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1
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Akepati PR, Gochanour EM. Investigational farnesoid X receptor agonists for the treatment of primary biliary cholangitis. Expert Opin Investig Drugs 2024; 33:627-638. [PMID: 38676426 DOI: 10.1080/13543784.2024.2348743] [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: 01/20/2024] [Accepted: 04/24/2024] [Indexed: 04/28/2024]
Abstract
INTRODUCTION Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments. AREAS COVERED We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov. EXPERT OPINION Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.
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Affiliation(s)
- Prithvi Reddy Akepati
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
| | - Eric M Gochanour
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
- The Gastroenterology Center, Valley View Hospital, Glenwood Springs, CO, USA
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2
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Arabpour J, Rezaei K, Khojini JY, Razi S, Hayati MJ, Gheibihayat SM. The potential role and mechanism of circRNAs in Ferroptosis: A comprehensive review. Pathol Res Pract 2024; 255:155203. [PMID: 38368664 DOI: 10.1016/j.prp.2024.155203] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/03/2024] [Accepted: 02/07/2024] [Indexed: 02/20/2024]
Abstract
Cell death encompasses various mechanisms, including necrosis and apoptosis. Ferroptosis, a unique form of regulated cell death, emerged as a non-apoptotic process reliant on iron and reactive oxygen species (ROS). Distinguishing itself from other forms of cell death, ferroptosis exhibits distinct morphological, biochemical, and genetic features. Circular RNAs (circRNAs), a novel class of RNA molecules, play crucial regulatory roles in ferroptosis-mediated pathways and cellular processes. With their circular structure and stability, circRNAs function as microRNA sponges and participate in protein regulation, offering diverse mechanisms for cellular control. Accumulating evidence indicates that circRNAs are key players in diseases associated with ferroptosis, presenting opportunities for diagnostic and therapeutic applications. This study explores the regulatory roles of circRNAs in ferroptosis and their potential in diseases such as cancer, neurological disorders, and cardiovascular diseases. By investigating the relationship between circRNAs and ferroptosis, this research provides new insights into the diagnosis, treatment, and prognosis of ferroptosis-related diseases. Furthermore, the therapeutic implications of targeting circRNAs in cancer treatment and the modulation of ferroptosis pathways demonstrate the potential of circRNAs as diagnostic markers and therapeutic targets. Overall, understanding the involvement of circRNAs in regulating ferroptosis opens up new avenues for advancements in disease management.
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Affiliation(s)
- Javad Arabpour
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Kimia Rezaei
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Javad Yaghmoorian Khojini
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Shokufeh Razi
- Department of Genetics, Faculty of Basic Sciences, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Javad Hayati
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Seyed Mohammad Gheibihayat
- Yazd Cardiovascular Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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3
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Ortega-Prieto P, Parlati L, Benhamed F, Regnier M, Cavalcante I, Montabord M, Onifarasoaniaina R, Favier M, Pavlovic N, Magusto J, Cauzac M, Pagesy P, Gautheron J, Desdouets C, Guilmeau S, Issad T, Postic C. O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis. JHEP Rep 2024; 6:100878. [PMID: 38298740 PMCID: PMC10827605 DOI: 10.1016/j.jhepr.2023.100878] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 07/06/2023] [Accepted: 07/24/2023] [Indexed: 02/02/2024] Open
Abstract
Background & Aims O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications Our study shows that hepatocyte-specific deletion of O-GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O-GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet (i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies.
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Affiliation(s)
| | - Lucia Parlati
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Fadila Benhamed
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Marion Regnier
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Isadora Cavalcante
- Team Genomics and Signaling of Endocrine Tumors, Institut Cochin, CNRS, INSERM, Université Paris Cité, Paris, France
| | | | | | - Maryline Favier
- HistIM Platform, Institut Cochin, CNRS, INSERM, Université de Paris Cité, Paris, France
| | - Natasa Pavlovic
- Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Julie Magusto
- Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France
| | - Michèle Cauzac
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Patrick Pagesy
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Jérémie Gautheron
- Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France
| | - Chantal Desdouets
- Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Sandra Guilmeau
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Tarik Issad
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Catherine Postic
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
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4
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Seguí-Ripoll JM, Candela-Gomis A, Compañy-Catalá L, Francés-Guarinos R, Payá-Romá A, Compañ-Rosique A, Such-Ronda J, Zapater-Hernández P. Lipid peroxidation and liver damage in double and simple common bile duct ligation models in male Sprague-Dawley rats. Life Sci 2023; 334:122238. [PMID: 37925139 DOI: 10.1016/j.lfs.2023.122238] [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: 08/20/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/06/2023]
Abstract
AIMS Bacterial translocation, defined as the presence of living bacteria or bacterial fragments in both mesenteric lymph nodes or systemic circulation, can cause a severe inflammatory reaction in patients with cirrhosis. This study aimed to compare lipid peroxidation associated with liver damage in different experimental models of bile duct ligation: proximal double ligation and transection versus proximal simple ligation versus sham. MATERIALS AND METHODS Sixty-two male rats underwent one of three bile duct surgical interventions: proximal double ligation and transection (n = 22); proximal simple ligation (n = 19); or sham operation (n = 21). We performed microbiological culture of mesenteric lymph nodes; portal and cava blood, spleen and liver cultures; and histological analysis of liver parenchyma. Samples of blood and liver were obtained at laparotomy for malondialdehyde quantification. KEY FINDINGS Serum malondialdehyde levels were significantly higher in simple ligature animals (3.7 nmol/mg, standard deviation [SD] 2.1) compared to controls (1.6 nmol/mg SD 0.5; p = 0.001) or double ligature (0.3 nmol/mg SD 0.3; p = 0.001). Liver malondialdehyde levels were significantly higher in animals subjected to double ligation vs controls (9.0 nmol/mg SD 2.8 vs. 1.7 nmol/mg SD 1.0; p = 0.0007) and simple ligature (2.9 nmol/mg SD 2.0; p = 0.0001). Overall incidence of bacterial translocation was similar in simple and double ligatures (22.2 % and 21 % respectively), and significantly higher than in controls. SIGNIFICANCE the type of bile duct ligation influences the type and localization of lipid peroxidation, but does not influence the development of bacterial translocation.
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Affiliation(s)
- José Miguel Seguí-Ripoll
- Department of Clinical Medicine, Miguel Hernández University, Elche, Spain; Internal Medicine Department, University Hospital of San Juan de Alicante, Spain.
| | - Asunción Candela-Gomis
- General and Digestive Surgery Service, University Hospital of San Juan de Alicante, Spain; Pathology and Surgery Department, Miguel Hernández University, Elche, Spain.
| | | | - Rubén Francés-Guarinos
- CIBERehd, Health Institute Carlos III, Madrid, Spain; Department of Clinical Medicine (Immunology Area), Miguel Hernández University, San Juan, Spain.
| | - Artemio Payá-Romá
- Pathology Department, Hospital General Universitario, Alicante, Spain.
| | - Antonio Compañ-Rosique
- General and Digestive Surgery Service, University Hospital of San Juan de Alicante, Spain; Pathology and Surgery Department, Miguel Hernández University, Elche, Spain.
| | - José Such-Ronda
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; Lerner School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
| | - Pedro Zapater-Hernández
- Unit of Clinical Pharmacology, General University Hospital of Alicante, Spain; IDiBE Institute, Miguel Hernández University, Elche, Spain; CIBERehd, Health Institute Carlos III, Madrid, Spain.
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5
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Khandelwal M, Krishna G, Ying Z, Gomez-Pinilla F. Liver acts as a metabolic gate for the traumatic brain injury pathology: Protective action of thyroid hormone. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166728. [PMID: 37137432 PMCID: PMC10601893 DOI: 10.1016/j.bbadis.2023.166728] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/16/2023] [Accepted: 04/25/2023] [Indexed: 05/05/2023]
Abstract
Clinical evidence indicates that injury to the brain elicits systemic metabolic disturbances that contributes to the brain pathology. Since dietary fructose is metabolized in the liver, we explored mechanisms by which traumatic brain injury (TBI) and dietary fructose influence liver function and their possible repercussions to brain. Consumption of fructose contributed to the detrimental effects of TBI on liver operation, in terms of glucose and lipid metabolism, de novo lipogenesis, lipid peroxidation. Thyroid hormone (T4) is metabolized in the liver and found that T4 supply improved lipid metabolism by reducing de novo lipogenesis, lipid accumulation, lipogenic enzymes (ACC, AceCS1, FAS), lipid peroxidation in liver in response to fructose and fructose-TBI. T4 supply also helped to normalize glucose metabolism and improve insulin sensitivity. Furthermore, T4 counteracted elevations of the pro-inflammatory cytokines, Tnfα and Mcp-1 after TBI and/or fructose intake in liver and circulation. T4 also exerted an effect on isolated primary hepatocytes by potentiating phosphorylation of AMPKα and AKT substrate, AS160, leading to increased glucose uptake. In addition, T4 restored the metabolism of DHA in the liver disrupted by TBI and fructose, adding important information to optimize the action of DHA in therapeutics. The overall evidence seems to indicate that the liver works as a gate for the regulation of the effects of brain injury and foods on brain pathologies.
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Affiliation(s)
- Mayuri Khandelwal
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Gokul Krishna
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Zhe Ying
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Fernando Gomez-Pinilla
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA.
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Protein Susceptibility to Peroxidation by 4-Hydroxynonenal in Hereditary Hemochromatosis. Int J Mol Sci 2023; 24:ijms24032922. [PMID: 36769239 PMCID: PMC9917916 DOI: 10.3390/ijms24032922] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/26/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Iron overload caused by hereditary hemochromatosis (HH) increases free reactive oxygen species that, in turn, induce lipid peroxidation. Its 4-hydroxynonenal (HNE) by-product is a well-established marker of lipid peroxidation since it reacts with accessible proteins with deleterious consequences. Indeed, elevated levels of HNE are often detected in a wide variety of human diseases related to oxidative stress. Here, we evaluated HNE-modified proteins in the membrane of erythrocytes from HH patients and in organs of Hfe-/- male and female mice, a mouse model of HH. For this purpose, we used one- and two-dimensional gel electrophoresis, immunoblotting and MALDI-TOF/TOF analysis. We identified cytoskeletal membrane proteins and membrane receptors of erythrocytes bound to HNE exclusively in HH patients. Furthermore, kidney and brain of Hfe-/- mice contained more HNE-adducted protein than healthy controls. Our results identified main HNE-modified proteins suggesting that HH favours preferred protein targets for oxidation by HNE.
