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1
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [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: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Lovrić J, Najafinobar N, Kurczy ME, De Castro O, Biesemeier A, von Sydow L, Klarqvist M, Wirtz T, Malmberg P. Correlative High-Resolution Imaging of Iron Uptake in Lung Macrophages. Anal Chem 2022; 94:12798-12806. [PMID: 36070604 PMCID: PMC9494303 DOI: 10.1021/acs.analchem.2c02675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
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Detection of iron at the subcellular level in order to
gain insights
into its transport, storage, and therapeutic prospects to prevent
cytotoxic effects of excessive iron accumulation is still a challenge.
Nanoscale magnetic sector secondary ion mass spectrometry (SIMS) is
an excellent candidate for subcellular mapping of elements in cells
since it provides high secondary ion collection efficiency and transmission,
coupled with high-lateral-resolution capabilities enabled by nanoscale
primary ion beams. In this study, we developed correlative methodologies
that implement SIMS high-resolution imaging technologies to study
accumulation and determine subcellular localization of iron in alveolar
macrophages. We employed transmission electron microscopy (TEM) and
backscattered electron (BSE) microscopy to obtain structural information
and high-resolution analytical tools, NanoSIMS and helium ion microscopy-SIMS
(HIM-SIMS) to trace the chemical signature of iron. Chemical information
from NanoSIMS was correlated with TEM data, while high-spatial-resolution
ion maps from HIM-SIMS analysis were correlated with BSE structural
information of the cell. NanoSIMS revealed that iron is accumulating
within mitochondria, and both NanoSIMS and HIM-SIMS showed accumulation
of iron in electrolucent compartments such as vacuoles, lysosomes,
and lipid droplets. This study provides insights into iron metabolism
at the subcellular level and has future potential in finding therapeutics
to reduce the cytotoxic effects of excessive iron loading.
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Affiliation(s)
- Jelena Lovrić
- DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden
| | - Neda Najafinobar
- Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden
| | - Michael E Kurczy
- DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden
| | - Olivier De Castro
- Advanced Instrumentation for Nano-Analytics (AINA), MRT Department, Luxembourg Institute of Science and Technology (LIST), L-4422 Belvaux, Luxembourg
| | - Antje Biesemeier
- Advanced Instrumentation for Nano-Analytics (AINA), MRT Department, Luxembourg Institute of Science and Technology (LIST), L-4422 Belvaux, Luxembourg
| | - Lena von Sydow
- Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden
| | - Magnus Klarqvist
- Early Product Development, Pharm Sci, IMED Biotech Unit, AstraZeneca, SE-431 50 Gothenburg, Sweden
| | - Tom Wirtz
- Advanced Instrumentation for Nano-Analytics (AINA), MRT Department, Luxembourg Institute of Science and Technology (LIST), L-4422 Belvaux, Luxembourg
| | - Per Malmberg
- Department of Chemistry and Chemical Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden
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Abstract
Virus-induced cell death has long been thought of as a double-edged sword in the inhibition or exacerbation of viral infections. The vital role of iron, an essential element for various enzymes in the maintenance of cellular physiology and efficient viral replication, places it at the crossroads and makes it a micronutrient of competition between the viruses and the host. Viruses can interrupt iron uptake and the antioxidant response system, while others can utilize iron transporter proteins as receptors. Interestingly, the unavailability of iron facilitates certain viral infections and causes cell death characterized by lipid peroxide accumulation and malfunction of the antioxidant system. In this review, we discuss how iron uptake, regulation and metabolism, including the redistribution of iron in the host defense system during viral infection, can induce ferroptosis. Fenton reactions, a central characteristic of ferroptosis, are caused by the increased iron content in the cell. Therefore, viral infections that increase cellular iron content or intestinal iron absorption are likely to cause ferroptosis. In addition, we discuss the hijacking of the iron regulatoy pathway and the antioxidant response, both of which are typical in viral infections. Understanding the potential signaling mechanisms of ferroptosis in viral infections will aid in the development of new therapeutic agents.
