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Rabelo ACS, Andrade AKDL, Costa DC. The Role of Oxidative Stress in Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Preclinical Studies. Nutrients 2024; 16:1174. [PMID: 38674865 PMCID: PMC11055095 DOI: 10.3390/nu16081174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/05/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Alcoholic Fatty Liver Disease (AFLD) is characterized by the accumulation of lipids in liver cells owing to the metabolism of ethanol. This process leads to a decrease in the NAD+/NADH ratio and the generation of reactive oxygen species. A systematic review and meta-analysis were conducted to investigate the role of oxidative stress in AFLD. A total of 201 eligible manuscripts were included, which revealed that animals with AFLD exhibited elevated expression of CYP2E1, decreased enzymatic activity of antioxidant enzymes, and reduced levels of the transcription factor Nrf2, which plays a pivotal role in the synthesis of antioxidant enzymes. Furthermore, animals with AFLD exhibited increased levels of lipid peroxidation markers and carbonylated proteins, collectively contributing to a weakened antioxidant defense and increased oxidative damage. The liver damage in AFLD was supported by significantly higher activity of alanine and aspartate aminotransferase enzymes. Moreover, animals with AFLD had increased levels of triacylglycerol in the serum and liver, likely due to reduced fatty acid metabolism caused by decreased PPAR-α expression, which is responsible for fatty acid oxidation, and increased expression of SREBP-1c, which is involved in fatty acid synthesis. With regard to inflammation, animals with AFLD exhibited elevated levels of pro-inflammatory cytokines, including TNF-a, IL-1β, and IL-6. The heightened oxidative stress, along with inflammation, led to an upregulation of cell death markers, such as caspase-3, and an increased Bax/Bcl-2 ratio. Overall, the findings of the review and meta-analysis indicate that ethanol metabolism reduces important markers of antioxidant defense while increasing inflammatory and apoptotic markers, thereby contributing to the development of AFLD.
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Affiliation(s)
- Ana Carolina Silveira Rabelo
- Postgraduate Program in Biological Sciences, Federal University of Ouro Preto, Ouro Preto 35402-163, Brazil
- Department of Biochemistry, Federal University of Alfenas, Alfenas 37130-001, Brazil
| | | | - Daniela Caldeira Costa
- Postgraduate Program in Biological Sciences, Federal University of Ouro Preto, Ouro Preto 35402-163, Brazil
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Huang J, Huang T, Li J. Regulation Mechanism and Potential Value of Active Substances in Spices in Alcohol-Liver-Intestine Axis Health. Int J Mol Sci 2024; 25:3728. [PMID: 38612538 PMCID: PMC11011869 DOI: 10.3390/ijms25073728] [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: 01/23/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Excessive alcohol intake will aggravate the health risk between the liver and intestine and affect the multi-directional information exchange of metabolites between host cells and microbial communities. Because of the side effects of clinical drugs, people tend to explore the intervention value of natural drugs on diseases. As a flavor substance, spices have been proven to have medicinal value, but they are still rare in treating hepatointestinal diseases caused by alcohol. This paper summarized the metabolic transformation of alcohol in the liver and intestine and summarized the potential value of various perfume active substances in improving liver and intestine diseases caused by alcohol. It is also found that bioactive substances in spices can exert antioxidant activity in the liver and intestine environment and reduce the oxidative stress caused by diseases. These substances can interfere with fatty acid synthesis, promote sugar and lipid metabolism, and reduce liver injury caused by steatosis. They can effectively regulate the balance of intestinal flora, promote the production of SCFAs, and restore the intestinal microenvironment.
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Affiliation(s)
- Jianyu Huang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China;
- College of Food and Pharmaceutical Science, Ningbo University, Ningbo 315211, China
| | - Tao Huang
- College of Food and Pharmaceutical Science, Ningbo University, Ningbo 315211, China
| | - Jinjun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China;
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Subramaiyam N. Insights of mitochondrial involvement in alcoholic fatty liver disease. J Cell Physiol 2023; 238:2175-2190. [PMID: 37642259 DOI: 10.1002/jcp.31100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/31/2023] [Accepted: 08/04/2023] [Indexed: 08/31/2023]
Abstract
Alcoholic liver disease (ALD) is a global concern affecting most of the population and leading to the development of end-stage liver disease. Metabolic alterations due to increased alcohol consumption surge the hepatic accumulation of lipids and develop into a severe form of alcoholic steatohepatitis (ASH), depending on age and the consumption rate. The mitochondria in the hepatocyte actively regulate metabolic homeostasis and are disrupted in ALD pathogenesis. The increased NADH upon ethanol metabolism inhibits the mitochondrial oxidation of fatty acids, alters oxidative phosphorylation, and favors de novo lipogenesis. The higher mitochondrial respiration in early ALD increases free radical generation, whereas mitochondrial respiration is uncoupled in chronic ALD, affecting the cellular energy status. The defective glutathione importer due to excessive cholesterol loading and low adenosine triphosphate accounts for additional oxidative stress leading to hepatocyte apoptosis. The defective mitochondrial transcription machinery and sirtuins function in ALD affect mitochondrial function and biogenesis. The metabolites of ethanol metabolism epigenetically alter the gene expression profile of hepatic cell populations by modulating the promoters and sirtuins, aiding hepatic fibrosis and inflammation. The defect in mitophagy increases the accumulation of megamitochondria in hepatocytes and attracts immune cells by releasing mitochondrial damage-associated molecular patterns to initiate hepatic inflammation and ASH progression. Thus, maintaining mitochondrial lipid homeostasis and antioxidant capacity pharmacologically could provide a better outcome for ALD management.
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Affiliation(s)
- Nithyananthan Subramaiyam
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Flores-Cotera LB, Chávez-Cabrera C, Martínez-Cárdenas A, Sánchez S, García-Flores OU. Deciphering the mechanism by which the yeast Phaffia rhodozyma responds adaptively to environmental, nutritional, and genetic cues. J Ind Microbiol Biotechnol 2021; 48:kuab048. [PMID: 34302341 PMCID: PMC8788774 DOI: 10.1093/jimb/kuab048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/16/2021] [Indexed: 11/13/2022]
Abstract
Phaffia rhodozyma is a basidiomycetous yeast that synthesizes astaxanthin (ASX), which is a powerful and highly valuable antioxidant carotenoid pigment. P. rhodozyma cells accrue ASX and gain an intense red-pink coloration when faced with stressful conditions such as nutrient limitations (e.g., nitrogen or copper), the presence of toxic substances (e.g., antimycin A), or are affected by mutations in the genes that are involved in nitrogen metabolism or respiration. Since cellular accrual of ASX occurs under a wide variety of conditions, this yeast represents a valuable model for studying the growth conditions that entail oxidative stress for yeast cells. Recently, we proposed that ASX synthesis can be largely induced by conditions that lead to reduction-oxidation (redox) imbalances, particularly the state of the NADH/NAD+ couple together with an oxidative environment. In this work, we review the multiple known conditions that elicit ASX synthesis expanding on the data that we formerly examined. When considered alongside the Mitchell's chemiosmotic hypothesis, the study served to rationalize the induction of ASX synthesis and other adaptive cellular processes under a much broader set of conditions. Our aim was to propose an underlying mechanism that explains how a broad range of divergent conditions converge to induce ASX synthesis in P. rhodozyma. The mechanism that links the induction of ASX synthesis with the occurrence of NADH/NAD+ imbalances may help in understanding how other organisms detect any of a broad array of stimuli or gene mutations, and then adaptively respond to activate numerous compensatory cellular processes.
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Affiliation(s)
- Luis B Flores-Cotera
- Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, México city 07360, México
| | - Cipriano Chávez-Cabrera
- Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, México city 07360, México
| | - Anahi Martínez-Cárdenas
- Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, México city 07360, México
| | - Sergio Sánchez
- Department of Molecular Biology and Biotechnology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México city 04510, México
| | - Oscar Ulises García-Flores
- Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, México city 07360, México
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CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload. Int J Mol Sci 2021; 22:ijms22158221. [PMID: 34360999 PMCID: PMC8348366 DOI: 10.3390/ijms22158221] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/09/2021] [Accepted: 07/13/2021] [Indexed: 02/08/2023] Open
Abstract
CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.
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Mas-Bargues C, Escrivá C, Dromant M, Borrás C, Viña J. Lipid peroxidation as measured by chromatographic determination of malondialdehyde. Human plasma reference values in health and disease. Arch Biochem Biophys 2021; 709:108941. [PMID: 34097903 DOI: 10.1016/j.abb.2021.108941] [Citation(s) in RCA: 151] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/12/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022]
Abstract
Free radicals and oxidants are involved in physiological signaling pathways, although an imbalance between pro-oxidant and anti-oxidant systems in favor of the former leads to major biomolecular damage. This is the so-called oxidative stress, a complex process that affects us all and is responsible for the development of many diseases. Lipids are very sensitive to oxidant attack and to-date, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE) and F2-isoprostane are the main biomarkers for lipid peroxidation assessment. They all derive from polyunsaturated fatty acids (PUFAs) either by enzyme-catalyzed reactions (physiological) or by non-enzyme reactions (pathological). The profile of PUFAs present in the tissue will determine the proportion of each biomarker. In this review we aim to discuss the proper method for MDA determination using HPLC. We also offer reference MDA values in humans in physiological and pathological conditions.
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Affiliation(s)
- Cristina Mas-Bargues
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES-ISCIII, INCLIVA, 46010, Valencia, Spain
| | - Consuelo Escrivá
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES-ISCIII, INCLIVA, 46010, Valencia, Spain
| | - Mar Dromant
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES-ISCIII, INCLIVA, 46010, Valencia, Spain
| | - Consuelo Borrás
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES-ISCIII, INCLIVA, 46010, Valencia, Spain
| | - José Viña
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES-ISCIII, INCLIVA, 46010, Valencia, Spain.
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Yu SCH, Hui JWY, Chong CCN, Chu CM, Cheung S, Wong J, Lee KF. Transarterial Ethanol Ablation for Small Hepatocellular Carcinoma (≤ 3 cm): A Comparative Study Versus Radiofrequency Ablation. Cardiovasc Intervent Radiol 2020; 43:732-739. [PMID: 32152720 DOI: 10.1007/s00270-020-02426-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/28/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE The objective was to evaluate the local treatment efficacy of transarterial ethanol ablation (TEA) as compared to radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC). MATERIALS AND METHODS This was a retrospective study between January 2005 and April 2017, in which the treatment outcomes of all patients who received either percutaneous TEA or RFA for HCC tumors of size ≤ 3 cm, of Child-Pugh grade A or B, received no prior treatment other than surgical resection, were compared. For TEA, a mixture of absolute ethanol and ethiodized oil at a proportion of 1:2 by volume was administered superselectively into the tumor via a microcatheter placed at the feeding arteries. The TEA group and the RFA group consisted of 68 consecutive patients (88 treated target tumors) and 129 consecutive patients (129 tumors), respectively. RESULTS Technical success was achieved in all the target tumors in both groups. Grade 3 complication (CIRSE Classification) of prolonged fever occurred in 3 cases with multi-focal and large tumors in the TEA group. There was no statistically significant difference in complete response rate between the TEA group (84/88 or 95.5%) and the RFA group (188/195 or 96.4%) (p = 0.7). Time to progression in the TEA group [median 11.9 months, interquartile range (IQR) 5.6-18 months] was not statistically different from that in the RFA group (median 9.5 months, IQR 3.5-18.7 months) (p = 0.773). CONCLUSION TEA could be an effective alternative of RFA for the local treatment of small HCC; it is especially valuable for tumors of unfavorable location.
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Affiliation(s)
- Simon Chun Ho Yu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR.