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7
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Yamkate P, Lidbury JA, Steiner JM, Suchodolski JS, Giaretta PR. Immunohistochemical Expression of Oxidative Stress and Apoptosis Markers in Archived Liver Specimens from Dogs with Chronic Hepatitis. J Comp Pathol 2022; 193:25-36. [DOI: 10.1016/j.jcpa.2022.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/20/2021] [Accepted: 02/17/2022] [Indexed: 02/08/2023]
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8
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Diurnal Variation in Biomarkers of Exposure to Endocrine-Disrupting Chemicals and Their Association with Oxidative Damage in Norwegian Adults: The EuroMix Study. TOXICS 2022; 10:toxics10040181. [PMID: 35448442 PMCID: PMC9028082 DOI: 10.3390/toxics10040181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/27/2022] [Accepted: 04/02/2022] [Indexed: 11/23/2022]
Abstract
Much evidence on the adverse health effects of endocrine-disrupting chemicals (EDCs) has accumulated during recent decades. EDCs are commonly found in various foods and personal care products (PCP). Data documenting a diurnally varying EDC metabolism in humans is scarce. This study examined (i) the time-of-day effect on the diurnal magnitude and variance of urinary biomarkers of exposure to EDCs, and (ii) the association between EDC exposures and oxidative damage in a Norwegian adult subpopulation. This was a cross-sectional panel study using biobanked samples from the EuroMix project. During a typical weekday, participants were asked to collect all day’s urine voids and record dietary and PCP habitual uses in a diary. Collected time stamps of urine voids were classified into three distinct periods in the day (morning 6 a.m.−12 p.m., mid-day 12 p.m.−6 p.m., evening 6 p.m.−6 a.m.). Questionnaires regarding demographic characteristics, personal care product usage, and dietary habits were completed. Urinary levels of EDCs (phthalates, parabens, and bisphenols) were measured using mass spectrometry and adjusted for urinary volume using specific gravity. Urinary 4-hydroxynonenal (4HNE), a lipid peroxidation marker, was measured using an immunoassay kit. Linear mixed-effect models identified EDCs under the influence of a diurnal variation effect that was adjusted for dietary habits and PCP use and examined associations between EDC and 4HNE. p-values were FDR-adjusted. Most phthalates appeared to be diurnally varying with higher urinary levels towards the evening (q < 0.001) than those measured during mid-day; this strong diurnal variation effect was not present for parabens and bisphenols. Significant (q < 0.001) positive associations were observed between all phthalates, parabens, and bisphenols (except bisphenol S) and 4HNE. This study’s findings highlighted the diurnal variation of excretion for certain EDC, but not for others, in real-life conditions. The degree of EDC chronotoxicity in distinct diurnal windows of the day warrants further investigation with longitudinal human studies.
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9
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Devi P, Khan A, Chattopadhyay P, Mehta P, Sahni S, Sharma S, Pandey R. Co-infections as Modulators of Disease Outcome: Minor Players or Major Players? Front Microbiol 2021; 12:664386. [PMID: 34295314 PMCID: PMC8290219 DOI: 10.3389/fmicb.2021.664386] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.
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Affiliation(s)
- Priti Devi
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Azka Khan
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Partha Chattopadhyay
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Priyanka Mehta
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Shweta Sahni
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Sachin Sharma
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Rajesh Pandey
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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10
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Tabakh H, McFarland AP, Thomason MK, Pollock AJ, Glover RC, Zaver SA, Woodward JJ. 4-Hydroxy-2-nonenal antimicrobial toxicity is neutralized by an intracellular pathogen. eLife 2021; 10:59295. [PMID: 33955352 PMCID: PMC8174450 DOI: 10.7554/elife.59295] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 05/05/2021] [Indexed: 01/03/2023] Open
Abstract
Pathogens encounter numerous antimicrobial responses during infection, including
the reactive oxygen species (ROS) burst. ROS-mediated oxidation of host membrane
poly-unsaturated fatty acids (PUFAs) generates the toxic alpha-beta carbonyl
4-hydroxy-2-nonenal (4-HNE). Although studied extensively in the context of
sterile inflammation, research into 4-HNE’s role during infection remains
limited. Here, we found that 4-HNE is generated during bacterial infection, that
it impacts growth and survival in a range of bacteria, and that the
intracellular pathogen Listeria monocytogenes induces many
genes in response to 4-HNE exposure. A component of the L.
monocytogenes 4-HNE response is the expression of the genes
lmo0103 and lmo0613, deemed
rha1 and rha2 (reductase of
host alkenals), respectively, which code for two
NADPH-dependent oxidoreductases that convert 4-HNE to the product
4-hydroxynonanal (4-HNA). Loss of these genes had no impact on L.
monocytogenes bacterial burdens during murine or tissue culture
infection. However, heterologous expression of rha1/2 in
Bacillus subtilis significantly increased bacterial
resistance to 4-HNE in vitro and promoted bacterial survival following
phagocytosis by murine macrophages in an ROS-dependent manner. Thus, Rha1 and
Rha2 are not necessary for 4-HNE resistance in L. monocytogenes
but are sufficient to confer resistance to an otherwise sensitive organism in
vitro and in host cells. Our work demonstrates that 4-HNE is a previously
unappreciated component of ROS-mediated toxicity encountered by bacteria within
eukaryotic hosts.
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Affiliation(s)
- Hannah Tabakh
- Department of Microbiology, University of Washington, Seattle, United States
| | - Adelle P McFarland
- Department of Microbiology, University of Washington, Seattle, United States.,Molecular and Cellular Biology Program, University of Washington, Seattle, United States
| | - Maureen K Thomason
- Department of Microbiology, University of Washington, Seattle, United States
| | - Alex J Pollock
- Department of Microbiology, University of Washington, Seattle, United States
| | - Rochelle C Glover
- Department of Microbiology, University of Washington, Seattle, United States
| | - Shivam A Zaver
- Department of Microbiology, University of Washington, Seattle, United States.,Molecular and Cellular Biology Program, University of Washington, Seattle, United States
| | - Joshua J Woodward
- Department of Microbiology, University of Washington, Seattle, United States
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11
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Abstract
Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health.
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Affiliation(s)
- Krys Bottrill
- FRAME, Russell & Burch House, 96–98 North Sherwood Street, Nottingham NG1 4EE, UK
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12
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Zou Y, Schreiber SL. Progress in Understanding Ferroptosis and Challenges in Its Targeting for Therapeutic Benefit. Cell Chem Biol 2020; 27:463-471. [PMID: 32302583 PMCID: PMC7346472 DOI: 10.1016/j.chembiol.2020.03.015] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 03/09/2020] [Accepted: 03/20/2020] [Indexed: 12/13/2022]
Abstract
Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage. In contrast to apoptosis, which enables organisms to eliminate targeted cells purposefully at specific times, ferroptosis appears to be a vulnerability of cells that otherwise use high levels of polyunsaturated lipids to their advantage. Cells in this high polyunsaturated lipid state generally have safeguards that mitigate ferroptotic risk. Since its recognition, ferroptosis has been implicated in degenerative diseases in tissues including kidney and brain, and is a targetable vulnerability in multiple cancers-each likely characterized by the high polyunsaturated lipid state with insufficient or overwhelmed ferroptotic safeguards. In this Perspective, we present progress toward defining the essential roles and key mediators of lipid peroxidation and ferroptosis in disease contexts. Moreover, we discuss gaps in our understanding of ferroptosis and list key challenges that have thus far limited the full potential of targeting ferroptosis for improving human health.
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Affiliation(s)
- Yilong Zou
- Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02142, USA.
| | - Stuart L Schreiber
- Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
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13
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Li D, Gu Z, Zhang J, Ma S. Protective effect of inducible aldo-keto reductases on 4-hydroxynonenal- induced hepatotoxicity. Chem Biol Interact 2019; 304:124-130. [PMID: 30849339 DOI: 10.1016/j.cbi.2019.02.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 01/17/2019] [Accepted: 02/14/2019] [Indexed: 12/30/2022]
Abstract
4-Hydroxynonenal (HNE), an end-product of lipid peroxidation generated in response to oxidative stress, has been implicated in the pathophysiology of chronic liver diseases. HNE is very reactive that forms Michael adducts with nucleophilic sites in DNA, lipids and proteins. At high concentrations, HNE causes rapid cell death associated with depletion of sulfhydryl groups and inhibition of key metabolic enzymes. At low concentrations, HNE stimulates expression of genes that are part of an adaptive response. In this study, we show that sub-lethal concentrations of HNE induce mRNA expression levels of heme oxygenase-1 (HO-1) (2.5-fold), NADPH:quinone oxidoreductase (NQO1) (4.5-fold), AKR1C3 (2-fold) and AKR7A2 (3-fold) enzymes. Protein expression levels of AKR1C and AKR7A2 are induced by 2- and 1.5-fold following exposure to HNE. The role of AKR1C3 and AKR7A2 in protecting HepG2 cells against HNE toxicity was investigated through using RNAi. Results show that AKR7A2, but not AKR1C3 contributes to the protection against HNE toxicity in HepG2 cells. Moreover, transcriptional factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is activated by HNE through translocation to the nucleus. Overexpressing AKR7A2 could rescue the effect of knocking down Nrf2 on HNE-induced cytotoxicity. Furthermore, a natural compound 7-hydroxycoumain, an AKR7A2 inducer, shows hepatoprotection against HNE via AKR7A2 induction. Hence, the inducible AKR7A2 has provided a new therapeutic target to treat chronic liver disease.
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Affiliation(s)
- Dan Li
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China.
| | - Zhuoliang Gu
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Jingdong Zhang
- Department of Medical Oncology, Cancer Hospital of China Medical University, China Medical University, Shenyang, 110001, China
| | - Shuren Ma
- Department of Endoscope, The General Hospital of Shenyang Military Region, Shenyang, 110016, China
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14
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Barry-Heffernan C, Ekena J, Dowling S, Pinkerton ME, Viviano K. Biomarkers of oxidative stress as an assessment of the redox status of the liver in dogs. J Vet Intern Med 2019; 33:611-617. [PMID: 30758875 PMCID: PMC6430861 DOI: 10.1111/jvim.15443] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 01/23/2019] [Indexed: 11/30/2022] Open
Abstract
Background Oxidative stress is associated with a diverse group of liver disorders across species. Objectives Determine whether glutathione (GSH) concentration in plasma and red blood cells correlates with liver GSH concentration in dogs and evaluate whether other markers of systemic oxidative stress, plasma vitamin E and urine 8‐isoprostanes/creatinine (F2‐IsoPs/Cr) concentrations, correlate with liver GSH. Animals Thirty‐four client‐owned dogs undergoing clinically indicated liver biopsy and 15 healthy control dogs. Methods Prospective, observational cross‐sectional study. Urine and blood were collected before liver biopsy. Plasma, erythrocyte, and liver GSH were measured using high performance liquid chromatography (HPLC); vitamin E was measured by HPLC, and F2‐IsoPs/Cr was measured by gas chromatography/mass spectrometry. Results All dogs were treated at the discretion of the attending clinician (24/34 received antioxidants; 4/34 fed therapeutic liver diet), which included dogs with primary or secondary liver disease (inflammatory (n = 21), metabolic (n = 9), vascular (n = 2), and neoplastic (n = 2)). Median GSH concentrations in plasma, erythrocyte, and liver were 0.18 mg/dL (range 0.14 to 0.56 mg/dL), 56.7 mg/dL (18.3 to 79.2 mg/dL), and 181 mg/dL (39.9 to 527 mg/dL), respectively. No significant correlations were found between liver GSH and erythrocyte GSH, plasma GSH, vitamin E, or F2‐IsoPs/Cr. Dogs undergoing clinically indicated liver biopsy had significantly higher urine F2‐IsoPs/Cr than did healthy controls (5.89 vs 2.98 ng/mg; P < .0001). Conclusions and Clinical Importance Erythrocyte and plasma GSH are not indicative of liver GSH concentration in dogs. In addition, dogs undergoing clinically indicated liver biopsy have evidence of increased systemic oxidative stress compared to healthy controls.
