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury. Exp Mol Med 2021; 53:168-188. [PMID: 33568752 PMCID: PMC8080618 DOI: 10.1038/s12276-021-00561-7] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 01/30/2023] Open
Abstract
Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer. Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE-alcohol-adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.
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Affiliation(s)
- Wiramon Rungratanawanich
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
| | - Ying Qu
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
| | - Xin Wang
- Neuroapoptosis Drug Discovery Laboratory, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA 02115 USA
| | - Musthafa Mohamed Essa
- grid.412846.d0000 0001 0726 9430Department of Food Science and Nutrition, Aging and Dementia Research Group, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al-Khoud, Muscat, Oman ,grid.412846.d0000 0001 0726 9430Aging and Dementia Research Group, Sultan Qaboos University, Muscat, Oman
| | - Byoung-Joon Song
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
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9
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Zhong Z, Lemasters JJ. A Unifying Hypothesis Linking Hepatic Adaptations for Ethanol Metabolism to the Proinflammatory and Profibrotic Events of Alcoholic Liver Disease. Alcohol Clin Exp Res 2018; 42:2072-2089. [PMID: 30132924 PMCID: PMC6214771 DOI: 10.1111/acer.13877] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/13/2018] [Indexed: 02/06/2023]
Abstract
The pathogenesis of alcoholic liver disease (ALD) remains poorly understood but is likely a multihit pathophysiological process. Here, we propose a hypothesis of how early mitochondrial adaptations for alcohol metabolism lead to ALD pathogenesis. Acutely, ethanol (EtOH) feeding causes a near doubling of hepatic EtOH metabolism and oxygen consumption within 2 to 3 hours. This swift increase in alcohol metabolism (SIAM) is an adaptive response to hasten metabolic elimination of both EtOH and its more toxic metabolite, acetaldehyde (AcAld). In association with SIAM, EtOH causes widespread hepatic mitochondrial depolarization (mtDepo), which stimulates oxygen consumption. In parallel, voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane close. Together, VDAC closure and respiratory stimulation promote selective and more rapid oxidation of EtOH first to AcAld in the cytosol and then to nontoxic acetate in mitochondria, since membrane-permeant AcAld does not require VDAC to enter mitochondria. VDAC closure also inhibits mitochondrial fatty acid oxidation and ATP release, promoting steatosis and a decrease in cytosolic ATP. After acute EtOH, these changes revert as EtOH is eliminated with little hepatocellular cytolethality. mtDepo also stimulates mitochondrial autophagy (mitophagy). After chronic high EtOH exposure, the capacity to process depolarized mitochondria by mitophagy becomes compromised, leading to intra- and extracellular release of damaged mitochondria, mitophagosomes, and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP) molecules. mtDAMPs cause inflammasome activation and promote inflammatory and profibrogenic responses, causing hepatitis and fibrosis. We propose that persistence of mitochondrial responses to EtOH metabolism becomes a tipping point, which links initial adaptive EtOH metabolism to maladaptive changes initiating onset and progression of ALD.
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Affiliation(s)
- Zhi Zhong
- Department of Drug Discovery & Biomedical Sciences and
| | - John J. Lemasters
- Department of Drug Discovery & Biomedical Sciences and
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
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10
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Kawaratani H, Moriya K, Namisaki T, Uejima M, Kitade M, Takeda K, Okura Y, Kaji K, Takaya H, Nishimura N, Sato S, Sawada Y, Seki K, Kubo T, Mitoro A, Yamao J, Yoshiji H. Therapeutic strategies for alcoholic liver disease: Focusing on inflammation and fibrosis (Review). Int J Mol Med 2017; 40:263-270. [PMID: 28627645 DOI: 10.3892/ijmm.2017.3015] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/30/2017] [Indexed: 11/06/2022] Open
Abstract
Excessive alcohol consumption is the most common cause of liver disease in the world. Chronic alcohol abuse leads to liver damage, liver inflammation, fibrosis and hepatocellular carcinoma. Inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, induce liver injury, which leads to the develo-pment of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as interleukin (IL)-6 and IL-10, are also associated with ALD. IL-6 improves ALD via the activation of STAT3 and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. Alcohol consumption promotes liver inflammation by incre-asing the translocation of gut-derived endotoxins to the portal circulation and by activating Kupffer cells through the lipopolysaccharide/Toll-like receptor 4 pathways. Oxidative stress and microflora products are also associated with ALD. Hepatic stellate cells play an important role in angiogenesis and liver fibrosis. Anti-angiogenic therapy has been found to be effective in the prevention of fibrosis. This suggests that blocking angiogenesis could be a promising therapeutic option for patients with advanced fibrosis. This review discusses the main pathways associated with liver inflammation and liver fibrosis as well as new therapeutic strategies.
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Affiliation(s)
- Hideto Kawaratani
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Masakazu Uejima
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Mitsuteru Kitade
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kousuke Takeda
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasushi Okura
- Department of Endoscopy and Ultrasound, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kousuke Kaji
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hiroaki Takaya
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Norihisa Nishimura
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Shinya Sato
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasuhiko Sawada
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kenichiro Seki
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takuya Kubo
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Akira Mitoro
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Junichi Yamao
- Department of Endoscopy and Ultrasound, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- The Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
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Scheer MA, Schneider KJ, Finnigan RL, Maloney EP, Wells MA, Clemens DL. The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment. Biomolecules 2016; 6:biom6020017. [PMID: 27043646 PMCID: PMC4919912 DOI: 10.3390/biom6020017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 03/09/2016] [Accepted: 03/24/2016] [Indexed: 01/15/2023] Open
Abstract
Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest. Methods: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis. Results: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21. Conclusions: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged cells.