- Vascular and Interventional Radiology Foundation Clinical Science Center, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR.
| | - Joyce Wai Yi Hui
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
- Vascular and Interventional Radiology Foundation Clinical Science Center, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
| | - Charing Ching Ning Chong
- Department of Surgery, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
| | - Cheuk Man Chu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
- Vascular and Interventional Radiology Foundation Clinical Science Center, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
| | - Sunny Cheung
- Department of Surgery, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
| | - John Wong
- Department of Surgery, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
| | - Kit Fai Lee
- Department of Surgery, The Chinese University of Hong Kong, c/o Rm 2A061, 2/F, Main Clinical Block and Trauma Centre, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR
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Tamai M, Uchisawa H, Saito Y, Matsue H, Kawase M, Naraoka T, Tagawa YI. Acorbine, a Corbicula japonica-derived tripeptide containing non-proteinogenic amino acids, suppresses ethanol-induced liver injury. Biochem Biophys Res Commun 2020; 522:580-584. [PMID: 31784088 DOI: 10.1016/j.bbrc.2019.11.131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 11/20/2019] [Indexed: 10/25/2022]
Abstract
Since ancient times, Corbicula extract has been believed in Japan to have hepatoprotective effects, but it remains unclear whether these claims are true, and if so, which component is responsible for hepatoprotection. In this study, we showed that Corbicula extract exerted a protective effect against liver damage. Recent work identified acorbine (β-alanyl-ornithyl-ornithine), a novel tripeptide containing non-proteinogenic amino acids, in the extract of Corbicula japonica. Synthesized acorbine cured alcohol-induced liver damage in mice. In addition, acorbine purified from Corbicula extract exerted a protective effect against alcohol-induced hepatotoxicity in a culture liver model derived from mouse ES/iPS cells. Thus, acorbine is one of the components of Corbicula extract that protects hepatocytes against ethanol-induced death.
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Affiliation(s)
- Miho Tamai
- Faculty of Dental Medicine, Hokkaido University, Kita 13-jo, Nishi 7-chome, Kita-ku, Sapporo, 060-8586, Japan; School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa, 226-8501, Japan; Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa, 226-8501, Japan
| | - Hidemitsu Uchisawa
- Industrial Research Institute, Aomori Prefectural Industrial Technology Research Center, 221-10 Yamaguchi, Nogi, Aomori, 030-0142, Japan
| | - Yukari Saito
- Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa, 226-8501, Japan
| | - Hajime Matsue
- Aomori University of Health and Welfare, 58-1 Mase, Hamadate, Aomori, 030-8505, Japan
| | - Masaya Kawase
- Nagahama Institute of Bio-Science and Technology, 1266 Tamura-cho, Nagahama-shi, Shiga, 526-0829, Japan
| | - Tetsushi Naraoka
- Industrial Research Institute, Aomori Prefectural Industrial Technology Research Center, 221-10 Yamaguchi, Nogi, Aomori, 030-0142, Japan
| | - Yoh-Ichi Tagawa
- School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa, 226-8501, Japan; Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa, 226-8501, Japan.
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Zamani P, Oskuee RK, Atkin SL, Navashenaq JG, Sahebkar A. MicroRNAs as important regulators of the NLRP3 inflammasome. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2020; 150:50-61. [PMID: 31100298 DOI: 10.1016/j.pbiomolbio.2019.05.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 05/13/2019] [Indexed: 12/28/2022]
Abstract
Inflammasomes are a group of cytosolic multi-protein signaling complexes that regulate maturation of the interleukin (IL)-1 family cytokines IL-1β and IL-18 through activation of inflammatory caspase-1. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is the best characterized and consists of several key components that are assembled and activated in response to different endogenous and exogenous signals. The NLRP3 inflammasome is common to a number of human inflammatory diseases and its targeting may lead to novel anti-inflammatory therapy. NLRP3 inflammasome activation is tightly regulated by different mechanisms especially post-transcriptional modulation via microRNAs (miRNA). MicroRNAs are small endogenous noncoding RNAs that are 21-23 nucleotides in length and control the expression of various genes through binding to the 3'-untranslated regions of the respective mRNA and subsequent post-transcriptional regulation. MicroRNAs have recently been recognized as crucial regulators of the NLRP3 inflammasome. In this review, we summarize the current understanding of the role of miRNAs in the regulation of NLRP3 inflammasome complexes and their impact on the pathogenesis of inflammatory disease processes.
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Affiliation(s)
- Parvin Zamani
- Nanotechnology Research Center, Student Research Committee, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Kazemi Oskuee
- Targeted Drug Delivery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Heo MJ, Kim TH, You JS, Blaya D, Sancho-Bru P, Kim SG. Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression. Gut 2019; 68:708-720. [PMID: 29475852 PMCID: PMC6581021 DOI: 10.1136/gutjnl-2017-315123] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 01/29/2018] [Accepted: 01/31/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Alcoholic liver disease (ALD) is a leading cause of death among chronic liver diseases. However, its pathogenesis has not been completely established. MicroRNAs (miRNAs) are key contributors to liver diseases progression. This study investigated hepatocyte-abundant miRNAs dysregulated by ALD, its impact on hepatocyte injury and the underlying basis. DESIGN Alcoholic hepatitis (AH) human and animal liver samples and hepatocytes were used to assess miR-148a levels. Pre-miR-148a was delivered specifically to hepatocytes in vivo using lentivirus. Immunoblottings, luciferase reporter assays, chromatin immunoprecipitation and immunofluorescence assays were carried out in cell models. RESULTS The miRNA profile and PCR analyses enabled us to find substantial decrease of miR-148a in the liver of patients with AH. In mice subjected to Lieber-DeCarli alcohol diet or binge alcohol drinking, miR-148a levels were also markedly reduced. In cultured hepatocytes and mouse livers, alcohol exposure inhibited forkhead box protein O1 (FoxO1) expression, which correlated with miR-148a levels and significantly decreased in human AH specimens. FoxO1 was identified as a transcription factor for MIR148A transactivation. MiR-148a directly inhibited thioredoxin-interacting protein (TXNIP) expression. Consequently, treatment of hepatocytes with ethanol resulted in TXNIP overexpression, activating NLRP3 inflammasome and caspase-1-mediated pyroptosis. These events were reversed by miR-148a mimic or TXNIP small-interfering RNA transfection. Hepatocyte-specific delivery of miR-148a to mice abrogated alcohol-induced TXNIP overexpression and inflammasome activation, attenuating liver injury. CONCLUSION Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD.
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Affiliation(s)
- Mi Jeong Heo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Tae Hyun Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jueng Soo You
- Department of Biochemistry, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Delia Blaya
- Laboratory of Liver Cell Plasticity and Tissue Repair, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas (CIBERehd), Barcelona, Spain
| | - Pau Sancho-Bru
- Laboratory of Liver Cell Plasticity and Tissue Repair, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas (CIBERehd), Barcelona, Spain
| | - Sang Geon Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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11
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Bo LY, Pang JN, Song CL, Li TJ. Effect of the Plastein Reaction in Presence of Extrinsic Amino Acids on the Protective Activity of Casein Hydrolysate against Ethanol-Induced Damage in HHL-5 Cells. Foods 2019; 8:E112. [PMID: 30934930 PMCID: PMC6518021 DOI: 10.3390/foods8040112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 12/05/2022] Open
Abstract
Casein hydrolysates (CH) were prepared using papain and modified by the plastein reaction (CH-P) in the presence of extrinsic phenylalanine (CH-P-Phe) or tryptophan (CH-P-Trp). The in vitro protective activity of CH and its modified products against ethanol-induced damage in HHL-5 cells was investigated. The results showed that the modification by the plastein reaction reduced the amino group content of CH. However, the modification by the plastein reaction in the presence of extrinsic amino acids could enhance the antioxidant, proliferative, cell cycle arresting, and anti-apoptosis activity of CH. Biological activities of CH and its modified products in the HHL-5 cells varied depending on the hydrolysate concentration (1, 2, and 3 mg/mL) and treatment time (24, 48, and 72 h). Generally, higher biological activities were found after cell treatment with CH or its modified products at concentration of 2 mg/mL for 48 h compared to other treatments. In addition, CH modified in the presence of tryptophan (CH-P-Trp) showed higher biological activity than that modified in the presence of phenylalanine (CH-P-Phe). Based on the obtained results, it can be concluded that casein hydrolysates with enhanced biological activity and potential health benefits can be produced by papain and the plastein reaction with the incorporation of extrinsic amino acids.
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Affiliation(s)
- Li-Ying Bo
- College of Light Industry, Liaoning University, Shenyang 110036, China.
- Faculty of Food Quality and Safety, Qiqihar University, Qiqihar 161006, China.
| | - Jia-Nan Pang
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China.
| | - Chun-Li Song
- Faculty of Food Quality and Safety, Qiqihar University, Qiqihar 161006, China.
| | - Tie-Jing Li
- College of Light Industry, Liaoning University, Shenyang 110036, China.
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China.
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12
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Le Daré B, Victoni T, Bodin A, Vlach M, Vene E, Loyer P, Lagente V, Gicquel T. Ethanol upregulates the P2X7 purinergic receptor in human macrophages. Fundam Clin Pharmacol 2018; 33:63-74. [PMID: 30447168 DOI: 10.1111/fcp.12433] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 09/19/2018] [Accepted: 11/07/2018] [Indexed: 12/11/2022]
Abstract
Alcohol consumption is considered to be the third leading cause of death in the United States. In addition to its direct toxicity, ethanol has two contrasting effects on the immune system: the nucleotide oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is inhibited by acute ethanol exposure but activated by chronic ethanol exposure. Purinergic receptors (especially the P2X7 receptor) are able to activate the NLRP3 inflammasome and are involved in many ethanol-related diseases (such as gout, pulmonary fibrosis, alcoholic steatohepatitis, and certain cancers). We hypothesized that ethanol regulates purinergic receptors and thus modulates the NLRP3 inflammasome's activity. In experiments with monocyte-derived macrophages, we found that interleukin (IL)-1β secretion was inhibited after 7 h of exposure (but not 48 h of exposure) to ethanol. The disappearance of ethanol's inhibitory effect on IL-1β secretion after 48 h was not mediated by the upregulated production of IL-1β, IL-1α, IL-6 or the inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase 1. P2X7R expression was upregulated by ethanol, whereas expression of the P2X4 and P2X1 receptors was not. Taken as a whole, our results suggest that ethanol induces NLRP3 inflammasome activation by upregulating the P2X7 receptor. This observation might have revealed a new mechanism for inflammation in ethanol-related diseases.
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Affiliation(s)
- Brendan Le Daré
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France.,Pharmacy Service, Pontchaillou University Hospital, F-35000, Rennes, France
| | - Tatiana Victoni
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France
| | - Aude Bodin
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France
| | - Manuel Vlach
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France
| | - Elise Vene
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France
| | - Pascal Loyer
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France
| | - Vincent Lagente
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France
| | - Thomas Gicquel
- INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France.,Forensic and Toxicology Laboratory, Pontchaillou University Hospital, F-35000, Rennes, France
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13
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Qinna NA, Ghanim BY. Chemical induction of hepatic apoptosis in rodents. J Appl Toxicol 2018; 39:178-190. [PMID: 30350376 DOI: 10.1002/jat.3740] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Accepted: 09/13/2018] [Indexed: 12/13/2022]
Abstract
The urge of identifying new pharmacological interventions to prevent or attenuate liver injury is of critical importance and needs an expanded experimental toolbox. Hepatocyte injury and cellular death is a prominent feature behind the pathology of liver diseases. Several research activities focused on identifying chemicals and hepatotoxicants that induce cell death by apoptosis, in addition to presenting its corresponding signaling pathway. Although such efforts provided further understanding of the mechanisms of cell death, it has also raised confusion concerning identifying the involvement of several modes of cell death including apoptosis, necrosis and fibrosis. The current review highlights the ability of several chemicals and potential hepatotoxicants to induce liver damage in rodents by means of apoptosis while the probable involvement of other modes of cell death is also exposed. Thus, several chemical substances including hepatotoxins, mycotoxins, hyperglycemia inducers, metallic nanoparticles and immunosuppressant drugs are reviewed to explore the hepatic cytotoxic spectrum they could exert on hepatocytes of rodents. In addition, the current review address the mechanism by which hepatotoxicity is initiated in hepatocytes in different rodents aiding the researcher in choosing the right animal model for a better research outcome.