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Affiliation(s)
| | - Joanne Ekena
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin
| | - Sarah Dowling
- Lancaster Veterinary Specialties, Lancaster, Pennsylvania
| | - Marie E Pinkerton
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin
| | - Katrina Viviano
- Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin
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15
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Wang JW, Wang JW, Zhang J, Wu CS, Fang Y, Su WW, Fan YC, Wang K. Decreased Methylation of IFNAR Gene Promoter from Peripheral Blood Mononuclear Cells Is Associated with Oxidative Stress in Chronic Hepatitis B. J Interferon Cytokine Res 2018; 38:480-490. [PMID: 30383464 DOI: 10.1089/jir.2018.0068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Type I interferons (IFNs) play an antiviral effect by binding to type I interferon receptor (IFNAR). Oxidative stress might induce the gene promoter methylation. The purpose of our study was to evaluate the potential relationship between the methylation of IFNAR promoter and the status of oxidative stress in chronic hepatitis B (CHB). The methylation level of the IFNAR promoter in patients with CHB and healthy controls (HCs) was determined by methylation-specific polymerase chain reaction (MS-PCR). The quantitative real-time PCR (RT-qPCR) was used to evaluate the IFNAR mRNA status in peripheral blood mononuclear cells from CHB and HCs. Level of plasma-soluble IFNAR and oxidative stress parameters, including malondialdehyde (MDA) and glutathione (GSH) were determined by enzyme-linked immunosorbent assay (ELISA). The frequency of IFNAR promoter methylation in CHB patients was significantly lower than that of HCs. The IFNAR mRNA level of patients with CHB was higher than HCs. MDA level was higher in CHB patients, whereas GSH level was lower in CHB patients than that of HCs. In CHB patients, plasma MDA level was significantly higher with IFNAR promoter methylation than unmethylation, and soluble IFNAR in the circulation of methylated patients with CHB was decreased than unmethylated patients with CHB. Our results indicated that the IFNAR promoter methylation might have a potential relationship with the status of oxidative stress.
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Affiliation(s)
- Jing-Wen Wang
- 1 Department of Hepatology, Qilu Hospital of Shandong University , Jinan, China
| | - Jing-Wei Wang
- 2 Department of Infectious Diseases, Qilu Hospital of Shandong University (Qingdao) , Qingdao, China
| | - Jun Zhang
- 1 Department of Hepatology, Qilu Hospital of Shandong University , Jinan, China
| | - Chen-Si Wu
- 1 Department of Hepatology, Qilu Hospital of Shandong University , Jinan, China
| | - Yu Fang
- 1 Department of Hepatology, Qilu Hospital of Shandong University , Jinan, China
| | - Wei-Wei Su
- 1 Department of Hepatology, Qilu Hospital of Shandong University , Jinan, China
| | - Yu-Chen Fan
- 1 Department of Hepatology, Qilu Hospital of Shandong University , Jinan, China
- 3 Institute of Hepatology, Shandong University , Jinan, China
| | - Kai Wang
- 1 Department of Hepatology, Qilu Hospital of Shandong University , Jinan, China
- 3 Institute of Hepatology, Shandong University , Jinan, China
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16
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Ali H, Assiri MA, Shearn CT, Fritz KS. Lipid peroxidation derived reactive aldehydes in alcoholic liver disease. CURRENT OPINION IN TOXICOLOGY 2018; 13:110-117. [PMID: 31263795 DOI: 10.1016/j.cotox.2018.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Lipid peroxidation is a known consequence of oxidative stress and is thought to play a key role in numerous disease pathologies, including alcoholic liver disease (ALD). The overaccumulation of lipid peroxidation products during chronic alcohol consumption results in pathogenic lesions on protein, DNA, and lipids throughout the cell. Molecular adducts due to secondary end products of lipid peroxidation impact a host of biochemical processes, including inflammation, antioxidant defense, and metabolism. The aggregate burden of lipid peroxidation which occurs due to chronic alcohol metabolism, including downstream signaling events, contributes to the development and progression of ALD. In this current opinion we highlight recent studies and approaches relating cellular mechanisms of lipid peroxidation to the pathogenesis of alcoholic liver disease.
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Affiliation(s)
- Hadi Ali
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Mohammed A Assiri
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Colin T Shearn
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Kristofer S Fritz
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
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17
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Pinzani M, Luong TV. Pathogenesis of biliary fibrosis. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1279-1283. [PMID: 28754450 DOI: 10.1016/j.bbadis.2017.07.026] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/19/2017] [Accepted: 07/21/2017] [Indexed: 12/12/2022]
Abstract
Chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, and, ultimately, to the development of cirrhosis. However, the precise relationship between cholestasis, in its broad meaning, and liver tissue fibrosis is still poorly defined. Fibrogenesis is currently viewed as a dynamic process that appears strictly related to the extent and duration of parenchymal injury. This relationship is clearly evident in the presence of reiterative hepatocellular necrosis due to viral infection or alcohol abuse. It appears that "pure" intralobular intrahepatic cholestasis secondary to biliary secretory failure of the hepatocyte, in absence of hepatocellular damage, lobular inflammation and bile duct damage and/or proliferation, is not associated with marked and/or progressive liver tissue fibrosis. In contrast, marked and progressive liver tissue fibrosis always follows liver diseases characterized by chronic inflammatory bile duct damage as seen in PBC and PSC or chronic mechanical obstruction of the biliary tree. Overall, the fibrogenic process in these clinical conditions appears to be related to a more complex interaction between immune/inflammatory mechanisms, cytokine networks and the derangement of the homeostasis between epithelial and mesenchymal cells. The elucidation of these mechanisms is indeed crucial for the identification of potential diagnostic and therapeutic targets.
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Affiliation(s)
- Massimo Pinzani
- UCL Institute for Liver and Digestive Health, London NW3 2QG, United Kingdom.
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free Hospital, London NW3 2QG, United Kingdom
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18
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Busch CJL, Hendrikx T, Weismann D, Jäckel S, Walenbergh SMA, Rendeiro AF, Weißer J, Puhm F, Hladik A, Göderle L, Papac-Milicevic N, Haas G, Millischer V, Subramaniam S, Knapp S, Bennett KL, Bock C, Reinhardt C, Shiri-Sverdlov R, Binder CJ. Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice. Hepatology 2017; 65:1181-1195. [PMID: 27981604 PMCID: PMC5892702 DOI: 10.1002/hep.28970] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 10/31/2016] [Accepted: 11/26/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED Diet-related health issues such as nonalcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet-induced changes (e.g., hyperlipidemia) and the ensuing inflammation have remained elusive so far. We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of low-density lipoprotein receptor-deficient mice on a Western-type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that malondialdehyde (MDA) epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo. MDA-induced cytokine secretion in vitro was dependent on the presence of the scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in low-density lipoprotein receptor-deficient mice on a Western-type diet. CONCLUSION Accumulation of MDA epitopes plays a major role during diet-induced hepatic inflammation and can be ameliorated by administration of an anti-MDA antibody. (Hepatology 2017;65:1181-1195).
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Affiliation(s)
- Clara Jana-Lui Busch
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Tim Hendrikx
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria,Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - David Weismann
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Sven Jäckel
- Center for Thrombosis and Haemostasis (CTH), University Medical Center Mainz, Mainz, Germany,German Center for Cardiovascular Research (DZHK), Partner Site Rhein/Main, Mainz, Germany
| | - Sofie M. A. Walenbergh
- Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - André F. Rendeiro
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Juliane Weißer
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Florian Puhm
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Anastasiya Hladik
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria,Laboratory of Infection Biology, Department of Medicine 1, Medical University of Vienna, Vienna, Austria
| | - Laura Göderle
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Nikolina Papac-Milicevic
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Gerald Haas
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Vincent Millischer
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Saravanan Subramaniam
- Center for Thrombosis and Haemostasis (CTH), University Medical Center Mainz, Mainz, Germany
| | - Sylvia Knapp
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria,Laboratory of Infection Biology, Department of Medicine 1, Medical University of Vienna, Vienna, Austria
| | - Keiryn L. Bennett
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Christoph Bock
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria,Max Planck Institute for Informatics, 66123 Saarbrücken, Germany
| | - Christoph Reinhardt
- Center for Thrombosis and Haemostasis (CTH), University Medical Center Mainz, Mainz, Germany,German Center for Cardiovascular Research (DZHK), Partner Site Rhein/Main, Mainz, Germany
| | - Ronit Shiri-Sverdlov
- Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Christoph J. Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
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19
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Karanjia RN, Crossey MME, Cox IJ, Fye HKS, Njie R, Goldin RD, Taylor-Robinson SD. Hepatic steatosis and fibrosis: Non-invasive assessment. World J Gastroenterol 2016; 22:9880-9897. [PMID: 28018096 PMCID: PMC5143756 DOI: 10.3748/wjg.v22.i45.9880] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/10/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic liver disease is a major cause of morbidity and mortality worldwide and usually develops over many years, as a result of chronic inflammation and scarring, resulting in end-stage liver disease and its complications. The progression of disease is characterised by ongoing inflammation and consequent fibrosis, although hepatic steatosis is increasingly being recognised as an important pathological feature of disease, rather than being simply an innocent bystander. However, the current gold standard method of quantifying and staging liver disease, histological analysis by liver biopsy, has several limitations and can have associated morbidity and even mortality. Therefore, there is a clear need for safe and non-invasive assessment modalities to determine hepatic steatosis, inflammation and fibrosis. This review covers key mechanisms and the importance of fibrosis and steatosis in the progression of liver disease. We address non-invasive imaging and blood biomarker assessments that can be used as an alternative to information gained on liver biopsy.
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20
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Kannan M, Wang L, Kang YJ. Myocardial Oxidative Stress and Toxicity Induced by Acute Ethanol Exposure in Mice. Exp Biol Med (Maywood) 2016; 229:553-9. [PMID: 15169975 DOI: 10.1177/153537020422900614] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Alcoholic cardiomyopathy has been known for a long time, but there is little mechanistic insight into this important clinical problem. The present study was undertaken using a mouse model to test the hypothesis that alcohol exposure induces cardiac injury through induction of oxidative stress. Adult female Friend Virius B-type (FVB) mice were treated with ethanol by gavage at a dose of 5 g/kg. Six hours after the treatment, ethanol-induced myocardial injury was observed, as indicated by a significant increase in serum creatine phosphokinase activity, a common biomarker of myocardial injury, and myocardial ultrastructural alterations, predominantly mitochondrial swelling and cristae disarray and reduction in numbers. The myocardial injury was associated with a significant increase in the myocardial lipid peroxidation, determined by measuring thiobarbituric acid reactive substances (TBARS), and a significant increase in protein oxidation as measured by a protein carbonyl content assay. Acute alcohol exposure decreased glutathione (GSH) content in the heart, more so in the mitochondria than in the cytosol. These alcohol-induced myocardial injuries and oxidative stresses were all significantly inhibited by supplementation with N-acetyl-L-cysteine (NAC) prior to alcohol exposure. However, NAC did not affect the rise in blood alcohol concentrations following alcohol exposure. This study thus demonstrates that acute alcohol administration causes myocardial injury through, at least in part, the induction of oxidative stress. A rapid decrease in mitochondrial GSH content may be partially responsible for the observed mitochondrial damage.