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Affiliation(s)
- Marc A Scheer
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Katrina J Schneider
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Nebraska and Western Iowa Veterans Administration Medical Center, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Rochelle L Finnigan
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Eamon P Maloney
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Mark A Wells
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Dahn L Clemens
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Nebraska and Western Iowa Veterans Administration Medical Center, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA.
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Kuttippurathu L, Juskeviciute E, Dippold RP, Hoek JB, Vadigepalli R. A novel comparative pattern analysis approach identifies chronic alcohol mediated dysregulation of transcriptomic dynamics during liver regeneration. BMC Genomics 2016; 17:260. [PMID: 27012785 PMCID: PMC4807561 DOI: 10.1186/s12864-016-2492-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 02/17/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Liver regeneration is inhibited by chronic ethanol consumption and this impaired repair response may contribute to the risk for alcoholic liver disease. We developed and applied a novel data analysis approach to assess the effect of chronic ethanol intake in the mechanisms responsible for liver regeneration. We performed a time series transcriptomic profiling study of the regeneration response after 2/3rd partial hepatectomy (PHx) in ethanol-fed and isocaloric control rats. RESULTS We developed a novel data analysis approach focusing on comparative pattern counts (COMPACT) to exhaustively identify the dominant and subtle differential expression patterns. Approximately 6500 genes were differentially regulated in Ethanol or Control groups within 24 h after PHx. Adaptation to chronic ethanol intake significantly altered the immediate early gene expression patterns and nearly completely abrogated the cell cycle induction in hepatocytes post PHx. The patterns highlighted by COMPACT analysis contained several non-parenchymal cell specific markers indicating their aberrant transcriptional response as a novel mechanism through which chronic ethanol intake deregulates the integrated liver tissue response. CONCLUSIONS Our novel comparative pattern analysis revealed new insights into ethanol-mediated molecular changes in non-parenchymal liver cells as a possible contribution to the defective liver regeneration phenotype. The results revealed for the first time an ethanol-induced shift of hepatic stellate cells from a pro-regenerative phenotype to that of an anti-regenerative state after PHx. Our results can form the basis for novel interventions targeting the non-parenchymal cells in normalizing the dysfunctional repair response process in alcoholic liver disease. Our approach is illustrated online at http://compact.jefferson.edu .
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Affiliation(s)
- Lakshmi Kuttippurathu
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Egle Juskeviciute
- MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Rachael P Dippold
- MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Jan B Hoek
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.,MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. .,MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
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13
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Mercer KE, Pulliam C, Hennings L, Lai K, Cleves M, Jones E, Drake RR, Ronis M. Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice. Cancer Prev Res (Phila) 2016; 9:466-75. [PMID: 27006377 DOI: 10.1158/1940-6207.capr-15-0417] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/02/2016] [Indexed: 12/16/2022]
Abstract
In this study, diethylnitrosamine-treated male mice were assigned to three groups: (i) a 35% high fat ethanol liquid diet (EtOH) with casein as the protein source, (ii) the same EtOH liquid diet with soy protein isolate as the sole protein source (EtOH/SPI), (iii) and a chow group. EtOH feeding continued for 16 weeks. As expected, EtOH increased the incidence and multiplicity of basophilic lesions and adenomas compared with the chow group, P < 0.05. Soy protein replacement of casein in the EtOH diet significantly reduced adenoma progression when compared with the EtOH and EtOH/SPI group (P < 0.05). Tumor reduction in the EtOH/SPI group corresponded to reduced liver injury associated with decreased hepatic Tnfα and Cd14 antigen (Cd14) expression and decreased nuclear accumulation of NF-κB1 protein compared with the EtOH group (P < 0.05). Detection of sphingolipids using high-resolution matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR) imaging mass spectrometry revealed increased accumulation of long acyl chain ceramide species, and sphingosine-1-phosphate (S1P) in the EtOH group that were significantly reduced in the EtOH/SPI group. Chronic EtOH feeding also increased mRNA expression of β-catenin transcriptional targets, including cyclin D1 (Ccnd1), matrix metallopeptidase 7 (Mmp7), and glutamine synthetase (Glns), which were reduced in the EtOH/SPI group (P < 0.05). We conclude that soy prevents tumorigenesis by reducing proinflammatory and oxidative environment resulting from EtOH-induced hepatic injury, and by reducing hepatocyte proliferation through inhibition of β-catenin signaling. These mechanisms may involve changes in sphingolipid signaling. Cancer Prev Res; 9(6); 466-75. ©2016 AACR.
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Affiliation(s)
- Kelly E Mercer
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Arkansas Children's Nutrition Center, Little Rock, Arkansas.
| | - Casey Pulliam
- Arkansas Children's Nutrition Center, Little Rock, Arkansas
| | - Leah Hennings
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Keith Lai
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Mario Cleves
- Arkansas Children's Nutrition Center, Little Rock, Arkansas
| | - Ellen Jones
- Medical University of South Carolina Proteomic Center, Charleston, South Carolina
| | - Richard R Drake
- Medical University of South Carolina Proteomic Center, Charleston, South Carolina
| | - Martin Ronis
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
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Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y. The Role of Oxidative Stress and Antioxidants in Liver Diseases. Int J Mol Sci 2015; 16:26087-26124. [PMID: 26540040 PMCID: PMC4661801 DOI: 10.3390/ijms161125942] [Citation(s) in RCA: 1056] [Impact Index Per Article: 105.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 09/20/2015] [Accepted: 10/19/2015] [Indexed: 12/15/2022] Open
Abstract
A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed.