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Rex DAB, Keshava Prasad TS, Kandasamy RK. Revisiting Regulated Cell Death Responses in Viral Infections. Int J Mol Sci 2022; 23:ijms23137023. [PMID: 35806033 PMCID: PMC9266763 DOI: 10.3390/ijms23137023] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/07/2023] Open
Abstract
The fate of a viral infection in the host begins with various types of cellular responses, such as abortive, productive, latent, and destructive infections. Apoptosis, necroptosis, and pyroptosis are the three major types of regulated cell death mechanisms that play critical roles in viral infection response. Cell shrinkage, nuclear condensation, bleb formation, and retained membrane integrity are all signs of osmotic imbalance-driven cytoplasmic swelling and early membrane damage in necroptosis and pyroptosis. Caspase-driven apoptotic cell demise is considered in many circumstances as an anti-inflammatory, and some pathogens hijack the cell death signaling routes to initiate a targeted attack against the host. In this review, the selected mechanisms by which viruses interfere with cell death were discussed in-depth and were illustrated by compiling the general principles and cellular signaling mechanisms of virus–host-specific molecule interactions.
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Affiliation(s)
| | - Thottethodi Subrahmanya Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India
- Correspondence: (T.S.K.P.); (R.K.K.)
| | - Richard K. Kandasamy
- Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai P.O Box 505055, United Arab Emirates
- Correspondence: (T.S.K.P.); (R.K.K.)
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5
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Han Y, Zhu J, Yang L, Nilsson-Payant BE, Hurtado R, Lacko LA, Sun X, Gade AR, Higgins CA, Sisso WJ, Dong X, Wang M, Chen Z, Ho DD, Pitt GS, Schwartz RE, tenOever BR, Evans T, Chen S. SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells. Circ Res 2022; 130:963-977. [PMID: 35255712 PMCID: PMC8963443 DOI: 10.1161/circresaha.121.320518] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/17/2022] [Accepted: 02/24/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling. METHODS We used both a hamster model and human ESC (hESC)-derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN-like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2-induced ferroptosis. RESULTS Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis. CONCLUSIONS Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.
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Affiliation(s)
- Yuling Han
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Jiajun Zhu
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Liuliu Yang
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Benjamin E. Nilsson-Payant
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY (B.E.N.-P., B.R.T.)
- Department of Microbiology, New York University (B.E.N.-P., C.A.H., B.R.T.)
| | - Romulo Hurtado
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Lauretta A. Lacko
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Xiaolu Sun
- Cardiovascular Research Institute (X.S., A.R.G., G.S.P.), Weill Cornell Medicine, New York, NY
| | - Aravind R. Gade
- Cardiovascular Research Institute (X.S., A.R.G., G.S.P.), Weill Cornell Medicine, New York, NY
| | | | - Whitney J. Sisso
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Xue Dong
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Maple Wang
- Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY (M.W., D.D.H.)
| | - Zhengming Chen
- Department of Population Health Sciences (Z.C.), Weill Cornell Medicine, New York, NY
| | - David D. Ho
- Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY (M.W., D.D.H.)
| | - Geoffrey S. Pitt
- Cardiovascular Research Institute (X.S., A.R.G., G.S.P.), Weill Cornell Medicine, New York, NY
| | - Robert E. Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine (R.E.S.), Weill Cornell Medicine, New York, NY
- Department of Physiology, Biophysics and Systems Biology (R.E.S.), Weill Cornell Medicine, New York, NY
| | - Benjamin R. tenOever
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY (B.E.N.-P., B.R.T.)