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Affiliation(s)
- Muralidhar Kannan
- Department of Physiology and Biophysics, University of Louisville School of Medicine, Kentucky 40202,USA
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21
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Sundaram SS, Halbower A, Pan Z, Robbins K, Capocelli KE, Klawitter J, Shearn CT, Sokol RJ. Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease. J Hepatol 2016; 65:560-9. [PMID: 27501738 PMCID: PMC4992457 DOI: 10.1016/j.jhep.2016.04.010] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 04/01/2016] [Accepted: 04/06/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Oxidative stress is proposed as a central mediator in NAFLD pathogenesis, but the specific trigger for reactive oxygen species generation has not been clearly delineated. In addition, emerging evidence shows that obesity related obstructive sleep apnea (OSA) and nocturnal hypoxia are associated with NAFLD progression in adults. The aim of this study was to determine if OSA/nocturnal hypoxia-induced oxidative stress promotes the progression of pediatric NAFLD. METHODS Subjects with biopsy proven NAFLD and lean controls were studied. Subjects underwent polysomnograms, liver histology scoring, laboratory testing, urine F(2)-isoprostanes (measure of lipid peroxidation) and 4-hydroxynonenal liver immunohistochemistry (in situ hepatic lipid peroxidation). RESULTS We studied 36 adolescents with NAFLD and 14 lean controls. The OSA/hypoxia group (69% of NAFLD subjects) had more severe fibrosis (64% stage 0-2; 36% stage 3) than those without OSA/hypoxia (100% stage 0-2), p=0.03. Higher F(2)-isoprostanes correlated with apnea/hypoxia index (r=0.39, p=0.03), % time SaO2 <90% (r=0.56, p=0.0008) and inversely with SaO2 nadir (r=-0.46, p=0.008). OSA/hypoxia was most severe in subjects with the greatest 4HNE staining (p=0.03). Increasing F(2)-isoprostanes(r=0.32, p=0.04) and 4HNE hepatic staining (r=0.47, p=0.007) were associated with worsening steatosis. Greater oxidative stress occurred in subjects with definite NASH as measured by F(2)-isoprostanes (p=0.06) and hepatic 4HNE (p=0.03) compared to those with borderline/not NASH. CONCLUSIONS These data support the role of nocturnal hypoxia as a trigger for localized hepatic oxidative stress, an important factor associated with the progression of NASH and hepatic fibrosis in obese pediatric patients. LAY SUMMARY Obstructive sleep apnea and low nighttime oxygen are associated with NAFLD progression in adults. In this study, we show that adolescents with NAFLD who have OSA and low oxygen have significant scar tissue in their livers. NAFLD subjects affected by OSA and low oxygen have a greater imbalance between the production of free radicals and their body's ability to counteract their harmful effects than subjects without OSA and low oxygen. This study shows that low oxygen levels may be an important trigger in the progression of pediatric NASH.
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Affiliation(s)
- Shikha S. Sundaram
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO
| | - Ann Halbower
- Section of Pulmonary Medicine, Department of Pediatrics, Children's Hospital Colorado and University of Colorado School of Medicine, Anschutz Medical Center, Aurora, CO
| | - Zhaoxing Pan
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO
| | - Kristen Robbins
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO
| | - Kelley E. Capocelli
- Pediatric Pathology, Department of Pathology, University of Colorado School of Medicine, Aurora, CO
| | - Jelena Klawitter
- iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO
| | - Colin T. Shearn
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Ronald J. Sokol
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO
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22
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Chan SW. Hydrogen peroxide induces La cytoplasmic shuttling and increases hepatitis C virus internal ribosome entry site-dependent translation. J Gen Virol 2016; 97:2301-2315. [PMID: 27436793 PMCID: PMC5042130 DOI: 10.1099/jgv.0.000556] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We have previously shown that physio/pathological levels of hydrogen peroxide (H2O2) stimulate translation from the hepatitis C virus (HCV) internal ribosome entry site (IRES) element in tissue-cultured cells. Here, using in vitro translation, we further show that H2O2 upregulates HCV IRES-dependent mRNA translation and correlates with an increase in intracellular oxidant level. Using Western blotting, immunocytochemistry, microscopy and affinity pulldown, we show that H2O2 stimulates HCV IRES-dependent translation and correlates with nuclear–cytoplasmic shuttling of the La autoantigen, resulting in enhanced binding of cytoplasmic La to HCV IRES RNA. The role of the La protein in H2O2-stimulated IRES-dependent translation is further confirmed by the ability of an anti-La antibody to suppress H2O2-activated IRES-dependent translation in vitro. This is further supported by the ability of an ectopically expressed dominant, negative La mutant protein to suppress H2O2-inducible IRES-mediated translation in Huh7 cells, transiently transfected with a bicistronic reporter and in a sub-genomic replicon cell line resembling a persistent infection. On the other hand, translation from the encephalomyocarditis virus IRES is diminished in the presence of H2O2, suggesting that H2O2 translational responsiveness is a specific property of the HCV IRES and is not a general phenomenon for all viral IRESs. Altogether, these results suggest that HCV adapts to physio/pathological oxidative stress in the host cell by mediating La cytoplasmic shuttling to enhance its IRES-dependent translation.
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Affiliation(s)
- Shiu-Wan Chan
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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23
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Busch CJ, Binder CJ. Malondialdehyde epitopes as mediators of sterile inflammation. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1862:398-406. [PMID: 27355566 DOI: 10.1016/j.bbalip.2016.06.016] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/21/2016] [Accepted: 06/24/2016] [Indexed: 12/14/2022]
Abstract
Enhanced lipid peroxidation occurs during oxidative stress and results in the generation of lipid peroxidation end products such as malondialdehyde (MDA), which can attach to autologous biomolecules, thereby generating neo-self epitopes capable of inducing potentially undesired biological responses. Therefore, the immune system has developed mechanisms to protect from MDA epitopes by binding and neutralizing them through both cellular and soluble effectors. Here, we briefly discuss innate immune responses targeting MDA epitopes and their pro-inflammatory properties, followed by a review of physiological carriers of MDA epitopes that are relevant in homeostasis and disease. Then we discuss in detail the evidence for cellular responses towards MDA epitopes mainly in lung, liver and the circulation as well as signal transduction mechanisms and receptors implicated in the response to MDA epitopes. Last, we hypothesize on the role of MDA epitopes as mediators of inflammation in diseases and speculate on their contribution to disease pathogenesis. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder.
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Affiliation(s)
- Clara J Busch
- Department of Laboratory Medicine, Medical University of Vienna, Austria; Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Austria; Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
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Yokota T, Nomura K, Nagashima M, Kamimura N. Fucoidan alleviates high-fat diet-induced dyslipidemia and atherosclerosis in ApoE(shl) mice deficient in apolipoprotein E expression. J Nutr Biochem 2016; 32:46-54. [PMID: 27142736 DOI: 10.1016/j.jnutbio.2016.01.011] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 01/05/2016] [Accepted: 01/23/2016] [Indexed: 10/22/2022]
Abstract
Fucoidan, a sulfated polysaccharide extracted from brown seaweeds, possesses many biological activities including anti-inflammatory and antioxidant activities. We aimed to investigate the protective effects of fucoidan on dyslipidemia and atherosclerosis in apolipoprotein E-deficient mice (ApoE(shl) mice) and to elucidate its molecular targets in the liver by using a transcriptomic approach. For 12weeks, ApoE(shl) mice were fed a high-fat diet (HFD) supplemented with either 1% or 5% fucoidan. Fucoidan supplementation significantly reduced tissue weight (liver and white adipose tissue), blood lipid, total cholesterol (TC), triglyceride (TG), non-high-density lipoprotein cholesterol (non-HDL-C) and glucose levels in HFD-fed ApoE(shl) mice but increased plasma lipoprotein lipase (LPL) activity and HDL-C levels. Fucoidan also reduced hepatic steatosis levels (liver size, TC and TG levels, and lipid peroxidation) and increased white adipose tissue LPL activity. DNA microarray analysis and quantitative reverse transcription-polymerase chain reaction demonstrated differential expression of genes encoding proteins involved in lipid metabolism, energy homeostasis and insulin sensitivity, by activating Ppara and inactivating Srebf1. Fucoidan supplementation markedly reduced the thickness of the lipid-rich plaque, lipid peroxidation and foaming macrophage accumulation in the aorta in HFD-fed ApoE(shl) mice. Thus, fucoidan supplementation appears to have anti-dyslipidemic and anti-atherosclerotic effects by inducing LPL activity and inhibiting the effects of inflammation and oxidative stress in HFD-fed ApoE(shl) mice.
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Affiliation(s)
- Takashi Yokota
- Department of Molecular Biology, Institute for Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki 1-396, Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.
| | - Koichi Nomura
- Department of Neurology, Shioda Hospital, Idemizu 1221, Katsuura-Shi, Chiba, Japan
| | - Mikio Nagashima
- Division of Internal Medicine, Kaihin Park Clinic, 2-1-2-5 Utase, Mihama-ku, Chiba-city, Chiba, 261-0013, Japan
| | - Naomi Kamimura
- Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki 1-396, Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan
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Kaffe ET, Rigopoulou EI, Koukoulis GK, Dalekos GN, Moulas AN. Oxidative stress and antioxidant status in patients with autoimmune liver diseases. Redox Rep 2015; 20:33-41. [PMID: 25117650 PMCID: PMC6837668 DOI: 10.1179/1351000214y.0000000101] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To estimate oxidative stress and antioxidant components during different stages of autoimmune liver diseases and assess their possible implication on disease progression. METHODS We determined several markers of oxidative injury (isoprostane, aldehydes, protein carbonyls, 3-nitrotyrosine, and myeloperoxidase) and antioxidant components (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase) in whole blood, serum, and urine in 49 patients with autoimmune cholestatic liver diseases (AC) and 36 patients with autoimmune hepatitis (AIH) and healthy subjects matched for sex and age. RESULTS Both AC and AIH patients had increased levels of all lipid and protein oxidative injury products and significantly decreased whole blood glutathione levels compared to controls. AIH patients had significantly higher levels of aldehydes and glutathione peroxidase activity and significantly lower protein carbonyl levels compared to AC patients. Protein carbonyl and isoprostane levels increased and glutathione levels decreased gradually with progression from mild fibrosis to severe fibrosis and cirrhosis in both AC and AIH patients. In addition, both cirrhotic AC and AIH patients had significantly higher protein carbonyls compared to non-cirrhotics. DISCUSSION We provide novel findings in support of a major contribution of oxidant/antioxidant imbalance in the progression of liver injury in AC and AIH.