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Affiliation(s)
- Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Zhang-Jin Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Lixing Lao
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Chi-Woon Wong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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15
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Lanthier N, Rubbia-Brandt L, Lin-Marq N, Clément S, Frossard JL, Goossens N, Hadengue A, Spahr L. Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis. J Hepatol 2015; 63:609-21. [PMID: 25872168 DOI: 10.1016/j.jhep.2015.04.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 03/10/2015] [Accepted: 04/01/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The role of liver progenitor cell (LPC) expansion, known as a marker of disease severity, as well as the impact of macrophage activation on liver regeneration remains unclear in humans. We aimed to characterize the LPC and macrophage compartments in alcoholic hepatitis (AH), as well as gene expression patterns to identify predictors of a good prognosis in this setting. METHODS Immunohistochemical studies for macrophages, proliferative hepatocytes, total and proliferative LPC, as well as whole liver microarray gene expression were performed on baseline liver biopsies of 58 AH patients early after admission. Abstinent cirrhotic patients were used as controls. Patients were qualified as "improvers" or "non-improvers" based on the change in MELD score three months after baseline. RESULTS Compared to controls, AH patients demonstrated a significant expansion of macrophages, invasion of LPC and a higher number of proliferating hepatocytes and LPC. In AH patients, total LPC expansion (total Keratin7(+) cells) was associated with liver disease severity. The group of improvers (n=34) was characterized at baseline by a higher number of proliferating hepatocytes, proliferative LPC (double Keratin7(+)Ki67(+) cells) and liver macrophages as compared to non-improvers (n=24), despite similar clinical and biological variables. Upregulated genes in improvers were associated with cell cycle mitosis together with a major expression of SPINK1. CONCLUSIONS Higher liver macrophage expansion, increased proliferative hepatocyte but also LPC number, as well as an upregulation of cell proliferation-related genes are associated with a favourable outcome. These new findings open novel therapeutic targets in AH.
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Affiliation(s)
- Nicolas Lanthier
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland; Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Laura Rubbia-Brandt
- Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Nathalie Lin-Marq
- Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Sophie Clément
- Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Jean-Louis Frossard
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Nicolas Goossens
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Antoine Hadengue
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Laurent Spahr
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
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Madrigal-Santillán E, Bautista M, Gayosso-De-Lucio JA, Reyes-Rosales Y, Posadas-Mondragón A, Morales-González &A, Soriano-Ursúa MA, García-Machorro J, Madrigal-Bujaidar E, Álvarez-González I, Morales-González JA. Hepatoprotective effect of Geranium schiedeanum against ethanol toxicity during liver regeneration. World J Gastroenterol 2015; 21:7718-7729. [PMID: 26167072 PMCID: PMC4491959 DOI: 10.3748/wjg.v21.i25.7718] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/25/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of an extract of Geranium schiedeanum (Gs) as a hepatoprotective agent against ethanol (EtOH)-induced toxicity in rats. METHODS Male Wistar rats weighing 200-230 g were subjected to a 70% partial hepatectomy (PH); they were then divided into three groups (groups 1-3). During the experiment, animals in group 1 drank only water. The other two groups (2-3) drank an aqueous solution of EtOH (40%, v/v). Additionally, rats in group 3 received a Gs extract daily at a dose of 300 mg/kg body weight intragastically. Subsequently, to identify markers of liver damage in serum, alanine aminotransferase, aspartate aminotransferase, albumin and bilirubin were measured by colorimetric methods. Glucose, triglyceride and cholesterol concentrations were also determined. In addition, oxidative damage was estimated by measuring lipid peroxidation [using thiobarbituric-acid reactive substances (TBARS)] in both plasma and the liver and by measuring the total concentration of antioxidants in serum and the total antioxidant capacity in the liver. In addition, a liver mass gain assessment, total DNA analysis and a morpho-histological analysis of the liver from animals in all three groups were performed and compared. Finally, the number of deaths observed in the three groups was analyzed. RESULTS Administration of the Geranium shiedeanum extract significantly reduced the unfavorable effect of ethanol on liver regeneration (restitution liver mass: PH-EtOH group 60.68% vs PH-Gs-EtOH group 69.22%). This finding was congruent with the reduced levels of hepatic enzymes and the sustained or increased levels of albumin and decreased bilirubin in serum. The extract also modified the metabolic processes that regulate glucose and lipid levels, as observed from the serum measurements. Lower antioxidant levels and the liver damage induced by EtOH administration appeared to be mitigated by the extract, as observed from the TBARs (PH-EtOH group 200.14 mmol/mg vs PH-Gs-EtOH group 54.20 mmol/mg; P < 0.05), total status of antioxidants (PH-EtOH group 1.43 mmol/L vs PH-Gs-EtOH group 1.99 mmol/L; P < 0.05), total antioxidant capacity values, liver mass gain and total DNA determination (PH-EtOH group 4.80 mg/g vs PH-Gs-EtOH 9.10 mg/g; P < 0.05). Overall, these processes could be related to decreased mortality in these treated animals. CONCLUSION The administered extract showed a hepatoprotective effect, limiting the EtOH-induced hepatotoxic effects. This effect can be related to modulating oxido-reduction processes.