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Affiliation(s)
- Nidal A Qinna
- University of Petra Pharmaceutical Center (UPPC), Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Bayan Y Ghanim
- University of Petra Pharmaceutical Center (UPPC), Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
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14
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Fernandes LMP, Lopes KS, Santana LNS, Fontes-Júnior EA, Ribeiro CHMA, Silva MCF, de Oliveira Paraense RS, Crespo-López ME, Gomes ARQ, Lima RR, Monteiro MC, Maia CSF. Repeated Cycles of Binge-Like Ethanol Intake in Adolescent Female Rats Induce Motor Function Impairment and Oxidative Damage in Motor Cortex and Liver, but Not in Blood. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3467531. [PMID: 30327712 PMCID: PMC6169231 DOI: 10.1155/2018/3467531] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 07/25/2018] [Accepted: 08/07/2018] [Indexed: 01/11/2023]
Abstract
Moderate ethanol consumption (MEC) is increasing among women. Alcohol exposure usually starts in adolescence and tends to continue until adulthood. We aimed to investigate MEC impacts during adolescence until young adulthood of female rats. Adolescent female Wistar rats received distilled water or ethanol (3 g/kg/day), in a 3 days on-4 days off paradigm (binge drinking) for 1 and 4 consecutive weeks. We evaluate liver and brain oxidative damage, peripheral oxidative parameters by SOD, catalase, thiol contents, and MDA, and behavioral motor function by open-field, pole, beam-walking, and rotarod tests. Our results revealed that repeated episodes of binge drinking during adolescence displayed lipid peroxidation in the liver and brain. Surprisingly, such oxidative damage was not detectable on blood. Besides, harmful histological effects were observed in the liver, associated to steatosis and loss of parenchymal architecture. In addition, ethanol intake elicited motor incoordination, bradykinesia, and reduced spontaneous exploratory behavior in female rats.
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Affiliation(s)
- Luanna Melo Pereira Fernandes
- Laboratory of Pharmacology of Inflammation and Behavior, Faculty of Pharmacy, Institute of Health Science, Federal University of Pará, Belém, PA, Brazil
| | - Klaylton Sousa Lopes
- Laboratory of Pharmacology of Inflammation and Behavior, Faculty of Pharmacy, Institute of Health Science, Federal University of Pará, Belém, PA, Brazil
| | - Luana Nazaré Silva Santana
- Laboratory of Pharmacology of Inflammation and Behavior, Faculty of Pharmacy, Institute of Health Science, Federal University of Pará, Belém, PA, Brazil
| | - Enéas Andrade Fontes-Júnior
- Laboratory of Pharmacology of Inflammation and Behavior, Faculty of Pharmacy, Institute of Health Science, Federal University of Pará, Belém, PA, Brazil
| | | | | | | | - Maria Elena Crespo-López
- Laboratory of Molecular Pharmacology, Institute of Biological Sciences, Federal University of Pará, Belém PA, Brazil
| | - Antônio Rafael Quadros Gomes
- Laboratory of Microbiology and Immunology of Teaching and Research, Pharmacy Faculty, Institute of Health Science, Federal University of Pará, Belém PA, Brazil
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil
| | - Marta Chagas Monteiro
- Laboratory of Microbiology and Immunology of Teaching and Research, Pharmacy Faculty, Institute of Health Science, Federal University of Pará, Belém PA, Brazil
| | - Cristiane Socorro Ferraz Maia
- Laboratory of Pharmacology of Inflammation and Behavior, Faculty of Pharmacy, Institute of Health Science, Federal University of Pará, Belém, PA, Brazil
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15
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Martínez-Cárdenas A, Chávez-Cabrera C, Vasquez-Bahena JM, Flores-Cotera LB. A common mechanism explains the induction of aerobic fermentation and adaptive antioxidant response in Phaffia rhodozyma. Microb Cell Fact 2018; 17:53. [PMID: 29615045 PMCID: PMC5883411 DOI: 10.1186/s12934-018-0898-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 03/26/2018] [Indexed: 01/07/2023] Open
Abstract
Background Growth conditions that bring about stress on Phaffia rhodozyma cells encourage the synthesis of astaxanthin, an antioxidant carotenoid, which protects cells against oxidative damage. Using P. rhodozyma cultures performed with and without copper limitation, we examined the kinetics of astaxanthin synthesis along with the expression of asy, the key astaxanthin synthesis gene, as well as aox, which encodes an alternative oxidase protein. Results Copper deficiency had a detrimental effect on the rates of oxygen consumption and ethanol reassimilation at the diauxic shift. In contrast, copper deficiency prompted alcoholic fermentation under aerobic conditions and had a favorable effect on the astaxanthin content of cells, as well as on aox expression. Both cultures exhibited strong aox expression while consuming ethanol, but particularly when copper was absent. Conclusion We show that the induction of either astaxanthin production, aox expression, or aerobic fermentation exemplifies the crucial role that redox imbalance plays in triggering any of these phenomena. Based on our own results and data from others, we propose a mechanism that rationalizes the central role played by changes of respiratory activity, which lead to redox imbalances, in triggering both the short-term antioxidant response as well as fermentation in yeasts and other cell types.
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Affiliation(s)
- Anahí Martínez-Cárdenas
- Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Mexico City, Mexico
| | - Cipriano Chávez-Cabrera
- Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Mexico City, Mexico.,College of Science and Technology Studies of the State of Michoacán, Loma de las Liebres 180, Fraccionamiento Lomas del Sur, 58095, Morelia, Michoacán, Mexico
| | - Jazmín M Vasquez-Bahena
- Avi-mex Laboratory S.A de C.V, Trigo 169, Col. Granjas Esmeralda, 09810, Mexico City, Mexico
| | - Luis B Flores-Cotera
- Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Mexico City, Mexico.
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16
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Chen D, Chen F, Xu Y, Zhang Y, Li Z, Zhang H, Pan T, Su Y, Wan M, Wang X, Ye J. AKT2 deficiency induces retardation of myocyte development through EndoG-MEF2A signaling in mouse heart. Biochem Biophys Res Commun 2017; 493:1410-1417. [PMID: 28965945 DOI: 10.1016/j.bbrc.2017.09.149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Accepted: 09/27/2017] [Indexed: 10/18/2022]
Abstract
Protein kinase B2 (AKT2) is implicated in diverse process of cardiomyocyte signaling including survival and metabolism. However, the role of AKT2 in myocardium development and the signaling pathway is rarely understood. Therefore, we sought to determine the effect of AKT2 deletion on heart development and its downstream targets. By using experimental animal models and neonatal rat cardiomyocytes (NRCMs), we observed that AKT2 deficiency induces retardation of heart development and increased systemic blood pressure (BP) without affecting cardiac function. Further investigation suggested that deficiency of AKT2 in myocardium results in diminished MEF2A abundance, which induced decreased size of cardiomyocytes. We additionally confirmed that EndoG, which is also regulated by AKT2, is a suppressor of MEF2A in myocardium. Finally, our results proved that AKT2 deficiency impairs the response to β-adrenergic stimuli that normally causes hypertrophy in cardiomyocytes by downregulating MEF2A expression. Our data are the first to show the important role of AKT2 in determining the size of myocardium, its deficiency causes retardation of cardiomyocyte development. We also proved a novel pathway of heart development involving EndoG and MEF2A regulated by AKT2.
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Affiliation(s)
- Dandan Chen
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Fan Chen
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Yitao Xu
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China; Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK
| | - Yubin Zhang
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Zhe Li
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Han Zhang
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Tianshu Pan
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Yuheng Su
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Miyang Wan
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Xiaochuan Wang
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Junmei Ye
- State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China.
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17
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Parira T, Laverde A, Agudelo M. Epigenetic Interactions between Alcohol and Cannabinergic Effects: Focus on Histone Modification and DNA Methylation. JOURNAL OF ALCOHOLISM AND DRUG DEPENDENCE 2017; 5:259. [PMID: 28730160 PMCID: PMC5515243 DOI: 10.4172/2329-6488.1000259] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Epigenetic studies have led to a more profound understanding of the mechanisms involved in chronic conditions. In the case of alcohol addiction, according to the National Institute on Alcohol Abuse and Alcoholism, 16 million adults suffer from Alcohol Use Disorders (AUDs). Even though therapeutic interventions like behavioral therapy and medications to prevent relapse are currently available, no robust cure exists, which stems from the lack of understanding the mechanisms of action of alcohol and the lack of development of precision medicine approaches to treat AUDs. Another common group of addictive substance, cannabinoids, have been studied extensively to reveal they work through cannabinoid receptors. Therapeutic applications have been found for the cannabinoids and a deeper understanding of the endocannabinoid system has been gained over the years. Recent reports of cannabinergic mechanisms in AUDs has opened an exciting realm of research that seeks to elucidate the molecular mechanisms of alcohol-induced end organ diseases and hopefully provide insight into new therapeutic strategies for the treatment of AUDs. To date, several epigenetic mechanisms have been associated with alcohol and cannabinoids independently. Therefore, the scope of this review is to compile the most recent literature regarding alcohol and cannabinoids in terms of a possible epigenetic connection between the endocannabinoid system and alcohol effects. First, we will provide an overview of epigenetics, followed by an overview of alcohol and epigenetic mechanisms with an emphasis on histone modifications and DNA methylations. Then, we will provide an overview of cannabinoids and epigenetic mechanisms. Lastly, we will discuss evidence of interactions between alcohol and cannabinergic pathways and possible insights into the novel epigenetic mechanisms underlying alcohol-cannabinergic pathway activity. Finalizing the review will be a discussion of future directions and therapeutic applications.
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Affiliation(s)
- Tiyash Parira
- Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, FL 33199, USA
| | - Alejandra Laverde
- Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, FL 33199, USA
| | - Marisela Agudelo
- Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, FL 33199, USA
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18
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Wang S, Ni HM, Dorko K, Kumer SC, Schmitt TM, Nawabi A, Komatsu M, Huang H, Ding WX. Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury. Oncotarget 2017; 7:17681-98. [PMID: 26769846 PMCID: PMC4951242 DOI: 10.18632/oncotarget.6893] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 12/23/2015] [Indexed: 12/13/2022] Open
Abstract
Chronic alcohol exposure increased hepatic receptor-interacting protein kinase (RIP) 3 expression and necroptosis in the liver but its mechanisms are unclear. In the present study, we demonstrated that chronic alcohol feeding plus binge (Gao-binge) increased RIP3 but not RIP1 protein levels in mouse livers. RIP3 knockout mice had decreased serum alanine amino transferase activity and hepatic steatosis but had no effect on hepatic neutrophil infiltration compared with wild type mice after Gao-binge alcohol treatment. The hepatic mRNA levels of RIP3 did not change between Gao-binge and control mice, suggesting that alcohol-induced hepatic RIP3 proteins are regulated at the posttranslational level. We found that Gao-binge treatment decreased the levels of proteasome subunit alpha type-2 (PSMA2) and proteasome 26S subunit, ATPase 1 (PSMC1) and impaired hepatic proteasome function. Pharmacological or genetic inhibition of proteasome resulted in the accumulation of RIP3 in mouse livers. More importantly, human alcoholics had decreased expression of PSMA2 and PSMC1 but increased protein levels of RIP3 compared with healthy human livers. Moreover, pharmacological inhibition of RIP1 decreased Gao-binge-induced hepatic inflammation, neutrophil infiltration and NF-κB subunit (p65) nuclear translocation but failed to protect against steatosis and liver injury induced by Gao-binge alcohol. In conclusion, results from this study suggest that impaired hepatic proteasome function by alcohol exposure may contribute to hepatic accumulation of RIP3 resulting in necroptosis and steatosis while RIP1 kinase activity is important for alcohol-induced inflammation.