- Department of Microbiology, New York University (B.E.N.-P., C.A.H., B.R.T.)
| | - Todd Evans
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
| | - Shuibing Chen
- Department of Surgery (Y.H., J.Z., L.Y., R.H., L.A.L., W.J.S., X.D., T.E., S.C.), Weill Cornell Medicine, New York, NY
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6
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Abstract
Ferroptosis is an iron-dependent cell death pathway and participates in various diseases. Current evidence suggests that ferroptosis can obviously affect the function of blood cells. This paper aims to elaborate the role of ferroptosis in blood cells and related diseases. First, abnormal ferroptosis damages the developing red blood cells by breaking systemic iron homeostasis, leading to erythropoiesis suppression and anaemia. Ferroptosis mediates neutrophils recruitment and neutrophil extracellular trap formation (NETosis). In T-cells, ferroptosis induces a novel point of synergy between immunotherapy and radiotherapy. Additionally, ferroptosis may mediate B cells differentiation, antibody responses and lymphoma. Nevertheless, increased ferroptosis can ameliorate acute myeloid leukaemia and T-cell leukaemia/lymphoma by inducing iron-dependent cancer cells death. Besides, ferroptosis activates platelets by increasing P-selectin, thus causing thromboembolism. Ferroptosis mediates virus infection and parasite infection by driving T-cell death and preventing T-cell immunity. Interestingly, ferroptosis is also considered as a critical player in COVID-19 infections, while targetting ferroptosis may also improve thromboembolism and prognosis in patients with COVID-19 infection. Overall, the crucial role of ferroptosis in blood cells will show a new therapeutic potential in blood cell-related diseases.HighlightsFerroptosis shows a new therapeutic potential for blood cell-related diseases.Ferroptosis damages erythropoiesis and thus induces anaemia.Ferroptosis induces platelet activation and leads to thromboembolism.Ferroptosis regulates T-cell and B-cell immunity, which participant in infectious diseases.Inversely, ferroptosis ameliorates acute myeloid leukaemia and T-cell leukaemia.
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Affiliation(s)
- Zhe Chen
- Institute of Pharmacy and Pharmacology, College of Basic Medical Science, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, China
| | - Jinyong Jiang
- Institute of Pharmacy and Pharmacology, College of Basic Medical Science, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, China
| | - Nian Fu
- Department of Gastroenterology, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, College of Basic Medical Science, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, China
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7
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Rizzollo F, More S, Vangheluwe P, Agostinis P. The lysosome as a master regulator of iron metabolism. Trends Biochem Sci 2021; 46:960-975. [PMID: 34384657 DOI: 10.1016/j.tibs.2021.07.003] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/05/2021] [Accepted: 07/19/2021] [Indexed: 12/15/2022]
Abstract
Intracellular iron fulfills crucial cellular processes, including DNA synthesis and mitochondrial metabolism, but also mediates ferroptosis, a regulated form of cell death driven by lipid-based reactive oxygen species (ROS). Beyond their established role in degradation and recycling, lysosomes occupy a central position in iron homeostasis and integrate metabolic and cell death signals emanating from different subcellular sites. We discuss the central role of the lysosome in preserving iron homeostasis and provide an integrated outlook of the regulatory circuits coupling the lysosomal system to the control of iron trafficking, interorganellar crosstalk, and ferroptosis induction. We also discuss novel studies unraveling how deregulated lysosomal iron-handling functions contribute to cancer, neurodegeneration, and viral infection, and can be harnessed for therapeutic interventions.