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18
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Bobat S, Cunningham AF. Bacterial infections and vaccines. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 828:75-98. [PMID: 25253028 DOI: 10.1007/978-1-4939-1489-0_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Affiliation(s)
- Saeeda Bobat
- The Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, West Midlands, UK,
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Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, Noguchi R, Yoshiji H, Fujimoto M, Fukui H. The effect of inflammatory cytokines in alcoholic liver disease. Mediators Inflamm 2013; 2013:495156. [PMID: 24385684 PMCID: PMC3872233 DOI: 10.1155/2013/495156] [Citation(s) in RCA: 167] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.
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Affiliation(s)
- Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Tatsuhiro Tsujimoto
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Akitoshi Douhara
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Masao Fujimoto
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Hiroshi Fukui
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
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Hisada M, Ota Y, Zhang X, Cameron AM, Gao B, Montgomery RA, Williams GM, Sun Z. Successful transplantation of reduced-sized rat alcoholic fatty livers made possible by mobilization of host stem cells. Am J Transplant 2012; 12:3246-56. [PMID: 22994609 PMCID: PMC4461878 DOI: 10.1111/j.1600-6143.2012.04265.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Livers from Lewis rats fed with 7% alcohol for 5 weeks were used for transplantation. Reduced sized (50%) livers or whole livers were transplanted into normal DA recipients, which, in this strain combination, survive indefinitely when the donor has not been fed alcohol. However, none of the rats survived a whole fatty liver transplant while six of seven recipients of reduced sized alcoholic liver grafts survived long term. SDF-1 and HGF were significantly increased in reduced size liver grafts compared to whole liver grafts. Lineage-negative Thy-1+CXCR4+CD133+ stem cells were significantly increased in the peripheral blood and in allografts after reduced size fatty liver transplantation. In contrast, there were meager increases in cells reactive with anti Thy-1, CXCR4 and CD133 in peripheral blood and allografts in whole alcoholic liver recipients. The provision of plerixafor, a stem cell mobilizer, salvaged 5 of 10 whole fatty liver grafts. Conversely, blocking SDF-1 activity with neutralizing antibodies diminished stem cell recruitment and four of five reduced sized fatty liver recipients died. Thus chemokine insufficiency was associated with transplant failure of whole grafts, which was overcome by the increased regenerative requirements promoted by the small grafts and mediated by SDF-1 resulting in stem cell influx.
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Affiliation(s)
- Masayuki Hisada
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yoshihiro Ota
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Xiuying Zhang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Andrew M Cameron
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, NIAAA, NIH, Bethesda, Maryland, USA
| | - Robert A Montgomery
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Clemens DL, Schneider KJM, Nuss RF. Ethanol metabolism activates cell cycle checkpoint kinase, Chk2. Alcohol 2011; 45:785-93. [PMID: 21924579 DOI: 10.1016/j.alcohol.2011.07.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2010] [Revised: 07/15/2011] [Accepted: 07/16/2011] [Indexed: 01/15/2023]
Abstract
Chronic ethanol abuse results in hepatocyte injury and impairs hepatocyte replication. We have previously shown that ethanol metabolism results in cell cycle arrest at the G2/M transition, which is partially mediated by inhibitory phosphorylation of the cyclin-dependent kinase, Cdc2. To further delineate the mechanisms by which ethanol metabolism mediates this G2/M arrest, we investigated the involvement of upstream regulators of Cdc2 activity. Cdc2 is activated by the phosphatase Cdc25C. The activity of Cdc25C can, in turn, be regulated by the checkpoint kinase, Chk2, which is regulated by the kinase ataxia telangiectasia mutated (ATM). To investigate the involvement of the regulators of Cdc2 activity, VA-13 cells, which are Hep G2 cells modified to efficiently express alcohol dehydrogenase, were cultured in the presence or absence of 25 mM ethanol. Immunoblots were performed to determine the effects of ethanol metabolism on the activation of Cdc25C, Chk2, and ATM. Ethanol metabolism increased the active forms of ATM and Chk2, as well as the phosphorylated form of Cdc25C. Additionally, inhibition of ATM resulted in approximately 50% of the cells being rescued from the G2/M cell cycle arrest and ameliorated the inhibitory phosphorylation of Cdc2. Our findings demonstrated that ethanol metabolism activates ATM. ATM can activate the checkpoint kinase Chk2, resulting in phosphorylation of Cdc25C and ultimately in the accumulation of inactive Cdc2. This may, in part, explain the ethanol metabolism-mediated impairment in hepatocyte replication, which may be important in the initiation and progression of alcoholic liver injury.
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Affiliation(s)
- Dahn L Clemens
- Research Service, Veterans Administration Medical Center, 4101 Woolworth Avenue, Omaha, NE 68105, USA.