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Affiliation(s)
- Shaogui Wang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.,Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Kenneth Dorko
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Sean C Kumer
- Department of General Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Timothy M Schmitt
- Department of General Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Atta Nawabi
- Department of General Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Masaaki Komatsu
- Department of Biochemistry, School of Medicine Niigata University, Chuo-ku, Niigata 951-8510, Japan
| | - Heqing Huang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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19
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Yao L, Chen W, Han C, Wu T. Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1071-80. [PMID: 27102561 PMCID: PMC4935489 DOI: 10.1152/ajpgi.00327.2015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 04/17/2016] [Indexed: 01/31/2023]
Abstract
Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme for the synthesis of prostaglandin E2 (PGE2), a proproliferative and antiapoptotic lipid molecule important for tissue regeneration and injury repair. In this study, we developed transgenic (Tg) mice with targeted expression of mPGES-1 in the liver to assess Fas-induced hepatocyte apoptosis and acute liver injury. Compared with wild-type (WT) mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, less hepatic necrosis/apoptosis, and lower level of caspase cascade activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analysis revealed increased expression and activation of the serine/threonine kinase Akt and associated antiapoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling and suggest that induction of mPGES-1 or treatment with PGE2 may represent important therapeutic strategy for the prevention and treatment of Fas-associated liver injuries.
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Affiliation(s)
| | | | | | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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20
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miR-223 Deficiency Protects against Fas-Induced Hepatocyte Apoptosis and Liver Injury through Targeting Insulin-Like Growth Factor 1 Receptor. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 185:3141-51. [PMID: 26598234 DOI: 10.1016/j.ajpath.2015.08.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/21/2015] [Accepted: 08/06/2015] [Indexed: 01/26/2023]
Abstract
The biological functions and molecular mechanisms of miR-223 action in liver cells and liver diseases remain unclear. We therefore determined the effect and mechanism of action of miR-233 in Fas-induced hepatocyte apoptosis and liver injury. Wild-type (WT) and miR-223 knockout (KO) mice were treated i.p. with 0.5 μg/g body weight anti-Fas antibody Jo2, and the animals were monitored for survival and the extent of liver injury. Although WT mice died 4 to 6 hours after Jo2 injection (n = 6), all of the miR-223 KO mice (n = 6) survived. In comparison to WT mice, the miR-223 KO mice showed resistance to Fas-induced liver injury, as indicated by less tissue damage under histopathological examination, fewer apoptotic hepatocytes under caspase-3 immunostaining, and less elevation of serum transaminases. miR-223 KO livers showed less caspase-3, caspase-8, and caspase-9 activation and less poly (ADP-ribose) polymerase cleavage compared with WT livers (P < 0.05). Furthermore, tail vein injection of miR-223 lentiviral vector to miR-223 KO mice restored Jo2-induced liver injury. Transfection of miR-223 KO hepatocytes with miR-223 mimic enhanced Jo2-induced activation of caspase-3, caspase-8, and caspase-9, whereas transfection of WT hepatocytes with the miR-223 inhibitor attenuated Jo2-induced apoptosis. These findings demonstrate that miR-223 deficiency protects against Fas-induced hepatocyte apoptosis and liver injury. Further in vitro and in vivo data indicate that miR-223 regulates Fas-induced hepatocyte apoptosis and liver injury by targeting the insulin-like growth factor 1 receptor.
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21
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Chen W, Han C, Zhang J, Song K, Wang Y, Wu T. Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1033-44. [PMID: 25794705 DOI: 10.1016/j.ajpath.2014.12.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 11/29/2014] [Accepted: 12/09/2014] [Indexed: 12/12/2022]
Abstract
Fas-induced apoptosis is involved in diverse liver diseases. Herein, we investigated the effect of Mir155 deletion on Fas-induced liver injury. Wild-type (WT) mice and Mir155 knockout (KO) mice were i.p. administered with the anti-Fas antibody (Jo2) to determine animal survival and the extent of liver injury. After Jo2 injection, the Mir155 KO mice exhibited prolonged survival versus the WT mice (P < 0.01). The Mir155 KO mice showed lower alanine aminotransferase and aspartate aminotransferase levels, less liver tissue damage, fewer apoptotic hepatocytes, and lower liver tissue caspase 3/7, 8, and 9 activities compared with the WT mice, indicating that Mir155 deletion prevents Fas-induced hepatocyte apoptosis and liver injury. Hepatocytes isolated from Mir155 KO mice also showed resistance to Fas-induced apoptosis, in vitro. Higher protein level of myeloid cell leukemia-1 (Mcl-1) was also observed in Mir155 KO hepatocytes compared to WT hepatocytes. A miR-155 binding site was identified in the 3'-untranslated region of Mcl-1 mRNA; Mcl1 was identified as a direct target of miR-155 in hepatocytes. Consistently, pretreatment with a siRNA specific for Mcl1 reversed Mir155 deletion-mediated protection against Jo2-induced liver tissue damage. Finally, restoration of Mir155 expression in Mir155 KO mice abolished the protection against Fas-induced hepatocyte apoptosis. Taken together, these findings demonstrate that deletion of Mir155 prevents Fas-induced hepatocyte apoptosis and liver injury through the up-regulation of Mcl1.
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Affiliation(s)
- Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Ying Wang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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22
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Ma Z, Hou T, Shi W, Liu W, He H. Inhibition of Hepatocyte Apoptosis: An Important Mechanism of Corn Peptides Attenuating Liver Injury Induced by Ethanol. Int J Mol Sci 2015; 16:22062-80. [PMID: 26378531 PMCID: PMC4613297 DOI: 10.3390/ijms160922062] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 09/01/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023] Open
Abstract
In this study, the effects of mixed corn peptides and synthetic pentapeptide (QLLPF) on hepatocyte apoptosis induced by ethanol were investigated in vivo. QLLPF, was previously characterized from corn protein hydrolysis, which had been shown to exert good facilitating alcohol metabolism activity. Mice were pre-treated with the mixed corn peptides and the pentapeptide for 1 week and then treated with ethanol. After treatment of three weeks, the biochemical indices and the key ethanol metabolizing enzymes, the serum TNF-α, liver TGF-β1 concentrations and the protein expressions related to apoptosis were determined. We found that the Bcl-2, Bax and cytochrome c expressions in the intrinsic pathway and the Fas, FasL and NF-κB expressions in the extrinsic pathway together with higher TNF-α and TGF-β1 concentrations were reversed compared with the model group by both the mixed corn peptides and the pentapeptide. The activation of caspase3 was also suppressed. Additionally, apoptosis was further confirmed with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and the TUNEL assay demonstrated peptides suppressed hepatocyte apoptosis. Our results suggest that apoptosis induced by ethanol is alleviated in response to the treatment of corn peptides, potentially due to reversing the related protein expression.
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Affiliation(s)
- Zhili Ma
- College of Food Science and Technology, Huazhong Agricultural University & Key Laboratory of Environment Correlative Dietology, Ministry of Education, Wuhan 430070, China.
| | - Tao Hou
- College of Food Science and Technology, Huazhong Agricultural University & Key Laboratory of Environment Correlative Dietology, Ministry of Education, Wuhan 430070, China.
| | - Wen Shi
- College of Food Science and Technology, Huazhong Agricultural University & Key Laboratory of Environment Correlative Dietology, Ministry of Education, Wuhan 430070, China.
| | - Weiwei Liu
- College of Food Science and Technology, Huazhong Agricultural University & Key Laboratory of Environment Correlative Dietology, Ministry of Education, Wuhan 430070, China.
| | - Hui He
- College of Food Science and Technology, Huazhong Agricultural University & Key Laboratory of Environment Correlative Dietology, Ministry of Education, Wuhan 430070, China.
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Antitumoral gene-based strategy involving nitric oxide synthase type III overexpression in hepatocellular carcinoma. Gene Ther 2015; 23:67-77. [PMID: 26204498 DOI: 10.1038/gt.2015.79] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 06/14/2015] [Accepted: 07/16/2015] [Indexed: 11/09/2022]
Abstract
Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoblastoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. The first-generation adenoviruses were designed to overexpress NOS-3 or green fluorescent protein, and luciferase complementary DNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenovirus and Hepa 1-6 cells were used for in vitro and in vivo experiments. Adenoviruses were administered through the tail vein 2 weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8, -9 and -3 activities in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by Nω-nitro-l-arginine methyl ester hydrochloride, p53 and CD95 small interfering RNA. AFP-NOS-3/RSV-luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.
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Chen W, Han C, Zhang J, Song K, Wang Y, Wu T. miR-150 Deficiency Protects against FAS-Induced Acute Liver Injury in Mice through Regulation of AKT. PLoS One 2015. [PMID: 26196694 PMCID: PMC4510058 DOI: 10.1371/journal.pone.0132734] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Although miR-150 is implicated in the regulation of immune cell differentiation and activation, it remains unknown whether miR-150 is involved in liver biology and disease. This study was performed to explore the potential role of miR-150 in LPS/D-GalN and Fas-induced liver injuries by using wild type and miR-150 knockout (KO) mice. Whereas knockout of miR-150 did not significantly alter LPS/D-GalN-induced animal death and liver injury, it protected against Fas-induced liver injury and mortality. The Jo2-induced increase in serum transaminases, apoptotic hepatocytes, PARP cleavage, as well as caspase-3/7, caspase-8, and caspase-9 activities were significantly attenuated in miR-150 KO mice. The liver tissues from Jo2-treated miR-150 KO mice expressed higher levels of Akt1, Akt2, total Akt, as well as p-Akt(Ser473) compared to the wild type livers. Pretreatment with the Akt inhibitor V reversed Jo2-induced liver injury in miR-150 KO mice. The primary hepatocytes isolated from miR-150 KO mice also showed protection against Fas-induced apoptosis in vitro (characterized by less prominent PARP cleavage, less nuclear fragmentation and less caspase activation) in comparison to hepatocytes from wild type mice. Luciferase reporter assays in hepatocytes transfected with the Akt1 or Akt2 3’-UTR reporter constructs (with or without mutation of miR-150 binding site) established Akt1 and Akt2 as direct targets of miR-150. Tail vein injection of lentiviral particles containing pre-miR-150 enhanced Jo2-induced liver injury in miR-150 KO mice. These findings demonstrate that miR-150 deficiency prevents Fas-induced hepatocyte apoptosis and liver injury through regulation of the Akt pathway.
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Affiliation(s)
- Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
| | - Ying Wang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
- Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine,1430 Tulane Avenue SL-79, New Orleans, Louisiana, United States of America
- * E-mail:
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Ma X, Han S, Zhang W, Fan YJ, Liu MN, Liu AY, Liu BR. Protection of cultured human hepatocytes from hydrogen peroxide‑induced apoptosis by relaxin‑3. Mol Med Rep 2014; 11:1228-34. [PMID: 25370004 DOI: 10.3892/mmr.2014.2842] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 10/01/2014] [Indexed: 11/06/2022] Open
Abstract
Previous studies have suggested that hepatocyte apoptosis may be a fundamental underlying mechanism of liver injury and diseases, such as liver fibrosis. Relaxin‑3 has been reported to have anti‑fibrotic actions in the heart and to attenuate isoproterenol‑induced myocardial injury; however, the beneficial role of relaxin‑3 on hepatocyte apoptosis remains to be elucidated. The aim of the present study was to explore the role and possible mechanisms of relaxin‑3 through hydrogen peroxide (H2O2)‑induced apoptosis in primary human hepatocytes. Cells were treated with relaxin‑3 and then cell viability, morphological features, the presence of cleaved caspases as well as the levels of endoplasmic reticulum stress (ERS) protein markers and autophagy markers were evaluated. The H2O2 group showed significantly decreased cell viability, increased apoptosis as well as upregulation of caspases (cleaved caspase‑3, ‑8 and ‑9) and ERS protein markers compared with those of the control group. However, cells treated with relaxin‑3 (10 ng/ml) demonstrated improved cell viability, reduced apoptosis and decreased expression of cleaved caspases and ERS markers. However, the expression of autophagy markers remained unchanged following H2O2‑induced apoptosis and relaxin‑3 treatment. In conclusion, relaxin‑3 was shown to protect hepatocytes from H2O2‑induced apoptosis via downregulation of cleaved caspase‑8 and ‑9, as well as inhibition of the ERS pathway.