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Affiliation(s)
| | | | - George K. Koukoulis
- Department of PathologyMedical School, University of Thessaly, Larissa, Greece
| | - George N. Dalekos
- Correspondence to: George N. Dalekos, Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, School of Medicine, Biopolis, Larissa 41110, Greece.
| | - Anargyros N. Moulas
- Laboratory of BiochemistryDepartment of Animal Production, Technological Education Institute (TEI), Larissa, Greece
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Guzzo-Merello G, Cobo-Marcos M, Gallego-Delgado M, Garcia-Pavia P. Alcoholic cardiomyopathy. World J Cardiol 2014; 6:771-781. [PMID: 25228956 PMCID: PMC4163706 DOI: 10.4330/wjc.v6.i8.771] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 05/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol is the most frequently consumed toxic substance in the world. Low to moderate daily intake of alcohol has been shown to have beneficial effects on the cardiovascular system. In contrast, exposure to high levels of alcohol for a long period could lead to progressive cardiac dysfunction and heart failure. Cardiac dysfunction associated with chronic and excessive alcohol intake is a specific cardiac disease known as alcoholic cardiomyopathy (ACM). In spite of its clinical importance, data on ACM and how alcohol damages the heart are limited. In this review, we evaluate available evidence linking excessive alcohol consumption with heart failure and dilated cardiomyopathy. Additionally, we discuss the clinical presentation, prognosis and treatment of ACM.
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Zheng R, Dragomir AC, Mishin V, Richardson JR, Heck DE, Laskin DL, Laskin JD. Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats. Toxicol Appl Pharmacol 2014; 279:43-52. [PMID: 24832492 DOI: 10.1016/j.taap.2014.04.026] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 04/18/2014] [Accepted: 04/28/2014] [Indexed: 01/07/2023]
Abstract
The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress.
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Affiliation(s)
- Ruijin Zheng
- Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA
| | - Ana-Cristina Dragomir
- Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA
| | - Vladimir Mishin
- Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA
| | - Jason R Richardson
- Environmental & Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA
| | - Diane E Heck
- Environmental Science, School of Health Sciences and Practice, New York Medical College, Valhalla, NY, USA
| | - Debra L Laskin
- Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ, USA
| | - Jeffrey D Laskin
- Environmental & Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA.
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Shearn CT, Backos DS, Orlicky DJ, Smathers-McCullough RL, Petersen DR. Identification of 5' AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol. J Biol Chem 2014; 289:15449-62. [PMID: 24722988 DOI: 10.1074/jbc.m113.543942] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The production of reactive aldehydes including 4-hydroxy-2-nonenal (4-HNE) is a key component of the pathogenesis in a spectrum of chronic inflammatory hepatic diseases including alcoholic liver disease (ALD). One consequence of ALD is increased oxidative stress and altered β-oxidation in hepatocytes. A major regulator of β-oxidation is 5' AMP protein kinase (AMPK). In an in vitro cellular model, we identified AMPK as a direct target of 4-HNE adduction resulting in inhibition of both H2O2 and 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced downstream signaling. By employing biotin hydrazide capture, it was confirmed that 4-HNE treatment of cells resulted in carbonylation of AMPKα/β, which was not observed in untreated cells. Using a murine model of alcoholic liver disease, treatment with high concentrations of ethanol resulted in an increase in phosphorylated as well as carbonylated AMPKα. Despite increased AMPK phosphorylation, there was no significant change in phosphorylation of acetyl CoA carboxylase. Mass spectrometry identified Michael addition adducts of 4-HNE on Cys(130), Cys(174), Cys(227), and Cys(304) on recombinant AMPKα and Cys(225) on recombinant AMPKβ. Molecular modeling analysis of identified 4-HNE adducts on AMPKα suggest that inhibition of AMPK occurs by steric hindrance of the active site pocket and by inhibition of hydrogen peroxide induced oxidation. The observed inhibition of AMPK by 4-HNE provides a novel mechanism for altered β-oxidation in ALD, and these data demonstrate for the first time that AMPK is subject to regulation by reactive aldehydes in vivo.
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Affiliation(s)
| | | | - David J Orlicky
- Department of Pathology, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado 80045 and
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Chan SW. Establishment of chronic hepatitis C virus infection: Translational evasion of oxidative defence. World J Gastroenterol 2014; 20:2785-2800. [PMID: 24659872 PMCID: PMC3961964 DOI: 10.3748/wjg.v20.i11.2785] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 12/03/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) causes a clinically important disease affecting 3% of the world population. HCV is a single-stranded, positive-sense RNA virus belonging to the genus Hepacivirus within the Flaviviridae family. The virus establishes a chronic infection in the face of an active host oxidative defence, thus adaptation to oxidative stress is key to virus survival. Being a small RNA virus with a limited genomic capacity, we speculate that HCV deploys a different strategy to evade host oxidative defence. Instead of counteracting oxidative stress, it utilizes oxidative stress to facilitate its own survival. Translation is the first step in the replication of a plus strand RNA virus so it would make sense if the virus can exploit the host oxidative defence in facilitating this very first step. This is particularly true when HCV utilizes an internal ribosome entry site element in translation, which is distinctive from that of cap-dependent translation of the vast majority of cellular genes, thus allowing selective translation of genes under conditions when global protein synthesis is compromised. Indeed, we were the first to show that HCV translation was stimulated by an important pro-oxidant-hydrogen peroxide in hepatocytes, suggesting that HCV is able to adapt to and utilize the host anti-viral response to facilitate its own translation thus allowing the virus to thrive under oxidative stress condition to establish chronicity. Understanding how HCV translation is regulated under oxidative stress condition will advance our knowledge on how HCV establishes chronicity. As chronicity is the initiator step in disease progression this will eventually lead to a better understanding of pathogenicity, which is particularly relevant to the development of anti-virals and improved treatments of HCV patients using anti-oxidants.
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30
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Do THT, Gaboriau F, Cannie I, Batusanski F, Ropert M, Moirand R, Brissot P, Loreal O, Lescoat G. Iron-mediated effect of alcohol on hepatocyte differentiation in HepaRG cells. Chem Biol Interact 2013; 206:117-25. [PMID: 24025710 DOI: 10.1016/j.cbi.2013.08.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 08/19/2013] [Accepted: 08/30/2013] [Indexed: 01/16/2023]
Abstract
The development of alcoholic liver diseases depends on the ability of hepatocyte to proliferate and differentiate in the case of alcohol-induced injury. Our previous work showed an inhibitory effect of alcohol on hepatocyte proliferation. However, the effect of alcohol on hepatocyte differentiation has not yet been precisely characterized. In the present study, we evaluated the effect of alcohol on hepatocyte differentiation in relationship with changes of iron metabolism in HepaRG cells. This unique bipotent human cell line can differentiate into hepatocytes and biliary epithelial cells, paralleling liver development. Results showed that alcohol reduced cell viability, total protein level and enhanced hepatic enzymes leakage in differentiated HepaRG cells. Moreover, it caused cell enlargement, decreased number of hepatocyte and expression of C/EBPα as well as bile canaliculi F-actin. Alcohol increased expression of hepatic cell-specific markers and alcohol-metabolizing enzymes (ADH2, CYP2E1). This was associated with a lipid peroxidation and an iron excess expressed by an increase in total iron content, ferritin level, iron uptake as well as an overexpression of genes involved in iron transport and storage. Alcohol-induced hepatoxicity was amplified by exogenous iron via exceeding iron overload. Taken together, our data demonstrate that in differentiated hepatocytes, alcohol reduces proliferation while increasing expression of hepatic cell-specific markers. Moreover, iron overload could be one of the underlying mechanisms of effect of alcohol on the whole differentiation process of hepatocytes.
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Affiliation(s)
- Thi Hong Tuoi Do
- Inserm, UMR 991, «Foie, Métabolismes et Cancer», F-35033 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; University of Medicine and Pharmacy at Ho Chi Minh City, Viet Nam.
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31
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Chang HF, Wu CH, Yang LL. Antitumour and free radical scavenging effects of γ-mangostin isolated from Garcinia mangostana pericarps against hepatocellular carcinoma cell. ACTA ACUST UNITED AC 2013; 65:1419-28. [PMID: 23927480 DOI: 10.1111/jphp.12111] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Accepted: 06/17/2013] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Liver cancer is one of the highest rate diseases in southeastern Asia. Recently, many of functional foods and alternative medicines are very popularly utilized to prevent chronic diseases and cancer in Taiwan. In this study, we wanted to select and develop some of novel effectual agents or phytochemicals of γ-mangostin for clinical management or prevent hepatocellular carcinoma cell (HCC). METHODS Lipid peroxidation (LPO) is an autocatalytic mechanism which induced tissue injure and carcinogenesis. In this study, the inhibitory activity of γ-mangostin on oxidative damage induced rat mitochondria LPO, the free radical scavenging of γ-mangostin and the apoptotic effects of γ-mangostin on HepG2 cells were investigated. KEY FINDINGS γ-Mangostin processed activity to inhibit LPO and scavenge 2,2-diphenyl-1-picrylhydrazyl. γ-Mangostin showed antiproliferative activity and induced nuclear condensation and apoptotic bodies appearance under Giemsa staining by microscopic observation. In addition, γ-mangostin showed increases of hypodiploid cells via propidium iodide, 2'7'-dichlorofluorescein diacetate, and 3,3'-dihexyloxacarbocyanine iodide staining by flow cytometry analysis in HepG2 cells. CONCLUSIONS γ-Mangostin has demonstrated free radical scavenging activity, and antiproliferative and apoptotic activity in HepG2 cells. The proof suggests that γ-mangostin is a lead compound candidate for clinical management or prevent HCC.
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Affiliation(s)
- Hui-Fang Chang
- Department of Pharmacognosy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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Wang T, Weinman SA. Interactions Between Hepatitis C Virus and Mitochondria: Impact on Pathogenesis and Innate Immunity. CURRENT PATHOBIOLOGY REPORTS 2013; 1:179-187. [PMID: 23956955 DOI: 10.1007/s40139-013-0024-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) causes a persistent chronic infection of hepatocytes resulting in progressive fibrosis and carcinogenesis. Abnormalities in mitochondria are prominent features of clinical disease where ultrastructural changes, alterations in electron transport, and excess reactive oxygen species (ROS) production occur. These mitochondrial abnormalities correlate with disease severity and resolve with viral eradication. Multiple viral proteins, particularly core and NS3/4a bind to mitochondria. The core and NS5a proteins primarily cause ER stress, ER Ca2+ release and enhance direct transfer of Ca2+ from ER to mitochondria. This results in electron transport changes, increased ROS production and sensitivity to mitochondrial permeability transition and cell death. The viral protease, NS3/4a, binds to mitochondria as well where it cleaves an important signaling adapter, MAVS, thus preventing viral clearance by endogenous interferon production. This review discusses the mechanisms by which HCV causes mitochondrial changes and consequences of these for disease.