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22
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Chavez PRG, Lian F, Chung J, Liu C, Paiva SAR, Seitz HK, Wang X. Long-term ethanol consumption promotes hepatic tumorigenesis but impairs normal hepatocyte proliferation in rats. J Nutr 2011; 141:1049-55. [PMID: 21490289 PMCID: PMC3095139 DOI: 10.3945/jn.110.136531] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Chronic and excessive alcohol consumption has been related to an increased risk of several cancers, including that of the liver; however, studies in animal models have yet to conclusively determine whether ethanol acts as a tumor promoter in hepatic tumorigenesis. We examined whether prolonged alcohol consumption could act as a hepatic tumor promoter after initiation by diethylnitrosamine (DEN) in a rat model. Male Sprague-Dawley rats were injected with 20 mg DEN/kg body weight 1 wk before introduction of either an ethanol liquid diet or an isoenergic control liquid diet. Hepatic pathological lesions, hepatocyte proliferation, apoptosis, PPARα and PPARγ, and plasma insulin-like growth factor 1 (IGF-1) levels were assessed after 6 and 10 mo. Mean body and liver weights, plasma IGF-1 concentration, hepatic expressions of proliferating cellular nuclear antigen and Ki-67, and cyclin D1 in ethanol-fed rats were all significantly lower after 10 mo of treatment compared with control rats. In addition, levels of hepatic PPARγ protein, not PPARα, were significantly higher in the ethanol-fed rats after prolonged treatment. Although ethanol feeding also resulted in significantly fewer altered hepatic foci, hepatocellular adenoma was detected in ethanol-fed rats at 10 mo, but not in control rats given the same dose of DEN. Together, these results indicate that chronic, excessive ethanol consumption impairs normal hepatocyte proliferation, which is associated with reduced IGF-1 levels, but promotes hepatic carcinogenesis.
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Affiliation(s)
- Pollyanna R. G. Chavez
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
| | - Fuzhi Lian
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
| | - Jayong Chung
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111,Department of Food and Nutrition, Kyung Hee University, Seoul 130-701, Korea
| | - Chun Liu
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
| | - Sergio A. R. Paiva
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111,Department of Medicine, Botucatu School of Medicine, University of Sao Paulo State, Botucatu 18618-000, SP, Brazil
| | - Helmut K. Seitz
- Center of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Xiang‐Dong Wang
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111,To whom correspondence should be addressed. E-mail:
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Kawaratani H, Tsujimoto T, Kitazawa T, Yoshiji H, Uemura M, Fukui H. Therapeutic effects of cytokine modulator Y-40138 in the rat alcoholic liver disease model. J Gastroenterol Hepatol 2011; 26:775-83. [PMID: 21251062 DOI: 10.1111/j.1440-1746.2011.06658.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ), induce liver injury in the rat alcoholic liver disease (ALD) model. Y-40138 is known to suppress the pro-inflammatory cytokines and augment the anti-inflammatory cytokines. We investigated whether or not Y-40138 may be effective as a novel immunotherapy in the rat ALD model. METHODS Male Wistar rats were fed Lieber-DeCarli ethanol liquid diet. The effects of Y-40138 treatment in the ALD models were assessed by analyzing the serum and the liver tissues. RESULTS The serum levels of alanine aminotransferase (ALT), TNF-α, and IFN-γ, and the liver levels of TNF-α and IFN-γ were significantly higher in the ethanol-fed group than in the pair-fed group. The immunohistochemistry of the liver TNF-α and 4-hydroxynonenal (4HNE), and the expressions of TNF-α and IFN-γ mRNA were increased, too. The gene expressions of interleukin-10 (IL-10) in the ethanol-fed group were suppressed as compared with the pair-fed group. The serum triglyceride (TG) and liver TG were increased, and Oil Red O and α-smooth muscle actin (α-SMA) staining showed greater expression by ethanol-fed feeding. After administration of Y-40138, enzyme linked immunosorbent assay and real-time polymerase chain reaction of the liver showed that the increased TNF-α and IFN-γ were suppressed, and that IL-10 was augmented. Moreover, ethanol-induced lipid accumulation in the liver was suppressed by administering Y-40138. CONCLUSIONS Y-40138 decreased the inflammation, fibrosis, oxidative stress, and lipid synthesis, and augmented the anti-inflammatory cytokines of the liver. These results indicate that the multiple cytokine production modulator, Y-40138, is a promising novel therapy for ALD.
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Affiliation(s)
- Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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Ronis MJJ, Hennings L, Stewart B, Basnakian AG, Apostolov EO, Albano E, Badger TM, Petersen DR. Effects of long-term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 2011; 300:G109-19. [PMID: 21051528 PMCID: PMC3025509 DOI: 10.1152/ajpgi.00145.2010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Male Sprague-Dawley rats were chronically fed a high-unsaturated-fat diet for 130 days by using total enteral nutrition (TEN), or the same diet in which ethanol (EtOH) isocalorically replaced carbohydrate calories. Additional groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g·kg(-1)·day(-1). Relative to an ad libitum chow-fed group, the high-fat-fed controls had three- to fourfold greater expression of fatty acid transporter CD36 mRNA and developed mild steatosis but little other hepatic pathology. NAC treatment resulted in increased somatic growth relative to controls (4.0 ± 0.1 vs. 3.1 ± 0.1 g/day) and increased hepatic steatosis score (3.5 ± 0.6 vs. 2.7 ± 1.2), associated with suppression of the triglyceride hydrolyzing protein adiponutrin, but produced no elevation in serum alanine aminotransferase (ALT). Chronic EtOH treatment increased expression of fatty acid transport protein FATP-2 mRNA twofold, resulting in marked hepatic steatosis, oxidative stress, and a twofold elevation in serum ALT. However, no changes in tumor necrosis factor-α or transforming growth factor-β expression were observed. Fibrosis, as measured by Masson's trichrome and picrosirius red staining, and a twofold increase in expression of type I and type III collagen mRNA, was only observed after EtOH treatment. Long-term EtOH treatment increased hepatocyte proliferation but did not modify the hepatic mRNAs for hedgehog pathway ligands or target genes or genes regulating epithelial-to-mesenchymal transition. Although the effects of NAC on EtOH-induced fibrosis could not be fully evaluated, NAC had additive effects on hepatocyte proliferation and prevented EtOH-induced oxidative stress and necrosis, despite a failure to reverse hepatic steatosis.