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Affiliation(s)
- Xiao Ma
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Su Han
- Department of Microbiology and Parasitology, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Wei Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yu-Jing Fan
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Ming-Na Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Ai-Yun Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Bing-Rong Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 2014; 20:12908-12933. [PMID: 25278688 PMCID: PMC4177473 DOI: 10.3748/wjg.v20.i36.12908] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/07/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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Shayakhmetova GM, Bondarenko LB, Matvienko AV, Kovalenko VM. Chronic alcoholism-mediated metabolic disorders in albino rat testes. Interdiscip Toxicol 2014; 7:165-72. [PMID: 26109895 PMCID: PMC4434111 DOI: 10.2478/intox-2014-0023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 09/13/2014] [Accepted: 09/14/2014] [Indexed: 12/17/2022] Open
Abstract
There is good evidence for impairment of spermatogenesis and reductions in sperm counts and testosterone levels in chronic alcoholics. The mechanisms for these effects have not yet been studied in detail. The consequences of chronic alcohol consumption on the structure and/or metabolism of testis cell macromolecules require to be intensively investigated. The present work reports the effects of chronic alcoholism on contents of free amino acids, levels of cytochrome P450 3A2 (CYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and protein thiol groups in rat testes. Wistar albino male rats were divided into two groups: I - control (intact animals), II - chronic alcoholism (15% ethanol self-administration during 150 days). Following 150 days of alcohol consumption, testicular free amino acid content was found to be significantly changed as compared with control. The most profound changes were registered for contents of lysine (-53%) and methionine (+133%). The intensity of DNA fragmentation in alcohol-treated rat testes was considerably increased, on the contrary CYP3A2 mRNA expression in testis cells was inhibited, testicular contents of total and etherified cholesterol increased by 25% and 45% respectively, and protein SH-groups decreased by 13%. Multidirectional changes of the activities of testicular dehydrogenases were detected. We thus obtained complex assessment of chronic alcoholism effects in male gonads, affecting especially amino acid, protein, ATP and NADPH metabolism. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed metabolic disorders can have negative implication on cellular regulation of spermatogenesis under long-term ethanol exposure.
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Affiliation(s)
- Ganna M Shayakhmetova
- General Toxicology Department, SI "Institute of Pharmacology & Toxicology", National Academy of Medical Sciences of Ukraine, Kyiv, 03680, Ukraine
| | - Larysa B Bondarenko
- General Toxicology Department, SI "Institute of Pharmacology & Toxicology", National Academy of Medical Sciences of Ukraine, Kyiv, 03680, Ukraine
| | - Anatoliy V Matvienko
- General Toxicology Department, SI "Institute of Pharmacology & Toxicology", National Academy of Medical Sciences of Ukraine, Kyiv, 03680, Ukraine
| | - Valentina M Kovalenko
- General Toxicology Department, SI "Institute of Pharmacology & Toxicology", National Academy of Medical Sciences of Ukraine, Kyiv, 03680, Ukraine
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Suzuki-Karasaki Y, Suzuki-Karasaki M, Uchida M, Ochiai T. Depolarization Controls TRAIL-Sensitization and Tumor-Selective Killing of Cancer Cells: Crosstalk with ROS. Front Oncol 2014; 4:128. [PMID: 24910845 PMCID: PMC4038927 DOI: 10.3389/fonc.2014.00128] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 05/14/2014] [Indexed: 01/22/2023] Open
Abstract
Conventional genotoxic anti-cancer drugs target the proliferative advantage of tumor cells over normal cells. This kind of approach lacks the selectivity of treatment to cancer cells, because most of the targeted pathways are essential for the survival of normal cells. As a result, traditional cancer treatments are often limited by undesirable damage to normal cells (side-effects). Ideal anti-cancer drugs are expected to be highly effective against malignant tumor cells with minimal cytotoxicity toward normal cells. Such selective killing can be achieved by targeting pathways essential for the survival of cancer cells, but not normal cells. As cancer cells are characterized by their resistance to apoptosis, selective apoptosis induction is a promising approach for selective killing of cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising tumor-selective anti-cancer drug. However, the congenital and acquired resistance of some cancer cell types, including malignant melanoma cells, currently impedes effective TRAIL therapy, and an innovative approach that can override TRAIL resistance is urgently required. Apoptosis is characterized by cell shrinkage caused by disruption of the maintenance of the normal physiological concentrations of K(+) and Na(+) and intracellular ion homeostasis. The disrupted ion homeostasis leads to depolarization and apoptosis. Recent evidence suggests that depolarization is an early and prerequisite event during TRAIL-induced apoptosis. Moreover, diverse natural products and synthetic chemicals capable of depolarizing the cell membrane exhibit tumor-selective killing and TRAIL-sensitizing effects. Here, we discuss the role of depolarization in selective killing of cancer cells in connection with the emerging concept that oxidative stress is a critical mediator of mitochondrial and endoplasmic reticulum dysfunctions and serves as a tumor-selective target in cancer treatment.
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Affiliation(s)
- Yoshihiro Suzuki-Karasaki
- Division of Physiology, Department of Biomedical Sciences, Nihon University School of Medicine , Tokyo , Japan ; Innovative Therapy Research Group, Nihon University Research Institute of Medical Science , Tokyo , Japan
| | | | - Mayumi Uchida
- Department of Dermatology, Nihon University Surugadai Hospital , Tokyo , Japan
| | - Toyoko Ochiai
- Department of Dermatology, Nihon University Surugadai Hospital , Tokyo , Japan
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Ischemic preconditioning protects cardiomyocyte mitochondria through mechanisms independent of cytosol. J Mol Cell Cardiol 2014; 68:79-88. [PMID: 24434643 DOI: 10.1016/j.yjmcc.2014.01.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 01/03/2014] [Indexed: 12/22/2022]
Abstract
Mitochondria play a central role in the protection conferred by ischemic preconditioning (IP) by not fully elucidated mechanisms. We investigated whether IP protects mitochondria against ischemia-reperfusion (IR) injury through mechanisms independent of cytosolic signaling. In isolated rat hearts, sublethal IR increased superoxide production and reduced complex-I- and II-mediated respiration in subsarcolemmal (SS), but not interfibrillar (IF) mitochondria. This effect of IR on mitochondrial respiration was significantly attenuated by IP. Similar results were obtained in isolated cardiac mitochondria subjected to in vitro IR. The reduction in SS mitochondrial respiration in the heart and in vitro model was paralleled by an increase in oxidized cysteine residues, which was also prevented by IP. IP was also protective in mitochondria submitted to lethal IR. The protective effect of IP against respiratory failure was unaffected by inhibition of mitochondrial KATP channels or mitochondrial permeability transition. However, IP protection was lost in mitochondria from genetically-modified animals in which connexin-43, a protein present in SS but not IF mitochondria, was replaced by connexin-32. Our results demonstrate the existence of a protective mitochondrial mechanism or "mitochondrial preconditioning" independent of cytosol that confers protection against IR-induced respiratory failure and oxidative damage, and requires connexin-43.
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Kang MC, Kim KN, Wijesinghe W, Yang X, Ahn G, Jeon YJ. Protective effect of polyphenol extracted from Ecklonia cava against ethanol induced oxidative damage in vitro and in zebrafish model. J Funct Foods 2014. [DOI: 10.1016/j.jff.2013.10.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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31
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Cui Y, Han Y, Yang X, Sun Y, Zhao Y. Protective effects of quercetin and quercetin-5',8-disulfonate against carbon tetrachloride-caused oxidative liver injury in mice. Molecules 2013; 19:291-305. [PMID: 24378968 PMCID: PMC6271165 DOI: 10.3390/molecules19010291] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 12/05/2013] [Accepted: 12/12/2013] [Indexed: 11/27/2022] Open
Abstract
Oxidative stress is one of the major factors in the pathogenesis of liver disease. Quercetin is a plant-based antioxidant traditionally used as a treatment for hepatic injury, but its poor solubility affects its bioavailability. We here report the regulative effects on hepatoprotection and absorption in mice of quercetin sulfation to form quercetin-5',8-disulfonate (QS), a novel synthetic compound. Oral administration of both QS and the parent quercetin at 100, 200 and 500 mg/kg·bw prior to acute CCl4 oxidative damage in mice, effectively attenuated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities and hepatic malondialdehyde (MDA) levels (p < 0.05), and suppressed the CCl4-induced depletion of glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD). Selective 5',8-sulfation of quercetin increased the hepatoprotective effect, and its relative absorption relative to quercetin (p < 0.05) as indicated by an improved 24-hour urinary excretion and a decreased fecal excretion determined by HPLC. These results and histopathological observations collectively demonstrate that quercetin sulfation increases its hepatoprotective effects and absorption in mice, and QS has potential as a chemopreventive and chemotherapeutic agent for liver diseases.
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Affiliation(s)
- Yanmang Cui
- School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Yong Han
- School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Xingbin Yang
- School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Yanfei Sun
- School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Yan Zhao
- School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
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Tang C, Liu H, Tang Y, Guo Y, Liang X, Guo L, Pi R, Yang J. Analysis of mitochondrial transcription factor A SNPs in alcoholic cirrhosis. Exp Ther Med 2013; 7:73-79. [PMID: 24348767 PMCID: PMC3861118 DOI: 10.3892/etm.2013.1353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 10/04/2013] [Indexed: 11/13/2022] Open
Abstract
Genetic susceptibility to alcoholic cirrhosis (AC) exists. We previously demonstrated hepatic mitochondrial DNA (mtDNA) damage in patients with AC compared with chronic alcoholics without cirrhosis. Mitochondrial transcription factor A (mtTFA) is central to mtDNA expression regulation and repair; however, it is unclear whether there are specific mtTFA single nucleotide polymorphisms (SNPs) in patients with AC and whether they affect mtDNA repair. In the present study, we screened mtTFA SNPs in patients with AC and analyzed their impact on the copy number of mtDNA in AC. A total of 50 patients with AC, 50 alcoholics without AC and 50 normal subjects were enrolled in the study. SNPs of full-length mtTFA were analyzed using the polymerase chain reaction (PCR) combined with gene sequencing. The hepatic mtTFA mRNA and mtDNA copy numbers were measured using quantitative PCR (qPCR), and mtTFA protein was measured using western blot analysis. A total of 18 mtTFA SNPs specific to patients with AC with frequencies >10% were identified. Two were located in the coding region and 16 were identified in non-coding regions. Conversely, there were five SNPs that were only present in patients with AC and normal subjects and had a frequency >10%. In the AC group, the hepatic mtTFA mRNA and protein levels were significantly lower than those in the other two groups. Moreover, the hepatic mtDNA copy number was significantly lower in the AC group than in the controls and alcoholics without AC. Based on these data, we conclude that AC-specific mtTFA SNPs may be responsible for the observed reductions in mtTFA mRNA, protein levels and mtDNA copy number and they may also increase the susceptibility to AC.