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Affiliation(s)
- Ting Wang
- Liver Center and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160
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33
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Cui WX, Li JJ, Chen XQ, Mao Q, Wei XL, Wen XD, Yang J, Wang Q. Ilexgenin A Obtained fromIlex hainanensisMerr. Improves Diet-Induced Non-Alcoholic Fatty Liver Disease in Rats. Drug Dev Res 2013. [DOI: 10.1002/ddr.21066] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Wei-xi Cui
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing; 210009; China
| | - Jing-Jing Li
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing; 210009; China
| | - Xiao-qing Chen
- School of Traditional Chinese Medicine; Capital Medical University; Beijing; 100069; China
| | - Qian Mao
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing; 210009; China
| | - Xiang-lan Wei
- Pharmaceutical Preparation Section; Xi'an Chest and Tuberculosis Hospital; Shanxi; China
| | - Xiao-dong Wen
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing; 210009; China
| | - Jie Yang
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing; 210009; China
| | - Qiang Wang
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing; 210009; China
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Goodwin M, Herath C, Jia Z, Leung C, Coughlan MT, Forbes J, Angus P. Advanced glycation end products augment experimental hepatic fibrosis. J Gastroenterol Hepatol 2013; 28:369-76. [PMID: 23173780 DOI: 10.1111/jgh.12042] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2012] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Advanced glycation end products (AGEs) are nonenzymatic modifications of proteins by reducing sugars. These compounds accumulate in a number of chronic disease states, contributing to tissue injury via several mechanisms, including activation of the receptor for advanced glycation end products (RAGE). We aimed to investigate whether AGEs can exacerbate chronic liver injury and contribute to hepatic fibrosis. METHODS We initially studied the effects of chronic hepatic exposure to high levels of AGEs given intraperitoneally as AGE-rat serum albumin. In a separate experiment, we examined the impact of high AGE exposure in rats following bile duct ligation (BDL). RESULTS In normal rats, chronic AGE-rat serum albumin administration induced significant increases in α-smooth muscle actin gene and protein expression but did not induce fibrosis or biochemical evidence of liver injury. However, in BDL animals, AGE-bovine serum albumin administration significantly increased hepatic fibrosis as evidenced by increased collagen content and α-smooth muscle actin expression, compared with BDL alone. Furthermore, AGEs increased hepatic oxidative stress and receptor for advanced glycation end products gene expression. CONCLUSIONS These findings suggest that AGEs may contribute to the pathogenesis of chronic liver injury and fibrosis.
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Affiliation(s)
- Michelle Goodwin
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
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35
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Kumari P, Singh RP, Bijo AJ, Reddy CRK, Jha B. Estimation of Lipid Hydroperoxide Levels in Tropical Marine Macroalgae. JOURNAL OF PHYCOLOGY 2012; 48:1362-1373. [PMID: 27009988 DOI: 10.1111/j.1529-8817.2012.01208.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 06/05/2012] [Indexed: 06/05/2023]
Abstract
The incipient levels of lipid hydroperoxides (LHPOs) were determined in selected green, brown, and red macroalgae by the FOX assay using hydroperoxy HPLC mix. The LHPOs contents varied between the investigated species and showed relatively low values in this study. Among the greens, it varied from 12 ± 6.2 μg · g(-1) (Codium sursum) to 31.5 ± 2.8 μg · g(-1) (Ulva lactuca), whereas in reds, from 5.7 ± 1.6 μg · g(-1) (Gracilaria corticata) to 46.2 ± 6 μg · g(-1) (Sarconema filiforme), and in browns, from 4.6 ± 4.4 μg · g(-1) (Dictyota bartayresiana) to 79 ± 5.0 μg · g(-1) (Sargassum tenerrimum), on fresh weight basis. These hydroperoxides represented a minor fraction of total lipids and ranged from 0.04% (S. swartzii) to 1.1% (S. tenerrimum) despite being a rich source of highly unsaturated fatty acids. The susceptibility of peroxidation was assessed by specific lipid peroxidazibility (SLP) values for macroalgal tissues. The LHPO values were found to be independent of both the PUFAs contents and their degree of unsaturation (DBI), as evident from the PCA analysis. SLP values were positively correlated with the LHPOs and negatively with DBI. The FOX assay gave ≥20-fold higher values for LHPOs as compared to the TBARS method for all the samples investigated in this study. Furthermore, U. lactuca cultured in artificial seawater (ASW) enriched with nutrients (N, P, and NP) showed a sharp decline in LHPOs contents relative to those cultured in ASW alone P ≤ 0.05. It is inferred from this study that the FOX assay is an efficient, rapid, sensitive, and inexpensive technique for detecting the incipient lipid peroxidation in macroalgal tissues.
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Affiliation(s)
- Puja Kumari
- Discipline of Marine Biotechnology and Ecology, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, 364002, Gujarat, India
| | - Ravindra Pal Singh
- Discipline of Marine Biotechnology and Ecology, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, 364002, Gujarat, India
| | - A J Bijo
- Discipline of Marine Biotechnology and Ecology, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, 364002, Gujarat, India
| | - C R K Reddy
- Discipline of Marine Biotechnology and Ecology, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, 364002, Gujarat, India
| | - Bhavanath Jha
- Discipline of Marine Biotechnology and Ecology, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, 364002, Gujarat, India
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Kaviarasan S, Sundarapandiyan R, Anuradha CV. Epigallocatechin gallate, a green tea phytochemical, attenuates alcohol-induced hepatic protein and lipid damage. Toxicol Mech Methods 2012; 18:645-52. [PMID: 20020850 DOI: 10.1080/15376510701884985] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
ABSTRACT Oxidative damage to cellular constituents is one of the major mechanisms of alcoholic liver injury, and administration of antioxidants ameliorates alcoholic liver disease. The present study investigated the influence of (-) epigallocatechin gallate (EGCG), a major polyphenol component of green tea, on oxidant-antioxidant balance, protein, and lipid damage in liver of rats fed ethanol. Chronic ethanol administration (6 g/kg/day x 60 days) caused liver damage that was manifested by excessive formation of lipid peroxidation end products such as thiobarbituric acid-reactive substances (TBARS), lipid hydroperoxides (LHP), and conjugated dienes (CD) accompanied by a reduction in enzymic and non-enzymic antioxidant levels. Further, ethanol caused a rise in protein carbonyl formation and loss of protein thiol groups. Ethanol-fed rats exhibited increased staining for the presence of 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT), and 2,4-dinitrophenol (DNP) protein adducts in liver. The detrimental effects of ethanol were alleviated upon simultaneous treatment with EGCG (100 mg/kg/day) for the last 30 days of alcohol feeding. These findings show that EGCG ameliorates protein and lipid damage induced by the hepatotoxin, ethanol.
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Affiliation(s)
- S Kaviarasan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, India
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PPARs and HCV-Related Hepatocarcinoma: A Mitochondrial Point of View. PPAR Res 2012; 2012:605302. [PMID: 22966221 PMCID: PMC3431172 DOI: 10.1155/2012/605302] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 07/16/2012] [Indexed: 12/24/2022] Open
Abstract
Hepatitis-C-virus-related infective diseases are worldwide spread pathologies affecting primarily liver. The infection is often asymptomatic, but when chronically persisting can lead to liver scarring and ultimately to cirrhosis, which is generally apparent after decades. In some cases, cirrhosis will progress to develop liver failure, liver cancer, or life-threatening esophageal and gastric varices. HCV-infected cells undergo profound metabolic dysregulation whose mechanisms are yet not well understood. An emerging feature in the pathogenesis of the HCV-related disease is the setting of a pro-oxidative condition caused by dysfunctions of mitochondria which proved to be targets of viral proteins. This causes deregulation of mitochondria-dependent catabolic pathway including fatty acid oxidation. Nuclear receptors and their ligands are fundamental regulators of the liver metabolic homeostasis, which are disrupted following HCV infection. In this contest, specific attention has been focused on the peroxisome proliferator activated receptors given their role in controlling liver lipid metabolism and the availability of specific pharmacological drugs of potential therapeutic utilization. However, the reported role of PPARs in HCV infection provides conflicting results likely due to different species-specific contests. In this paper we summarize the current knowledge on this issue and offer a reconciling model based on mitochondria-related features.
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Shearn CT, Reigan P, Petersen DR. Inhibition of hydrogen peroxide signaling by 4-hydroxynonenal due to differential regulation of Akt1 and Akt2 contributes to decreases in cell survival and proliferation in hepatocellular carcinoma cells. Free Radic Biol Med 2012; 53:1-11. [PMID: 22580126 PMCID: PMC3377776 DOI: 10.1016/j.freeradbiomed.2012.04.021] [Citation(s) in RCA: 217] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 04/18/2012] [Accepted: 04/22/2012] [Indexed: 11/16/2022]
Abstract
Dysregulation of cell signaling by electrophiles such as 4-hydroxynonenal (4-HNE) is a key component in the pathogenesis of chronic inflammatory liver disease. Another consequence of inflammation is the perpetuation of oxidative damage by the production of reactive oxidative species such as hydrogen peroxide. Previously, we have demonstrated Akt2 as a direct target of 4-HNE in hepatocellular carcinoma cells. In the present study, we used the hepatocellular carcinoma cell line HepG2 as model to understand the combinatorial effects of 4-HNE and hydrogen peroxide. We demonstrate that 4-HNE inhibits hydrogen peroxide-mediated phosphorylation of Akt1 but not Akt2. Pretreatment of HepG2 cells with 4-HNE prevented hydrogen peroxide stimulation of Akt-dependent phosphorylation of downstream targets and intracellular Akt activity compared with untreated control cells. Using biotin hydrazide capture, it was confirmed that 4-HNE treatment resulted in carbonylation of Akt1, which was not observed in untreated control cells. Using a synthetic GSK3α/β peptide as a substrate, treatment of recombinant human myristoylated Akt1 (rAkt1) with 20 or 40 μΜ 4-HNE inhibited rAkt1 activity by 29 and 60%, respectively. We further demonstrate that 4-HNE activates Erk via a PI3 kinase and PP2A-dependent mechanism leading to increased Jnk phosphorylation. At higher concentrations, 4-HNE decreased both cell survival and proliferation as evidenced by MTT assays and EdU incorporation as well as decreased expression of cyclin D1 and β-catenin, an effect only moderately increased by the addition of hydrogen peroxide. The ability of 4-HNE to exert combinatorial effects on Erk, Jnk, and Akt-dependent cell survival pathways provides additional insight into the mechanisms of cellular damage associated with chronic inflammation.