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Affiliation(s)
- Martin J. J. Ronis
- Departments of 1Pharmacology and Toxicology, ,2University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center, Little Rock, Arkansas;
| | | | - Ben Stewart
- 4Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado; and
| | | | | | - Emanuele Albano
- 5Department of Medical Sciences, University A Avogadro of East Piedmonte, Novara, Italy
| | - Thomas M. Badger
- 6Physiology and Biophysics, ,2University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center, Little Rock, Arkansas;
| | - Dennis R. Petersen
- 4Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado; and
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Orellana D, Liu X, Wang GL, Jin J, Iakova P, Timchenko NA. Calmodulin controls liver proliferation via interactions with C/EBPbeta-LAP and C/EBPbeta-LIP. J Biol Chem 2010; 285:23444-56. [PMID: 20498378 DOI: 10.1074/jbc.m110.129825] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A truncated isoform of C/EBPbeta, C/EBPbeta-LIP, is required for liver proliferation. This isoform is expressed at high levels in proliferating liver and in liver tumors. However, high levels of C/EBPbeta-LIP are also observed in non-proliferating livers during acute phase response (APR). In this paper we present mechanisms by which liver regulates activities of C/EBPbeta-LIP. We found that calmodulin (CaM) inhibits the ability of C/EBPbeta-LIP to promote liver proliferation during APR through direct interactions. This activity of CaM is under negative control of Ca(2+), which is reduced in nuclei of livers with APR, whereas it is increased in nuclei of proliferating livers. A mutant CaM, which does not interact with C/EBPbeta-LIP, also fails to inhibit the growth promotion activity of C/EBPbeta-LIP. Down-regulation of CaM in livers of LPS-treated mice causes liver proliferation via activation of C/EBPbeta-LIP. Overexpression of C/EBPbeta-LIP above levels of CaM also initiates liver proliferation in LPS-treated mice. In addition, CaM regulates transcriptional activity of another isoform of C/EBPbeta, C/EBPbeta-LAP, and might control liver biology through the regulation of both isoforms of C/EBPbeta. In searching for molecular mechanisms by which C/EBPbeta-LIP promotes cell proliferation, we found that C/EBPbeta-LIP releases E2F.Rb-dependent repression of cell cycle genes by a disruption of E2F1.Rb complexes and by a direct interaction with E2F-dependent promoters. CaM inhibits these growth promotion activities of C/EBPbeta-LIP and, therefore, supports liver quiescence. Thus, our findings discover a new pathway of the regulation of liver proliferation that involves calcium-CaM signaling.
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Affiliation(s)
- Daniel Orellana
- Huffington Center on Aging and Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
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Abstract
Alcoholic liver disease and non-alcoholic liver disease share a similar histological spectrum that starts with 'simple' steatosis, and may be accompanied by inflammation. Alcoholic steatohepatitis and non-alcoholic steatohepatitis (NASH) are progressive forms of alcoholic liver disease and non-alcoholic liver disease, respectively, and can evolve into cirrhosis. The currently accepted minimum diagnostic criteria for steatohepatitis include steatosis, lobular inflammation and hepatocellular injury, but not fibrosis. Steatosis involving more than 5% of hepatocytes is required for the diagnosis of non-alcoholic fatty liver disease, but is not necessary for the diagnosis of alcoholic liver disease. Lobular inflammation is usually mild and frequently consists of a mixed, acute and chronic, inflammatory cell infiltrate composed of neutrophils and mononuclear cells. The presence of large numbers of neutrophils favors an alcoholic etiology. Hepatocellular injury in fatty liver disease usually occurs in the form of ballooning, but it can also present as apoptotic (acidophilic) bodies and lytic necrosis. The characteristic pattern of fibrosis in non-cirrhotic steatohepatitis is pericellular/perisinusoidal and is the result of deposition of collagen in the space of Disse. In both alcoholic steatohepatitis and NASH, sinusoidal collagen formation is the result of hepatic stellate cell activation that, in NASH, has been correlated with the grade of steatosis and fibrosis.
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Affiliation(s)
- D G Tiniakos
- Laboratory of Histology & Embryology, Medical School, University of Athens, 75, M. Asias street, Goudi, 11527 Athens, Greece.
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Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab 2009; 20:171-6. [PMID: 19359195 DOI: 10.1016/j.tem.2009.01.005] [Citation(s) in RCA: 159] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Revised: 01/14/2009] [Accepted: 01/15/2009] [Indexed: 12/12/2022]
Abstract
The loss of regenerative capacity is the most dramatic age-associated alteration in the liver. Although this phenomenon was reported over 50 years ago, the molecular basis for the loss of regenerative capacity of aged livers has not been fully elucidated. Aging causes alterations of several signal-transduction pathways and changes in the expression of CCAAT/enhancer-binding protein (C/EBP) and chromatin-remodeling proteins. Consequently, aging livers accumulate a multi-protein C/EBPalpha-Brm-HDAC1 complex that occupies and silences E2F-dependent promoters, reducing the regenerative capacity of livers in older mice. Recent studies have provided evidence for the crucial role of epigenetic silencing in the age-dependent inhibition of liver proliferation. This review focuses on mechanisms of age-dependent inhibition of liver proliferation and approaches for correcting liver regeneration in the elderly.