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Affiliation(s)
- Chun Tang
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
| | - Hongming Liu
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
| | - Yongliang Tang
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
| | - Yong Guo
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
| | - Xianchun Liang
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
| | - Liping Guo
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
| | - Ruxian Pi
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
| | - Juntao Yang
- Department of Hepatobiliary Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China
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Lu Y, Ward SC, Nieto N. Ethanol plus the Jo2 Fas agonistic antibody-induced liver injury is attenuated in mice with partial ablation of argininosuccinate synthase. Alcohol Clin Exp Res 2013; 38:649-56. [PMID: 24224890 DOI: 10.1111/acer.12309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 09/24/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Argininosuccinate synthase (ASS) is an enzyme shared by the urea cycle and the l-citrulline/nitric oxide (NO·) cycle. ASS is the rate-limiting enzyme in the urea cycle and along with nitric oxide synthase 2 (NOS2), it endows cells with the l-citrulline/NO· salvage pathway to continuously supply l-arginine from l-citrulline for sustained NO· generation. Thus, ASS conditions NO· synthesis by NOS2. Because of the relevance of NOS2 activation for liver injury, we examined the contribution of ASS to NO· generation and how it impacts liver injury. METHODS Wild-type (WT) mice and Ass(+/-) mice (Ass(-/-) mice are lethal) were intraperitoneally injected with ethanol (EtOH) at a dose of 2.5 g/kg of body weight twice a day for 3 days. Two hours after the last dose of EtOH, mice were administered the agonistic Jo2 anti-mouse Fas monoclonal antibody (Ab) at a dose of 0.2 μg/g of body weight. Mice were sacrificed 8 hours after the Jo2 Ab injection. Markers of nitrosative and oxidative stress as well as liver damage were analyzed. RESULTS EtOH plus Jo2 injection induced liver injury as shown by serum alanine aminotransferase and aspartate aminotransferase activity, liver pathology, TUNEL, and cleaved caspase-3 were lower in Ass(+/-) mice compared with WT mice, suggesting that ASS contributes to EtOH plus Jo2-mediated liver injury. CYP2E1 induction, glutathione depletion, and elevated thiobarbituric acid reactive substances were comparable in both groups of mice, suggesting that CYP2E1-mediated oxidative stress is not linked to ASS-induced liver injury. In contrast, NOS2 induction, 3-nitrotyrosine adducts formation and elevated nitrites, nitrates, and S-nitrosothiols were higher in livers from WT mice than from Ass(+/-) mice. CONCLUSION Decreased nitrosative stress causes lower EtOH plus Jo2-induced liver injury in Ass(+/-) mice.
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Affiliation(s)
- Yongke Lu
- Division of Liver Diseases , Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Sid B, Verrax J, Calderon PB. Role of oxidative stress in the pathogenesis of alcohol-induced liver disease. Free Radic Res 2013; 47:894-904. [PMID: 23800214 DOI: 10.3109/10715762.2013.819428] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chronic alcohol consumption is a well-known risk factor for liver disease, which represents a major cause of morbidity and mortality worldwide. The pathological process of alcohol-induced liver disease is characterized by a broad spectrum of morphological changes ranging from steatosis with minimal injury to more advanced liver damage, including steato-hepatitis and fibrosis/cirrhosis. Experimental and clinical studies increasingly show that the oxidative damage induced by ethanol contribute in many ways to the pathogenesis of alcohol hepatotoxicity. This article describes the contribution of oxidative mechanisms to liver damage by alcohol.
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Affiliation(s)
- B Sid
- Université Catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group (GTOX) , Brussels , Belgium
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Inoue T, Suzuki-Karasaki Y. Mitochondrial superoxide mediates mitochondrial and endoplasmic reticulum dysfunctions in TRAIL-induced apoptosis in Jurkat cells. Free Radic Biol Med 2013; 61:273-84. [PMID: 23608466 DOI: 10.1016/j.freeradbiomed.2013.04.020] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 03/21/2013] [Accepted: 04/12/2013] [Indexed: 12/30/2022]
Abstract
Reactive oxygen species (ROS), such as superoxide (O2(•-)) and hydrogen peroxide (H2O2), have been reported to be important mediators of the apoptosis induced by death ligands, including Fas, tumor necrosis factor-α, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Conversely, there is evidence that H2O2 and prooxidative conditions are protective. Therefore, the roles of ROS in death ligand-induced apoptosis are a matter of debate. In this study, we attempted to define the oxidant species mediating TRAIL-induced apoptosis in human tumor cells. The generation of intracellular O2(•-), but not H2O2, was correlated with apoptosis in the cells. TRAIL treatment resulted in increased mitochondrial O2(•-) generation and the oxidation of cardiolipin. The O2(•-)-selective scavenger MnTBaP [Mn(III) tetrakis (4-benzoic acid) porphyrin chloride] specifically blocked TRAIL-induced apoptosis and proapoptotic events including mitochondrial membrane collapse and caspase-3/7 activation. TRAIL also induced endoplasmic reticulum (ER) stress responses including caspase-12 activation, while inhibition of caspase-12 prevented the apoptosis. In addition, increased mitochondrial O2(•-) generation by uncoupling of oxidative phosphorylation or inhibition of the electron transport chain amplified the TRAIL-induced apoptosis and proapoptotic events. This amplification was also significantly abolished by MnTBaP treatment. Our data indicate that mitochondrial O2(•-) mediates mitochondrial and ER dysfunctions during TRAIL-induced apoptosis in Jurkat cells. The present findings suggest that pharmacological agents increasing mitochondrial O2(•-) may serve as clinical drugs that amplify TRAIL effectiveness toward cancer cells.
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Affiliation(s)
- Toshio Inoue
- Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan
| | - Yoshihiro Suzuki-Karasaki
- Division of Molecular Cell Immunology and Allergology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan; Division of Physiology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan; Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Tokyo, Japan.
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Morio Y, Tsuji M, Inagaki M, Nakagawa M, Asaka Y, Oyamada H, Furuya K, Oguchi K. Ethanol-induced apoptosis in human liver adenocarcinoma cells (SK-Hep1): Fas- and mitochondria-mediated pathways and interaction with MAPK signaling system. Toxicol In Vitro 2013; 27:1820-9. [PMID: 23726865 DOI: 10.1016/j.tiv.2013.05.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 04/03/2013] [Accepted: 05/16/2013] [Indexed: 12/19/2022]
Abstract
For studying molecular mechanisms regulating the fate of ethanol-treated hepatocytes, involvement of Fas in ethanol-induced apoptosis was examined in human liver adenocarcinoma (SK-Hep1) cells in which the function of Fas-associated death domain (FADD) protein was knocked down by transfection. In FADD-knocked down cells, while ethanol-induced increase in generation of reactive oxygen species (ROS) was unaffected, apoptosis was significantly suppressed, demonstrating the involvement of Fas in ethanol-induced hepatocyte apoptosis more directly than in the past reports. On the other hand, effects of mitogen-activated protein kinase (MAPK), which is well known to determine the fate of various cells, on ethanol-induced apoptosis have not been examined in SK-Hep1 cells. Of three major MAPKs, only p38 MAPK and JNK were found activated by 200 mM ethanol treatment. When cells were incubated with inhibitors of p38 MAPK and JNK, ethanol-induced apoptosis was decreased while ROS generation was unaffected, and examination of pro-apoptotic Bax and anti-apoptotic Bcl-2 levels showed decrease of the former and increase of the latter. We concluded that oxidative stress inflicted by ROS triggered Fas-mediated and mitochondria-mediated apoptotic pathways in ethanol-treated SK-Hep1 cells, and that p38 MAPK and JNK were promoting mitochondrial pathway, suggesting interaction between apoptosis and MAPK signaling systems.
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Affiliation(s)
- Yuri Morio
- Department of Pharmacology, School of Medicine, Showa University, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142-8555, Japan
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González R, Ferrín G, Aguilar-Melero P, Ranchal I, Linares CI, Bello RI, De la Mata M, Gogvadze V, Bárcena JA, Alamo JM, Orrenius S, Padillo FJ, Zhivotovsky B, Muntané J. Targeting hepatoma using nitric oxide donor strategies. Antioxid Redox Signal 2013; 18:491-506. [PMID: 22861189 DOI: 10.1089/ars.2011.4476] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
AIMS The study evaluated the role of increased intracellular nitric oxide (NO) concentration using NO donors or stably NO synthase-3 (NOS-3) overexpression during CD95-dependent cell death in hepatoma cells. The expression of cell death receptors and caspase activation, RhoA kinase activity, NOS-3 expression/activity, oxidative/nitrosative stress, and p53 expression were analyzed. The antitumoral activity of NO was also evaluated in the subcutaneous implantation of NOS-3-overexpressing hepatoma cells, as well NO donor injection into wild-type hepatoma-derived tumors implanted in xenograft mouse models. RESULTS NO donor increased CD95 expression and activation of caspase-8 and 3 in HepG2, Huh7, and Hep3B cells. NOS-3 overexpression increased oxidative/nitrosative stress, p53 and CD95 expression, cellular Fas-associated death domain (FADD)-like IL-1beta converting enzyme (FLICE) inhibitory protein long (cFLIP(L)) and its short isoform (cFLIP(S)) shift, and cell death in HepG2 (4TO-NOS) cells. The inhibition of RhoA kinase and p53 knockdown using RNA interference reduced cell death in 4TO-NOS cells. The supplementation with hydrogen peroxide (H(2)O(2)) increased NOS-3 activity and cell death in 4TO-NOS cells. NOS-3 overexpression or NO donor injection into hepatoma-derived tumors reduced the size and increased p53 and cell death receptor expression in nude mice. INNOVATION AND CONCLUSIONS The increase of intracellular NO concentration promoted oxidative and nitrosative stress, Rho kinase activity, p53 and CD95 expression, and cell death in cultured hepatoma cells. NOS-3-overexpressed HepG2 cells or intratumoral NO donor administration reduced tumor cell growth and increased the expression of p53 and cell death receptors in tumors developed in a xenograft mouse model.
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Affiliation(s)
- Raúl González
- Department of Biochemistry and Molecular Biology, University of Córdoba, Córdoba, Spain
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Canová NK, Martínek J, Kmonícková E, Zídek Z, Kameníková L, Farghali H. Modulation of spontaneous and lipopolysaccharide-induced nitric oxide production and apoptosis by d-galactosamine in rat hepatocyte culture: the significance of combinations of different methods. Toxicol Mech Methods 2012; 18:63-74. [PMID: 20020892 DOI: 10.1080/15376510701738421] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
ABSTRACT Apoptotic markers and signals produced by xenobiotics as hepatotoxic D-galactosamine (D-GalN) and lipopolysaccharide (LPS) are extensively investigated in vivo. The contribution of various cells and factors as nitric oxide (NO) in mediating hepatocyte apoptosis in a rat model of systemic endotoxemia was reported. Therefore, the aim of the present work was to study the in vitro effect of D-GalN on nonstimulated or LPS-treated rat hepatocytes in culture and the potential involvement of NO in this process. Our results showed that the spontaneous and LPS-induced NO production was completely blocked by D-GalN during 0 to 24 hours. However, D-GalN slightly enhanced NO production during 24 to 48 hours. D-GalN was more potent to induce hepatocyte apoptosis and necrosis during 24 to 48 than 0 to 24 hours as evidenced morphologically (Annexin V/propidium iodide staining) and biochemically (caspase-3-like activity, alanine-aminotransferase leakage, MTT test). Interestingly, D-GalN treatment suppressed mitochondrial cytochrome C release throughout the study. LPS addition to D-GalN considerably aggravated apoptotic/necrotic markers only during 0 to 24 hours. Surprisingly, a share of apoptotic cells was distinctly lower after LPS + GalN treatment than after LPS alone during 0 to 24 hours, while 24- to 48-hour incubation produced massive apoptotic/necrotic hepatocytes. It may be concluded that there is a significant modulation of NO production by D-GalN. Because the role of NO is only partly decisive in the apoptotic/necrotic events, and considering the fraction of the cells completing apoptosis while others that turn toward necrosis (aponecrosis), caution should be exercised in apoptosis data interpretation and combinations of different test methods should be applied.