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Affiliation(s)
| | | | - Dennis R. Petersen
- To whom correspondence should be addressed: Dennis Petersen, University of Colorado Denver, School of Pharmacy, Department of Pharmaceutical Sciences, 12850 East Montview Blvd Box C238, Building V20 Room 2131, Ph. 303-724-3397, Fax 303-724-7266,
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Smathers RL, Fritz KS, Galligan JJ, Shearn CT, Reigan P, Marks MJ, Petersen DR. Characterization of 4-HNE modified L-FABP reveals alterations in structural and functional dynamics. PLoS One 2012; 7:e38459. [PMID: 22701647 PMCID: PMC3368874 DOI: 10.1371/journal.pone.0038459] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 05/05/2012] [Indexed: 01/01/2023] Open
Abstract
4-Hydroxynonenal (4-HNE) is a reactive α,β-unsaturated aldehyde produced during oxidative stress and subsequent lipid peroxidation of polyunsaturated fatty acids. The reactivity of 4-HNE towards DNA and nucleophilic amino acids has been well established. In this report, using proteomic approaches, liver fatty acid-binding protein (L-FABP) is identified as a target for modification by 4-HNE. This lipid binding protein mediates the uptake and trafficking of hydrophobic ligands throughout cellular compartments. Ethanol caused a significant decrease in L-FABP protein (P<0.001) and mRNA (P<0.05), as well as increased poly-ubiquitinated L-FABP (P<0.001). Sites of 4-HNE adduction on mouse recombinant L-FABP were mapped using MALDI-TOF/TOF mass spectrometry on apo (Lys57 and Cys69) and holo (Lys6, Lys31, His43, Lys46, Lys57 and Cys69) L-FABP. The impact of 4-HNE adduction was found to occur in a concentration-dependent manner; affinity for the fluorescent ligand, anilinonaphthalene-8-sulfonic acid, was reduced from 0.347 µM to Kd(1) = 0.395 µM and Kd(2) = 34.20 µM. Saturation analyses revealed that capacity for ligand is reduced by approximately 50% when adducted by 4-HNE. Thermal stability curves of apo L-FABP was also found to be significantly affected by 4-HNE adduction (ΔTm = 5.44°C, P<0.01). Computational-based molecular modeling simulations of adducted protein revealed minor conformational changes in global protein structure of apo and holo L-FABP while more apparent differences were observed within the internal binding pocket, revealing reduced area and structural integrity. New solvent accessible portals on the periphery of the protein were observed following 4-HNE modification in both the apo and holo state, suggesting an adaptive response to carbonylation. The results from this study detail the dynamic process associated with L-FABP modification by 4-HNE and provide insight as to how alterations in structural integrity and ligand binding may a contributing factor in the pathogenesis of ALD.
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Affiliation(s)
- Rebecca L. Smathers
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Kristofer S. Fritz
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - James J. Galligan
- Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Colin T. Shearn
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Philip Reigan
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
| | - Michael J. Marks
- Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, United States of America
| | - Dennis R. Petersen
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America
- * E-mail:
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Lim JS, Park SH, Jang KL. Hepatitis C virus Core protein overcomes stress-induced premature senescence by down-regulating p16 expression via DNA methylation. Cancer Lett 2012; 321:154-61. [PMID: 22326283 DOI: 10.1016/j.canlet.2012.01.044] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2011] [Revised: 01/31/2012] [Accepted: 01/31/2012] [Indexed: 12/22/2022]
Abstract
Hepatitis C virus Core plays a vital role in the development of hepatocellular carcinoma; however, the mechanism is still controversial. Here, we show that Core overcomes premature senescence provoked by a reactive oxygen species inducer, H2O2, in human liver cells. For this effect, Core down-regulated levels of p16 via promoter hypermethylation and subsequently induced phosphorylation of Rb in the presence of H2O2. Levels of p21 and p27, however, were little affected by Core under the condition. The potentials of Core to inactivate Rb and suppress H2O2-mediated cellular senescence were abolished when levels of p16 were recovered by either exogenous complementation or inhibition of DNA methylation. Considering that cellular senescence provoked by oxidative stresses is an important tumor suppression process, our present study provides a new strategy by which HCV promotes development of hepatocellular carcinoma.
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Affiliation(s)
- Joo Song Lim
- Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea
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Miloudi K, Comte B, Rouleau T, Montoudis A, Levy E, Lavoie JC. The mode of administration of total parenteral nutrition and nature of lipid content influence the generation of peroxides and aldehydes. Clin Nutr 2012; 31:526-34. [PMID: 22230256 DOI: 10.1016/j.clnu.2011.12.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Revised: 12/21/2011] [Accepted: 12/23/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS The absence of light protection of neonatal total parenteral nutrition (PN) contributes to the generation of 4-hydroxynonenal and peroxides. 4-Hydroxynonenal is suspected to be involved in PN-related liver complications. AIMS To find a practical modality to reduce 4-hydroxynonenal in PN and assess in vivo the impact of PN containing low 4-hydroxynonenal concentration. METHODS Six modalities of delivering PN were compared for the in vitro generation of peroxides and 4-hydroxynonenal: 1) MV-AA-L: light-protected (-L) solution containing multivitamin (MV) mixed with amino acids + dextrose (AA); 2) MV-AA+L: MV-AA without photo-protection (+L); 3) MV-LIP+L: MV mixed with lipid emulsion (LIP). LIP was a) Intralipid20%(®) or b) Omegaven(®). Hepatic markers of oxidative stress (glutathione, F(2α)-isoprostanes, GS-HNE) and inflammation (mRNA of TNF-α and IL-1) were measured in newborn guinea pigs infused during 4-days with MV-AA+L compounded with Intralipid20%(®) or Omegaven(®). RESULTS Hydroperoxides and 4-hydroxynonenal were the lowest in MV-AA-L and the highest in MV-LIP+L. MV-AA+L with Omegaven(®) was associated with the lowest levels of markers of oxidative stress and inflammation. CONCLUSION Compared to Intralipid20%(®), Omegaven(®) reduces oxidative stress associated with PN and prevents liver inflammation. These findings offer an alternative strategy to light protection of PN, which in the clinical setting is a cumbersome modality.
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Affiliation(s)
- Khalil Miloudi
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
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Theise ND, Bodenheimer HC, Ferrell LD. Acute and chronic viral hepatitis. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:361-401. [DOI: 10.1016/b978-0-7020-3398-8.00007-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Li T, Meng QH, Zou ZQ, Fan YC, Long B, Guo YM, Hou W, Zhao J, Li J, Yu HW, Zhu YK, Wang K. Correlation between promoter methylation of glutathione-S-tranferase P1 and oxidative stress in acute-on-chronic hepatitis B liver failure. J Viral Hepat 2011; 18:e226-e231. [PMID: 21692937 DOI: 10.1111/j.1365-2893.2011.01438.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Promoter methylation of glutathione-S-transferase P1 (GSTP1) may be involved in liver damage caused by oxidative stress in acute-on-chronic hepatitis B-induced liver failure (ACHBLF). This study aimed to explore GSTP1 promoter methylation status and oxidative stress in such patients. DNA was extracted from peripheral blood mononuclear cells (PBMCs) of patients with acute-on-chronic liver hepatitis B-induced liver failure, chronic hepatitis B (CHB) and normal controls, followed by sodium-bisulfite treatment and methylation-specific PCR (MSP) analysis. Plasma malondialdehyde (MDA) adducts levels were detected by enzyme-linked immunosorbent assay as oxidative stress marker. Model for end-stage liver disease (MELD) score was employed to estimate the severity of the liver failure. Eleven of 35 patients with acute-on-chronic liver failure and 3 of 35 patients with stab le hepatitis B displayed GSTP1 promoter methylation, and the difference was significant (χ2) = 5.71, P = 0.02). No differences in standard liver function tests were found in patients with acute-on-chronic liver failure with and without GSTP1 promoter methylation although the levels of total bilirubin were greater in those with methylation. The levels of MDA adducts were significantly higher in patients with liver failure when compared to those with CHB (12.44 ± 5.38 pmol/mg vs 8.42 ± 5.49 pmol/mg, P < 0.01), and in the patients with liver failure who had promoter methylation the levels were higher than in those who did not (15.2 ± 4.68 pmol/mg vs 11.17 ± 5.29 pmol/mg, P < 0.01). The MELD score was not significantly different between methylated and unmethylated patients with liver failure (P > 0.05), although MDA adducts were correlated with MELD scores in patients with acute-on-chronic liver failure (r = 0.579, P < 0.01). GSTP1 promoter methylation may facilitate oxidative stress-associated liver damage in ACHBLF, and oxidative stress is correlated with ACHBLF severity.
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Affiliation(s)
- T Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
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Smathers RL, Galligan JJ, Stewart BJ, Petersen DR. Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease. Chem Biol Interact 2011; 192:107-12. [PMID: 21354120 PMCID: PMC3109208 DOI: 10.1016/j.cbi.2011.02.021] [Citation(s) in RCA: 300] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 02/17/2011] [Accepted: 02/18/2011] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Oxidative stress is one component of alcoholic liver disease (ALD) that is manifested in the peroxidation of cellular lipids producing the electrophile, 4-hydroxynonenal (4-HNE). This electrophile is proposed to modify essential cellular proteins resulting in loss of protein function and cellular homeostasis. Studies were initiated to identify hepatic proteins that are targets of 4-HNE modification and determine their relationship with progression of the early stages of ALD. METHODS Rat and mouse models were developed using the Lieber-DeCarli diet to simulate early stages of ALD consisting of fatty liver (steatosis) and hepatocellular injury indicated by a 1.5-2-fold elevation of plasma ALT activity. Liver samples obtained from control and ethanol treated animals were subjected to two-dimensional electrophoresis and immunoblotting using polyclonal antibodies generated against 4-HNE epitopes for detection of proteins modified by 4-HNE. Following identification of 4-HNE adducted proteins, the respective recombinant proteins modified with physiologic concentrations of 4-HNE were evaluated to determine the functional consequences of 4-HNE modification. RESULTS One group of proteins identified included Hsp70, Hsp90 and protein disulfide isomerase (PDI), all of which are involved in protein folding or processing are targets of adduction. In vitro assays indicated significant impairment of the protein activities following modification with physiologically relevant concentrations of 4-HNE. Liver fatty acid binding protein, L-FABP, was also identified as a target and additional studies revealed that the levels of this protein were significantly decreased because of chronic ethanol ingestion. Erk1/2 was identified as a target for modification and subsequently determined to have impaired activity. CONCLUSIONS Inhibition of Hsp70, Hsp90 and PDI function could be involved in initiation of the early phases of ER stress contributing to stimulation and accumulation of hepatic lipids. Likewise, impairment of L-FABP activity could also disrupt lipid transport also contributing to steatosis. The modification and inhibition of Erk1/2 by 4-HNE may also contribute to the decreased hepatocellular proliferation associated with ALD. Collectively, these results provide new information concerning the mechanisms whereby the modification of hepatic proteins by 4-HNE contributes to ALD.