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Affiliation(s)
- Nikolai A Timchenko
- Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
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28
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Abstract
Alcoholic liver disease still represents an important cause for death and disability in most well-developed countries and is becoming a leading cause of disease in developing countries. It is now increasingly clear that, besides the formation of acetaldehyde, alcohol effects on the liver include oxidative stress, disturbances in methionine metabolism, endoplasmic reticulum stress, inflammatory/immune responses and adipokine imbalances. This article will discuss the most recent findings on the mechanisms by which alcohol abuse causes hepatic steatosis and steatohepatitis, and now it contributes to the progression of fibrosis. Although still incomplete, these data shed new light on the multifactorial pathogenesis of alcoholic liver disease and open new possibilities in the understanding of how gender and genetic factors can influence disease progression.
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Affiliation(s)
- Emanuele Albano
- Department of Medical Science, University Amedeo Avogadro of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
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Kawaratani H, Tsujimoto T, Kitazawa T, Kitade M, Yoshiji H, Uemura M, Fukui H. Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet. World J Gastroenterol 2008; 14:6655-61. [PMID: 19034968 PMCID: PMC2773307 DOI: 10.3748/wjg.14.6655] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the innate immune reactivity of tumor necrosis factor-alpha (TNF-α), Toll-like receptor 4 (TLR4), and CD14 in the liver of non-alcoholic steatohepatitis (NASH) model rats.
METHODS: Male F344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet. The rats were killed after 4 or 8 wk of the diet, and their livers were removed for immunohistochemical investigation and RNA extraction. The liver specimens were immunostained for TNF-α, TLR4, and CD14. The gene expressions of TNF-α, TLR4, and CD14 were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). Kupffer cells were isolated from the liver by Percoll gradient centrifugation, and were then cultured to measure TNF-α production.
RESULTS: The serum and liver levels of TNF-α in the CDAA-fed rats increased significantly as compared with the control group, as did the immunohistochemical values and gene expressions of TNF-α, TLR4, and CD14 with the progression of steatohepatitis. TNF-α production from the isolated Kupffer cells of the CDAA-fed rats was elevated by lipopolysaccharide stimulation.
CONCLUSION: The expressions of TNF-α, TLR4, and CD14 increased in the NASH model, suggesting that TLR4 and CD14-mediated endotoxin liver damage may also occur in NASH.
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Spahr L, Lambert JF, Rubbia-Brandt L, Chalandon Y, Frossard JL, Giostra E, Hadengue A. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology 2008; 48:221-9. [PMID: 18537187 DOI: 10.1002/hep.22317] [Citation(s) in RCA: 176] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED Liver failure is the major cause of death in alcoholic steatohepatitis (ASH). In experimental hepatitis, granulocyte-colony stimulating factor (G-CSF) mobilizes hematopoietic stem cells, induces liver regeneration, and improves survival. We studied the short-term effects of G-CSF on CD34+ stem cell mobilization, liver cell proliferation, and liver function in patients with ASH. Twenty-four patients (mean age 54 years) with alcoholic cirrhosis [Child-Turcotte-Pugh score 10 (7-12)] and concomitant biopsy-proven ASH [Maddrey score 36 (21-60)] were randomized to standard care associated with 5 days of G-CSF (10 microg/kg/day, group A, n = 13) or standard care alone (group B, n = 11). Serial measurement of CD34+ cells, liver tests, cytokines [hepatocyte growth factor (HGF); tumor necrosis factor alpha; tumor necrosis factor-R1; interleukin-6; alfa-fetoprotein], and (13)C-aminopyrine breath tests were performed. Proliferating hepatic progenitor cells [HPC; double immunostaining (Ki67/cytokeratin 7)], histology, and neutrophils were assessed on baseline and day 7 biopsies. Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry. G-CSF was well tolerated. At day 7, both CD34+ cells (+747% versus -6%, P < 0.003), and HGF (+212% versus -7%, P < 0.03) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups. On repeat biopsy, a >50% increase in proliferating HPC was more frequent in group A than in group B (11 versus 2, P < 0.003). Changes in Ki67+/cytokeratin 7+ cells correlated with changes in CD34+ cells (r = 0.65, P < 0.03). Neutrophils and histological changes were similar in both groups. CONCLUSION G-CSF mobilizes CD34+ cells, increases HGF, and induces HPC to proliferate within 7 days of administration. Larger trials would be required to determine whether these changes translate into improved liver function.
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Affiliation(s)
- Laurent Spahr
- Department of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland.