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Affiliation(s)
- Nikolina Kutinová Canová
- Institute of Pharmacology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic
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Mahfoudh W, Bouaouina N, Gabbouj S, Chouchane L. FASL-844 T/C polymorphism: a biomarker of good prognosis of breast cancer in the Tunisian population. Hum Immunol 2012; 73:932-8. [PMID: 22732091 DOI: 10.1016/j.humimm.2012.06.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Revised: 06/05/2012] [Accepted: 06/14/2012] [Indexed: 01/16/2023]
Abstract
The single nucleotide polymorphism, rs763110 (-844 T/C) of the FASL gene, is located within a putative binding motif of CAAT/enhancer-binding protein β transcription factor. Higher basal expression of FASL is significantly associated with the FASL-844 C allele compared with the FASL-844 T allele suggesting that the FASL-844 T/C polymorphism may influence FASL expression and FASL-mediated signalling, and ultimately, the susceptibility to cancer. Therefore, we carried out a population-based study to estimate the FASL-844 C allele frequency in our population and to investigate, in a case-control study, the potential association of the FASL-844 T/C polymorphism with the risk and prognosis of breast cancer in Tunisia. FASL-844 T/C polymorphism was examined in a Tunisian population-based case-control of 438 patients with breast cancer and 332 control subjects using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. By using TT genotype as reference, no significant association was found between any genotype and the risk of developing breast cancer. The frequency of the FASL-844 C allele was 46.3% among the cases and 43.7% among the controls. Similarly, by using T allele as reference, this difference was also not statistically significant. We observed FASL-844 CC genotype and FASL-844 C allele were significantly associated with SBR 1-2 tumour grade (OR=0.42, P=0.007; OR=0.65, P=0.005, respectively). In patients with diagnosis age ≤ 50 years, FASL-844 CC genotype and C allele showed significant associations with T(1)-T(2) clinical tumour size (OR=0.34, P=0.01; OR=0.65, P=0.02, respectively) and SBR grade 1-2 (OR=0.41, P=0.02; OR=0.62, P=0.01, respectively). A marginally significant association was also found with negative nodal status (OR=0.53, P=0.06; OR=0.73, P=0.07, respectively). Thus, the FASL-844 CC genotype and C allele seem to be associated with a good prognosis in patients with diagnosis age ≤ 50 years.
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Affiliation(s)
- Wijden Mahfoudh
- Laboratoire d'Immuno-Oncologie Moléculaire, Faculté de Médecine de Monastir, Université de Monastir, 5019 Monastir, Tunisia.
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Camel's milk alleviates alcohol-induced liver injury in rats. Food Chem Toxicol 2012; 50:1377-83. [PMID: 22281157 DOI: 10.1016/j.fct.2012.01.016] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 12/22/2011] [Accepted: 01/10/2012] [Indexed: 12/20/2022]
Abstract
Alcoholic liver disease (ALD) represents a spectrum of clinical illness and morphological changes that range from fatty liver, hepatic inflammation and necrosis to progressive fibrosis. For the etiology of ALD, oxidative stress, increased expression of proinflammatory cytokines and apoptosis have been described. The present study aimed to investigate the effectiveness of camel's milk (CM) in alleviating alcohol-induced hepatotoxicity as a model of clinical liver illness. Male rats were grouped into four groups from which one group received normal saline and served as control. Groups from 2 to 4 received a daily oral dose of 56% ethanol for 4 weeks. Group 2 served as untreated control while groups 3 and 4 were respectively treated with CM either in a prophylactic or a curative approach. Alanine transaminase, aspartate transaminase, alkaline phosphatase, triglycerides, as well as cholesterol levels were estimated in the serum. Malondialdehyde, total antioxidant capacity, and tumor necrosis factor-alpha levels along with caspase-3 activity were determined in liver tissue homogenate. A histopathological analysis of liver tissue was also achieved. Results showed amelioration of all tested parameters following administration of CM. Conclusively, treatment with camel's milk alleviates alcohol-associated hazards and protects hepatic tissue from alcohol-induced toxicity.
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Smallwood HS, López-Ferrer D, Squier TC. Aging enhances the production of reactive oxygen species and bactericidal activity in peritoneal macrophages by upregulating classical activation pathways. Biochemistry 2011; 50:9911-22. [PMID: 21981794 DOI: 10.1021/bi2011866] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Maintenance of macrophages in their basal state and their rapid activation in response to pathogen detection are central to the innate immune system, acting to limit nonspecific oxidative damage and promote pathogen killing following infection. To identify possible age-related alterations in macrophage function, we have assayed the function of peritoneal macrophages from young (3-4 months) and aged (14-15 months) Balb/c mice. In agreement with prior suggestions, we observe age-dependent increases in the extent of recruitment of macrophages into the peritoneum, as well as ex vivo functional changes involving enhanced nitric oxide production under resting conditions that contribute to a reduction in the time needed for full activation of senescent macrophages following exposure to lipopolysaccharides (LPS). Further, we observe enhanced bactericidal activity following Salmonella uptake by macrophages isolated from aged Balb/c mice in comparison with those isolated from young animals. Pathways responsible for observed phenotypic changes were interrogated using tandem mass spectrometry, which identified age-dependent increases in levels of proteins linked to immune cell pathways under basal conditions and following LPS activation. Immune pathways upregulated in macrophages isolated from aged mice include proteins critical to the formation of the immunoproteasome. Detection of these latter proteins is dramatically enhanced following LPS exposure for macrophages isolated from aged animals; in comparison, the identification of immunoproteasome subunits is insensitive to LPS exposure for macrophages isolated from young animals. Consistent with observed global changes in the proteome, quantitative proteomic measurements indicate that there are age-dependent abundance changes involving specific proteins linked to immune cell function under basal conditions. LPS exposure selectively increases the levels of many proteins involved in immune cell function in aged Balb/c mice. Collectively, these results indicate that macrophages isolated from old mice are in a preactivated state that enhances their sensitivities to LPS exposure. The hyper-responsive activation of macrophages in aged animals may act to minimize infection by general bacterial threats that arise due to age-dependent declines in adaptive immunity. However, this hypersensitivity and the associated increase in the level of formation of reactive oxygen species are likely to contribute to observed age-dependent increases in the level of oxidative damage that underlie many diseases of the elderly.
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Affiliation(s)
- Heather S Smallwood
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States
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Chen CC, Liou SW, Chen CC, Chen WC, Hu FR, Wang IJ, Lin SJ. Coenzyme Q10 reduces ethanol-induced apoptosis in corneal fibroblasts. PLoS One 2011; 6:e19111. [PMID: 21556371 PMCID: PMC3083429 DOI: 10.1371/journal.pone.0019111] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Accepted: 03/27/2011] [Indexed: 11/18/2022] Open
Abstract
Dilute ethanol (EtOH) is a widely used agent to remove the corneal epithelium during the modern refractive surgery. The application of EtOH may cause the underlying corneal fibroblasts to undergo apoptosis. This study was designed to investigate the protective effect and potential mechanism of the respiratory chain coenzyme Q(10) (CoQ(10)), an electron transporter of the mitochondrial respiratory chain and a ubiquitous free radical scavenger, against EtOH-induced apoptosis of corneal fibroblasts. Corneal fibroblasts were pretreated with CoQ(10) (10 µM) for 2 h, followed by exposure to different concentrations of EtOH (0.4, 2, 4, and 20%) for 20 s. After indicated incubation period (2-12 h), MTT assay was used to examine cell viability. Treated cells were further assessed by flow cytometry to identify apoptosis. Reactive oxygen species (ROS) and the change in mitochondrial membrane potential were assessed using dichlorodihydrofluorescein diacetate/2',7'-dichlorofluorescein (DCFH-DA/DCF) assays and flow-cytometric analysis of JC-1 staining, respectively. The activity and expression of caspases 2, 3, 8, and 9 were evaluated with a colorimetric assay and western blot analysis. We found that EtOH treatment significantly decreased the viability of corneal fibroblasts characterized by a higher percentage of apoptotic cells. CoQ(10) could antagonize the apoptosis inducing effect of EtOH. The inhibition of cell apoptosis by CoQ(10) was significant at 8 and 12 h after EtOH exposure. In EtOH-exposed corneal fibroblasts, CoQ(10) pretreatment significantly reduced mitochondrial depolarization and ROS production at 30, 60, 90, and 120 min and inhibited the activation and expression of caspases 2 and 3 at 2 h after EtOH exposure. In summary, pretreatment with CoQ(10) can inhibit mitochondrial depolarization, caspase activation, and cell apoptosis. These findings support the proposition that CoQ(10) plays an antiapoptotic role in corneal fibroblasts after ethanol exposure.
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Affiliation(s)
- Chun-Chen Chen
- Department of Ophthalmology, Taipei City Hospital Renai Branch, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shiow-Wen Liou
- Department of Ophthalmology, Taipei City Hospital Renai Branch, Taipei, Taiwan
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Taipei Medical University, Taipei, Taiwan
| | - Chi-Chih Chen
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wen-Chung Chen
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fung-Rong Hu
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - I-Jong Wang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- * E-mail: (IJW); (SJL)
| | - Shing-Jong Lin
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- * E-mail: (IJW); (SJL)
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Gam CMB, Nielsen HB, Secher NH, Larsen FS, Ott P, Quistorff B. In cirrhotic patients reduced muscle strength is unrelated to muscle capacity for ATP turnover suggesting a central limitation. Clin Physiol Funct Imaging 2010; 31:169-74. [PMID: 21143366 DOI: 10.1111/j.1475-097x.2010.00998.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND AIMS We investigated whether in patients with liver cirrhosis reduced muscle strength is related to dysfunction of muscle mitochondria. METHODS The mitochondrial respiratory capacity of the tibial anterior muscle was evaluated in seven patients and eight healthy control subjects by 31P nuclear magnetic resonance spectroscopy (31PMRS) to express ATP turnover in vivo and by respirometry of permeabilized fibres from the same muscle to express the in vitro capacity for oxygen consumption. RESULTS Maximal voluntary contraction force for plantar extension was low in the patients (46% of the control value; P < 0.05), but neither the capacity for mitochondrial ATP synthesis, V(max-ATP) (0.38 ± 0.26 vs. 0.50 ± 0.07 mM s(-1) ; P = 0.13) nor the in vitro VO(2max) (0.52 ± 0.21 vs. 0.48 ± 0.21 μmol O2 (min g wet wt.)(-1) P = 0.25) were lowered correspondingly. Also, the activity of citrate synthesis and the respiratory chain complexes II and IV were similar in patients and controls. However during the contractions, the contribution to initial anaerobic ATP production from glycolysis relative to that from PCr was reduced in the patients (0.73 ± 0.22 vs. 0.99 ± 0.09; P < 0.01). CONCLUSIONS These results demonstrate that the markedly lower capacity for force generation in patients with liver cirrhosis is unrelated to their capacity for muscle ATP turnover, but the attenuated initial acceleration of anaerobic glycolysis suggests that these patients could be affected by a central limitation to force generation.