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Affiliation(s)
- Rebecca L Smathers
- Molecular Toxicology Program, Department of Pharmaceutical Sciences, University of Colorado Denver, USA
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45
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Lipid Peroxidation in Acute Respiratory Distress Syndrome and Liver Failure. J Surg Res 2011; 168:243-52. [DOI: 10.1016/j.jss.2009.10.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2009] [Revised: 09/07/2009] [Accepted: 10/19/2009] [Indexed: 12/12/2022]
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Shearn CT, Smathers RL, Stewart BJ, Fritz KS, Galligan JJ, Hail N, Petersen DR. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition by 4-hydroxynonenal leads to increased Akt activation in hepatocytes. Mol Pharmacol 2011; 79:941-52. [PMID: 21415306 PMCID: PMC3102545 DOI: 10.1124/mol.110.069534] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Accepted: 03/17/2011] [Indexed: 12/13/2022] Open
Abstract
The production of reactive aldehydes such as 4-hydroxynonenal (4-HNE) is proposed to be an important factor in the etiology of alcoholic liver disease. To understand the effects of 4-HNE on homeostatic signaling pathways in hepatocytes, cellular models consisting of the human hepatocellular carcinoma cell line (HepG2) and primary rat hepatocytes were evaluated. Treatment of both HepG2 cells and primary hepatocytes with subcytotoxic concentrations of 4-HNE resulted in the activation of Akt within 30 min as demonstrated by increased phosphorylation of residues Ser473 and Thr308. Quantification and subsequent immunocytochemistry of phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)[rsqb] resulted in a 6-fold increase in total PtdIns(3,4,5)P(3) and increased immunostaining at the plasma membrane after 4-HNE treatment. Cotreatment of HepG2 cells with 4-HNE and the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (Ly294002) or the protein phosphatase 2A (PP2A) inhibitor okadaic acid revealed that the mechanism of activation of Akt is PI3K-dependent and PP2A-independent. Using biotin hydrazide detection, it was established that the incubation of HepG2 cells with 4-HNE resulted in increased carbonylation of the lipid phosphatase known as "phosphatase and tensin homolog deleted on chromosome 10" (PTEN), a key regulator of Akt activation. Activity assays both in HepG2 cells and recombinant PTEN revealed a decrease in PTEN lipid phosphatase activity after 4-HNE application. Mass spectral analysis of 4-HNE-treated recombinant PTEN detected a single 4-HNE adduct. Subsequent analysis of Akt dependent physiological consequences of 4-HNE in HepG2 cells revealed significant increases in the accumulation of neutral lipids. These results provide a potential mechanism of Akt activation and cellular consequences of 4-HNE in hepatocytes.
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Affiliation(s)
- Colin T Shearn
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, Colorado, USA
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Simula MP, De Re V. Hepatitis C virus-induced oxidative stress and mitochondrial dysfunction: a focus on recent advances in proteomics. Proteomics Clin Appl 2011; 4:782-93. [PMID: 21137022 DOI: 10.1002/prca.201000049] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The natural history of chronic hepatitis C virus (HCV) infection presents two major aspects. On one side, the illness is by itself benign, whereas, on the other side, epidemiological evidence clearly identifies chronic HCV infection as the principal cause of cirrhosis, hepatocellular carcinoma, and extrahepatic diseases, such as autoimmune type II mixed cryoglobulinemia and some B cell non-Hodgkin's lymphomas. The mechanisms responsible for the progression of liver disease to severe liver injury are still poorly understood. Nonetheless, considerable biological data and studies from animal models suggest that oxidative stress contributes to steatohepatitis and that the increased generation of reactive oxygen and nitrogen species, together with the decreased antioxidant defense, promotes the development of hepatic and extrahepatic complications of HCV infection. The principal mechanisms causing oxidative stress in HCV-positive subjects have only been partially elucidated and have identified chronic inflammation, iron overload, ER stress, and a direct activity of HCV proteins in increasing mitochondrial ROS production, as key events. This review summarizes current knowledge regarding mechanisms of HCV-induced oxidative stress with its long-term effects in the context of HCV-related diseases, and includes a discussion of recent contributions from proteomics studies.
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Affiliation(s)
- Maria Paola Simula
- Experimental and Clinical Pharmacology Unit, CRO Centro di Riferimento Oncologico, IRCCS National Cancer Institute, AVIANO (PN), Italy
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Shearn CT, Fritz KS, Reigan P, Petersen DR. Modification of Akt2 by 4-Hydroxynonenal Inhibits Insulin-Dependent Akt Signaling in HepG2 Cells. Biochemistry 2011; 50:3984-96. [DOI: 10.1021/bi200029w] [Citation(s) in RCA: 247] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- C. T. Shearn
- Department of Pharmaceutical Sciences, University of Colorado—Denver, Aurora, Colorado 80045, United States
| | - K. S. Fritz
- Department of Pharmaceutical Sciences, University of Colorado—Denver, Aurora, Colorado 80045, United States
| | - P. Reigan
- Department of Pharmaceutical Sciences, University of Colorado—Denver, Aurora, Colorado 80045, United States
| | - Dennis R. Petersen
- Department of Pharmaceutical Sciences, University of Colorado—Denver, Aurora, Colorado 80045, United States
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Baum MK, Sales S, Jayaweera DT, Lai S, Bradwin G, Rafie C, Page JB, Campa A. Coinfection with hepatitis C virus, oxidative stress and antioxidant status in HIV-positive drug users in Miami. HIV Med 2011; 12:78-86. [PMID: 20500231 PMCID: PMC2974022 DOI: 10.1111/j.1468-1293.2010.00849.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND The pathogenesis of HIV/hepatitis C virus (HCV) coinfection is poorly understood. We examined markers of oxidative stress, plasma antioxidants and liver disease in HIV/HCV-coinfected and HIV-monoinfected adults. METHODS Demographics, medical history, and proof of infection with HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) and HCV were obtained. HIV viral load, CD4 cell count, complete blood count (CBC), complete metabolic panel, lipid profile, and plasma concentrations of zinc, selenium, and vitamins A and E were determined. Malondialdehyde (MDA) and glutathione peroxidase concentrations were obtained as measures of oxidative stress. Aminotransferase to platelet ratio index (APRI) and fibrosis index (FIB-4) markers were calculated. RESULTS Significant differences were found between HIV/HCV-coinfected and HIV-monoinfected participants in levels of alanine aminotransferase (ALT) (mean±standard deviation: 51.4±50.6 vs. 31.9±43.1 U/L, respectively; P=0.014), aspartate aminotransferase (AST) (56.2±40.9 vs. 34.4±30.2 U/L; P<0.001), APRI (0.52±0.37 vs. 0.255±0.145; P=0.0001), FIB-4 (1.64±.0.91 vs. 1.03±0.11; P=0.0015) and plasma albumin (3.74±0.65 vs. 3.94±0.52 g/dL; P=0.038). There were no significant differences in CD4 cell count, HIV viral load or antiretroviral therapy (ART) between groups. Mean MDA was significantly higher (1.897±0.835 vs. 1.344± 0.223 nmol/mL, respectively; P=0.006) and plasma antioxidant concentrations were significantly lower [vitamin A, 39.5 ± 14.1 vs. 52.4±16.2 μg/dL, respectively (P=0.0004); vitamin E, 8.29±2.1 vs. 9.89±4.5 μg/mL (P=0.043); zinc, 0.61±0.14 vs. 0.67±0.15 mg/L (P=0.016)] in the HIV/HCV-coinfected participants than in the HIV-monoinfected participants, and these differences remained significant after adjusting for age, gender, CD4 cell count, HIV viral load, injecting drug use and race. There were no significant differences in glutathione peroxidase concentration, selenium concentration, body mass index (BMI), alcohol use or tobacco use between groups. Glutathione peroxidase concentration significantly increased as liver disease advanced, as measured by APRI (β=0.00118; P=0.0082) and FIB-4 (β=0.0029; P=0.0177). Vitamin A concentration significantly decreased (β=-0.00581; P=0.0417) as APRI increased. CONCLUSION HIV/HCV coinfection is associated with increased oxidative stress and decreased plasma antioxidant concentrations compared with HIV monoinfection. Research is needed to determine whether antioxidant supplementation delays liver disease in HIV/HCV coinfection.
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Affiliation(s)
- M K Baum
- Florida International University, R. Stempel College of Public Health and Social Work, Miami, FL 33199, USA.
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González-Cuevas J, Navarro-Partida J, Marquez-Aguirre AL, Bueno-Topete MR, Beas-Zarate C, Armendáriz-Borunda J. Ethylenediaminetetraacetic acid induces antioxidant and anti-inflammatory activities in experimental liver fibrosis. Redox Rep 2011; 16:62-70. [PMID: 21722414 PMCID: PMC6837538 DOI: 10.1179/174329211x13002357050851] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
BACKGROUND Experimental liver fibrosis induced by carbon tetrachloride (CCl(4)) is associated with oxidative stress, lipid peroxidation, and inflammation. This work was focused on elucidating the anti-inflammatory and antioxidant effects of ethylenediaminetetraacetic acid (EDTA) in this model of hepatotoxicity. METHODS Wistar male rats were treated with CCl(4) and EDTA (60, 120, or 240 mg/kg). Morphometric analyses were carried out in Masson's stained liver sections to determine fibrosis index. Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) were also determined. Gene expression for transforming growth factor beta (TGF-beta1), alpha1(I) procollagen gene (alpha1 Col I), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and superoxide dismutase (SOD) was monitored by real-time PCR. Antioxidant effect of EDTA was measured by its effects on lipid peroxidation; biological activity of ceruloplasmin (Cp), SOD, and catalase (Cat) were analyzed by zymography assays. RESULTS Animals with CCl(4)-hepatic injury that received EDTA showed a decrement in fibrosis (20%) and lipid peroxidation (22%). The mRNA expression for TNF-alpha (55%), TGF-beta1 (50%), IL-6 (52%), and alpha1 Col I (60%) was also decreased. This group of animals showed increased Cp (62%) and SOD (25%) biological activities. Coagulation blood tests, Cat activity, and gene expression for SOD were not modified by EDTA treatment. CONCLUSION This study demonstrates that EDTA treatment induces the activity of antioxidant enzymes, decreases lipid peroxidation, hepatic inflammation, and fibrosis in experimental liver fibrosis induced by CCl(4).
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Affiliation(s)
- J González-Cuevas
- Instituto de Biología Molecular en Medicina y Terapia Génica Centro Universitario de Ciencias de la SaludUniversidad de Guadalajara, Guadalajara, Jalisco 44340 México
| | - J Navarro-Partida
- Instituto de Biología Molecular en Medicina y Terapia Génica Centro Universitario de Ciencias de la SaludUniversidad de Guadalajara, Guadalajara, Jalisco 44340 México
| | - A L Marquez-Aguirre
- Centro de Investigación y Asistencia en Tecnología y Diseño del Estado deJalisco, CIATEJ, Guadalajara, Jalisco, México
| | - M R Bueno-Topete
- Instituto de Biología Molecular en Medicina y Terapia Génica Centro Universitario de Ciencias de la SaludUniversidad de Guadalajara, Guadalajara, Jalisco 44340 México
| | - C Beas-Zarate
- Departamento de Biologia Celular y Molecular, CUCBA, Universidad de Guadalajara
| | - J Armendáriz-Borunda
- Instituto de Biología Molecular en Medicina y Terapia Génica Centro Universitario de Ciencias de la SaludUniversidad de Guadalajara, Guadalajara, Jalisco 44340 México
- O.P.D. Hospital Civil de GuadalajaraGuadalajara, Jalisco, México
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