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31
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Jung Y, Brown KD, Witek RP, Omenetti A, Yang L, Vandongen M, Milton RJ, Hines IN, Rippe RA, Spahr L, Rubbia–Brandt L, Diehl AM. Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans. Gastroenterology 2008; 134:1532-43. [PMID: 18471524 PMCID: PMC3611332 DOI: 10.1053/j.gastro.2008.02.022] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2007] [Accepted: 01/31/2008] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Improving outcomes in alcoholic liver disease (ALD) necessitates better understanding of how habitual ethanol (EtOH) consumption alters normal regenerative mechanisms within the liver. Hedgehog (Hh) pathway activation promotes expansion of progenitor populations in other tissues. We evaluated the hypothesis that chronic EtOH exposure activates Hh signaling in liver. METHODS Hh signaling, liver progenitors, transforming growth factor (TGF)-beta induction, and liver damage were compared in mice fed chow, high-fat diets (HF), or HF + EtOH for 4 weeks. Susceptibility to TGF-beta-mediated apoptosis was compared in Hh-responsive liver cells (eg, immature cholangiocytes and oval cells) and mature hepatocytes (which are unresponsive to Hh). Hepatic accumulation of Hh-responsive cells were compared in controls and ALD patients and correlated with a discriminant function (DF) that predicts subacute mortality. RESULTS Hh signaling and numbers of Hh-responsive cells were increased in HF mice and greatest in HF+EtOH mice. In both, progenitor and stromal cell populations harbored Hh-responsive cells. More ductular-type progenitors and fibrosis markers were noted in HF+EtOH mice than in HF mice. The former also expressed more TGF-beta-1. TGF-beta-1 treatment selectively promoted the viability of Hh-responsive immature liver cells and caused mature hepatocytes that survived to produce Hh ligands. Hh-responsive cells were increased in ALD patients. Lobular accumulation of Hh-responsive immature ductular cells was greater in those with a DF >32 than those with a DF <32. CONCLUSIONS Hh signaling is increased in ALD and may influence ALD outcomes by promoting hepatic accumulation of immature ductular cells.
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Affiliation(s)
- Youngmi Jung
- Department of Medicine, Duke University, Durham, North Carolina
| | - Kevin D. Brown
- Department of Medicine, Duke University, Durham, North Carolina
| | - Rafal P. Witek
- Department of Medicine, Duke University, Durham, North Carolina
| | | | - Liu Yang
- Department of Medicine, Duke University, Durham, North Carolina
| | | | - Richard J. Milton
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Ian N. Hines
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Richard A. Rippe
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | | | | | - Anna Mae Diehl
- Department of Medicine, Duke University, Durham, North Carolina
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Pritchard MT, McMullen MR, Edward Medof M, Stavitsky A, Nagy LE. Role of Complement in Ethanol-Induced Liver Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008. [DOI: 10.1007/978-0-387-78952-1_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Abstract
Alcohol excess is associated with a spectrum of disease ranging from simple steatosis through steatohepatitis to cirrhosis and, in some, hepatocellular carcinoma. Alcoholic steatohepatitis itself has a variable histological picture, but a constant feature is the presence of ballooning degeneration of hepatocytes. Recent studies have emphasized the importance of apoptosis as a mechanism of cell death in this condition. It is accompanied by varying degrees of perivenular, centrilobular, and pericellular fibrosis. When severe and associated with perivenular liver cell necrosis (central sclerosing hyaline necrosis), there may be precirrhotic portal hypertension. The pattern of fibrosis may initially be diffuse with little nodule formation, but in time there is frequently the development of a micronodular cirrhosis. In approximately 15% of patients with established cirrhosis, hepatocellular carcinoma develops; several precursor lesions are now recognized which can be detected histologically. Several authors have drawn attention to additional components of the spectrum of alcoholic liver disease, including vascular changes, portal tract inflammation and fibrosis, ductular reaction, and iron overload. The morphology of alcoholic liver disease can be significantly affected by abstinence; furthermore, the clinical and morphological phenotype can be significantly influenced by the presence of comorbid conditions such as nonalcoholic fatty liver disease or viral hepatitis. Biopsy appearances can provide important prognostic information in alcoholic liver disease, and this review incorporates a proposed grading and staging schema for assessment of histological severity.
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Affiliation(s)
- William W Yip
- Department of Pathology, Alice Ho Miu Ling Nethersole Hospital, Tai Po, New Territories, Hong Kong
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Abstract
PURPOSE OF REVIEW To apprise the reader of advances in 2005 in the epidemiology, pathogenesis, prognosis and treatment of alcoholic liver disease. Alcohol use has declined in developed countries, but the opposite is true elsewhere; alcoholic liver disease is a considerable burden worldwide. RECENT FINDINGS Genetic mechanisms for alcoholic liver disease are being discovered in addition to aggravating cofactors, such as hepatitis C, obesity and iron overload, and ameliorating ones, like coffee and tea drinking. The involvement of the innate immune system and the mechanisms of apoptosis in alcoholic liver disease are better appreciated, especially the emerging role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Steroid use and nutrition for alcoholic hepatitis are being refined, and the validity of the model for end-stage liver disease (MELD) score in predicting the outcome of alcoholic liver disease is upheld. Recidivism after liver transplantation for alcoholic liver disease adversely impacts long-term survival. SUMMARY Inroads are being made into the genetics of alcoholic liver disease and new phenomena are being uncovered in its pathogenesis, but safe and effective therapies for both alcoholic hepatitis and alcoholic cirrhosis are still wanting.
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Affiliation(s)
- Adrian Reuben
- Liver Service, Division of Gastroenterology/Hepatology and Liver Transplant Program, Medical University of South Carolina, Charleston, 29425, USA.
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35
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McKillop IH, Schrum LW. Alcohol and liver cancer. Alcohol 2005; 35:195-203. [PMID: 16054981 DOI: 10.1016/j.alcohol.2005.04.004] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2005] [Revised: 04/20/2005] [Accepted: 04/20/2005] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.
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Affiliation(s)
- Iain H McKillop
- Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
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