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Affiliation(s)
- C M B Gam
- Department of Anaesthesia, Rigshospitalet, Copenhagen, Denmark
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De Minicis S, Seki E, Paik YH, Österreicher CH, Kodama Y, Kluwe J, Torozzi L, Miyai K, Benedetti A, Schwabe RF, Brenner DA. Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis. Hepatology 2010; 52:1420-30. [PMID: 20690191 PMCID: PMC2947612 DOI: 10.1002/hep.23804] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate oxidase (NOX) is required for liver fibrosis. This study investigates the role of NOX in ROS production and the differential contribution of NOX from bone marrow (BM)-derived and non-BM-derived liver cells. Hepatic fibrosis was induced by bile duct ligation (BDL) for 21 days or by methionine-choline-deficient (MCD) diet for 10 weeks in wild-type (WT) mice and mice deficient in p47phox (p47phox knockout [KO]), a component of NOX. The p47phox KO chimeric mice were generated by the combination of liposomal clodronate injection, irradiation, and BM transplantation of p47phox KO BM into WT recipients and vice versa. Upon BDL, chimeric mice with p47phox KO BM-derived cells, including Kupffer cells, and WT endogenous liver cells showed a ∼25% reduction of fibrosis, whereas chimeric mice with WT BM-derived cells and p47phox KO endogenous liver cells, including hepatic stellate cells, showed a ∼60% reduction of fibrosis. In addition, p47phox KO compared to WT mice treated with an MCD diet showed no significant changes in steatosis and hepatocellular injury, but a ∼50% reduction in fibrosis. Cultured WT and p47phox KO hepatocytes treated with free fatty acids had a similar increase in lipid accumulation. Free fatty acids promoted a 1.5-fold increase in ROS production both in p47phox KO and in WT hepatocytes. CONCLUSION NOX in both BM-derived and non-BM-derived cells contributes to liver fibrosis. NOX does not play a role in experimental steatosis and the generation of ROS in hepatocytes, but exerts a key role in fibrosis.
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Affiliation(s)
- Samuele De Minicis
- Department of Medicine, University of California San Diego, School of Medicine, California, Gastrointestinal Unit, University of Ancona, Italy
| | - Ekihiro Seki
- Department of Medicine, University of California San Diego, School of Medicine, California
| | - Yong-Han Paik
- Department of Medicine, University of California San Diego, School of Medicine, California, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | - Yuzo Kodama
- Department of Medicine, University of California San Diego, School of Medicine, California
| | | | | | - Katsumi Miyai
- Department of Pathology, University of California San Diego, School of Medicine, California
| | | | | | - David A. Brenner
- Department of Medicine, University of California San Diego, School of Medicine, California
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Alcohol withdrawal and brain injuries: beyond classical mechanisms. Molecules 2010; 15:4984-5011. [PMID: 20657404 PMCID: PMC6257660 DOI: 10.3390/molecules15074984] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 07/15/2010] [Accepted: 07/19/2010] [Indexed: 01/12/2023] Open
Abstract
Unmanaged sudden withdrawal from the excessive consumption of alcohol (ethanol) adversely alters neuronal integrity in vulnerable brain regions such as the cerebellum, hippocampus, or cortex. In addition to well known hyperexcitatory neurotransmissions, ethanol withdrawal (EW) provokes the intense generation of reactive oxygen species (ROS) and the activation of stress-responding protein kinases, which are the focus of this review article. EW also inflicts mitochondrial membranes/membrane potential, perturbs redox balance, and suppresses mitochondrial enzymes, all of which impair a fundamental function of mitochondria. Moreover, EW acts as an age-provoking stressor. The vulnerable age to EW stress is not necessarily the oldest age and varies depending upon the target molecule of EW. A major female sex steroid, 17β-estradiol (E2), interferes with the EW-induced alteration of oxidative signaling pathways and thereby protects neurons, mitochondria, and behaviors. The current review attempts to provide integrated information at the levels of oxidative signaling mechanisms by which EW provokes brain injuries and E2 protects against it.
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Hou Z, Qin P, Ren G. Effect of anthocyanin-rich extract from black rice (Oryza sativa L. Japonica) on chronically alcohol-induced liver damage in rats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:3191-3196. [PMID: 20143824 DOI: 10.1021/jf904407x] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
The study evaluated the protective effect of anthocyanin-rich extract from black rice (AEBR) on chronic ethanol-induced biochemical changes in male Wistar rats. Administration of ethanol (3.7 g/kg/day) to Wistar rats for 45 days induced liver damage with a significant increase (P < 0.05) of aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase (GGT) in the serum and the hepatic malondialdehyde (MDA) level. In contrast, administration of AEBR (500 mg/kg) along with alcohol significantly (P < 0.01) decreased the activities of liver enzymes (AST, ALT and GGT) in serum, the MDA levels and the concentrations of serum and hepatic triglyceride (TG) and total cholesterol (TCH). Rats treated with AEBR showed a better profile of the antioxidant system with normal glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and glutathione S-transferase (GST) activities. All these results were accompanied by histological observations in liver. The results demonstrate that AEBR has a beneficial effect in reducing the adverse effect of alcohol.
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Affiliation(s)
- Zhaohua Hou
- Institute of Crop Science, Chinese Academy of Agricultural Sciences No. 80 South Xueyuan Road, Haidian District, Beijing100081, P. R. China
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Chronic alcohol consumption is associated with an increased cytotoxic profile of circulating lymphocytes that may be related with the development of liver injury. Alcohol Clin Exp Res 2010; 34:876-85. [PMID: 20201930 DOI: 10.1111/j.1530-0277.2010.01160.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Apoptosis has recently emerged as a key component of acute and chronic liver diseases and it could be related to alcoholic liver disease. In the present study, we attempted to analyze the cytotoxic profile of circulating lymphocytes in chronic alcoholic patients grouped according to ethanol intake status and presence of liver disease. METHODS We investigate the phenotypic and functional behavior of different compartments of peripheral blood (PB) cytotoxic T and natural killer (NK) cells in chronic alcoholic patients without liver disease and active ethanol intake (AWLD group; n = 22), and in subjects with alcohol liver cirrhosis (ALC group; n = 22). RESULTS AWLD patients showed an expansion of both CD4+/CD8+ cytotoxic T cells and NK/T cells, in association with an enhanced cytolytic activity against K562 cells and a higher ability to induce in vitro expression of the pro-apoptotic protein APO2.7 in HepG2 cells. Conversely, ethanol intake in ALC patients was associated with decreased NK cell numbers, a reduced cytotoxic activity against K562 cells without significant changes in the expression of APO2.7, and a pro-fibrotic profile of cytokine secretion. CONCLUSIONS Overall, our results suggest that alcoholic patients display different phenotypical and functional changes in circulating PB cytotoxic lymphocytes according to the presence of alcoholic liver disease, which could be related to the development and progress of liver injury.
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Wang Y, Seitz HK, Wang XD. Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats. Alcohol Clin Exp Res 2009; 34:567-73. [PMID: 20028348 DOI: 10.1111/j.1530-0277.2009.01122.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. METHODS Sprague-Dawley rats were first fed ad libitum with Lieber-DeCarli high-fat diet (71% energy from fat) for 6 weeks to induce NASH, as demonstrated previously. Afterwards, these rats were continuously fed with high-fat diet (HFD, 55% total energy from fat) or high fat plus alcohol diet (HFA, 55% energy from fat and 16% energy from alcohol) for an additional 4 weeks. Pathological lesions including fat accumulation and inflammatory foci in liver were examined and graded. Lipid peroxidation and apoptotic hepatocytes in the liver were assessed. The mRNA expressions of tumor necrosis factor-alpha (TNFalpha) and TNF receptor 1 (TNF-R1), Fas death receptor (Fas) and Fas ligant (FasL), IL-1beta and IL-12 were determined by real-time PCR. Protein levels of total and cleaved caspase-3, CYP2E1, Bax, and Bcl-2 were measured by western blotting. RESULTS The number of hepatic inflammatory foci and apoptotic hepatocytes were significantly increased in rats fed with HFA as compared with those in HFD-fed rats. The aggravated inflammatory response and cellular apoptosis mediated by HFA were associated with elevated mRNA expression of Fas/FasL and cleaved caspase-3 protein. Although no significant differences were observed between HFD and HFA groups, the levels of lipid peroxidation, Bax and Bcl-2 protein concentration, and mRNA levels of other inflammatory cytokines were significantly higher in these 2 groups than those in the control group. CONCLUSIONS These data suggest that even moderate alcohol consumption can cause more hepatic inflammation and cellular apoptosis in a pre-existing NASH condition.
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Affiliation(s)
- Yan Wang
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA
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Fan XP, Wang K, Liu Y, Wang JF. Plasma alpha-tocopherol is negatively correlated with hepatocyte apoptosis in chronic hepatitis B patients. Intern Med 2009; 48:1585-1593. [PMID: 19755759 DOI: 10.2169/internalmedicine.48.2336] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
AIM Hepatocyte apoptosis is involved in the pathogenesis of liver diseases, while at the same time oxidative stress plays an important role in liver cell damage. This prompted us to evaluate the possible relationship between hepatocyte apoptosis and oxidative stress in patients with chronic hepatitis B. METHODS CHB patients were placed in groups A (ALT >40 IU/L) and B (ALT RESULTS SOD, GSH-Px, and MDA did not differ between groups. alpha-Tocopherol was significantly decreased in groups A (p<0.01) and B (p<0.05) when compared with group C and it was negatively correlated with the apoptosis index (r=-0.575, p<0.01). CONCLUSION Only the plasma concentration of alpha-tocopherol rather than the other oxidative stress markers changed significantly in patients with normal alanine aminotransferase levels (ALT <40 IU/L) when compared with healthy controls and correlated significantly with the apoptosis index, suggesting that alpha-tocopherol may be a possible marker to reflect liver cell damage, especially in the absence of serum aminotransferase elevation.
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Affiliation(s)
- Xiao-Peng Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
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Wang X, Lu Y, Xie B, Cederbaum AI. Chronic ethanol feeding potentiates Fas Jo2-induced hepatotoxicity: role of CYP2E1 and TNF-alpha and activation of JNK and P38 MAP kinase. Free Radic Biol Med 2009; 47:518-28. [PMID: 19477265 PMCID: PMC2966279 DOI: 10.1016/j.freeradbiomed.2009.05.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Revised: 05/05/2009] [Accepted: 05/16/2009] [Indexed: 01/13/2023]
Abstract
We have previously shown that treatment of mice with pyrazole or acute ethanol potentiated Fas agonistic Jo2 antibody-induced liver injury by a mechanism involving induction of CYP2E1 and elevated oxidative stress. The current study evaluated whether chronic alcohol feeding potentiates Fas-induced liver injury and whether CYP2E1 plays a role in any enhanced hepatotoxicity. Wild-type and CYP2E1 knockout mice were fed ethanol or isocaloric dextrose for 4 weeks followed by a single treatment with either saline or Jo2. Mice were killed 8 h after the Jo2 challenge. There were three- to five fold increases in transaminases and more extensive eosinophilic necrosis, hemorrhage, and infiltration of inflammatory cells in the central zone of the hepatic lobule in the ethanol-fed mice treated with Jo2 compared to the dextrose/Jo2- or ethanol/saline-treated mice. Liver injury was blunted in ethanol-fed CYP2E1 knockout mice treated with Jo2. The chronic ethanol feeding produced steatosis, elevation of CYP2E1, and oxidative stress in wild-type but not CYP2E1 knockout mice. These changes in wild-type mice fed ethanol were similar after saline or Jo2 treatment. The Jo2 treatment produced activation of JNK and P38 MAP kinase, increased activity of caspase-8 and -3, and lowered hepatic GSH levels in both the dextrose- and the alcohol-fed mice. JNK was activated at early times after Jo2 treatment in the ethanol-fed mice. Serum TNF-alpha levels were strikingly elevated in the wild-type ethanol/Jo2 group, which showed liver injury, compared to all the other groups, which did not show liver injury. Inhibition of JNK or P38 MAPK partially, but not completely, prevented the elevated liver injury in the wild-type ethanol/Jo2 mice. These results show that chronic ethanol feeding enhances Fas-induced liver injury by a mechanism associated with induction of CYP2E1, elevated serum TNF-alpha levels, and activation of MAPK.
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Affiliation(s)
- Xiaodong Wang
- Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA
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