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Affiliation(s)
- Francesca Rizzollo
- Laboratory of Cell Death and Research, Vlaams Instituut voor Biotechnologie (VIB)-Katholieke Universiteit (KU) Leuven Center for Cancer Biology, Leuven, Belgium; Laboratory of Cell Death and Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Sanket More
- Laboratory of Cell Death and Research, Vlaams Instituut voor Biotechnologie (VIB)-Katholieke Universiteit (KU) Leuven Center for Cancer Biology, Leuven, Belgium; Laboratory of Cell Death and Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Peter Vangheluwe
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
| | - Patrizia Agostinis
- Laboratory of Cell Death and Research, Vlaams Instituut voor Biotechnologie (VIB)-Katholieke Universiteit (KU) Leuven Center for Cancer Biology, Leuven, Belgium; Laboratory of Cell Death and Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
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8
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Yang M, Lai CL. SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement? Cell Death Discov 2020; 6:130. [PMID: 33251029 PMCID: PMC7687212 DOI: 10.1038/s41420-020-00369-w] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/15/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Since the outbreak of the new coronavirus in 2019 (SARS-CoV-2), many studies have been performed to better understand the basic mechanisms and clinical features of the disease. However, uncertainties of the underlying mechanisms of multiple organ involvement remain. A substantial proportion of severe coronavirus disease 2019 (COVID-19) patients have lymphopenia, low serum iron levels, and multiple organ involvement. Several therapeutic agents have been used for different stages of the disease, but the treatment for severe disease is still suboptimal. Understanding the mechanism of programmed cell death in COVID-19 may lead to better therapeutic strategies for these patients. On the basis of observations of basic science studies and clinical researches on COVID-19, we hypothesize that ferroptosis, a novel programmed cell death, may be an important cause of multiple organ involvement in COVID-19 and it might serve as a new treatment target. In spite of the existing findings on the involvement of ferroptosis in SARS-CoV-2 infection, there is no reported study to uncover how does ferroptosis acts in SARS-CoV-2 infection yet. Uncovering the role of ferroptosis in SARS-CoV-2 infection is essential to develop new treatment strategies for COVID-19. Intracellular cell iron depletion or new generation of ferroptosis inhibitors might be potential drug candidates for COVID-19. We hope this hypothesis may launch a new wave of studies to uncover the association of ferroptosis and SARS-CoV-2 infection in vitro and in vivo.
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Affiliation(s)
- Ming Yang
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ching Lung Lai
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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9
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Shoja Z, Chenari M, Jafarpour A, Jalilvand S. Role of iron in cancer development by viruses. Rev Med Virol 2019; 29:e2045. [PMID: 30994254 DOI: 10.1002/rmv.2045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 02/21/2019] [Indexed: 12/19/2022]
Abstract
Increased levels of iron in body are attributed to higher cancer risk. Given the fact that 16% of all human cancers are caused by viral infections, iron is suggested to play an important role in carcinogenesis particularly those induced by viral infections. The present study provides an updated summary of the literature and the plausible mechanisms of iron involvement in cancer development by viruses. Our understanding about the interplay between viral infections and iron in different settings particularly cancer development is yet to be improved as it may shed a new light in development of new therapeutic strategies.
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Affiliation(s)
| | - Maryam Chenari
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Jafarpour
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Jalilvand
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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10
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Role of transferrin receptor in hepatitis C viral infection. INFECTION INTERNATIONAL 2018. [DOI: 10.2478/ii-2018-0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Hepatitis C virus (HCV) is the main pathogen causing chronic hepatitis and primary liver cancer. Various viral proteins and host cell molecules are involved in the HCV cell entry, but the mechanism of infection has not been completely elucidated. The transferrin receptor can act as a receptor for many viruses during cell entry. The transferrin receptor is not only closely related to HCV-induced iron metabolism disorders but also mediates the fusion of HCV with the host cell membrane as a specific receptor for CD81-dependent viral adhesion.
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11
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Wessling-Resnick M. Crossing the Iron Gate: Why and How Transferrin Receptors Mediate Viral Entry. Annu Rev Nutr 2018; 38:431-458. [PMID: 29852086 DOI: 10.1146/annurev-nutr-082117-051749] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Because both the host and pathogen require iron, the innate immune response carefully orchestrates control over iron metabolism to limit its availability during times of infection. Nutritional iron deficiency can impair host immunity, while iron overload can cause oxidative stress to propagate harmful viral mutations. An emerging enigma is that many viruses use the primary gatekeeper of iron metabolism, the transferrin receptor, as a means to enter cells. Why and how this iron gate is a viral target for infection are the focus of this review.
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Affiliation(s)
- Marianne Wessling-Resnick
- Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA;
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12
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Tan CH, Venkatesh SK. Magnetic Resonance Elastography and Other Magnetic Resonance Imaging Techniques in Chronic Liver Disease: Current Status and Future Directions. Gut Liver 2017; 10:672-86. [PMID: 27563019 PMCID: PMC5003189 DOI: 10.5009/gnl15492] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/29/2015] [Accepted: 12/15/2015] [Indexed: 12/13/2022] Open
Abstract
Recent advances in the noninvasive imaging of chronic liver disease have led to improvements in diagnosis, particularly with magnetic resonance imaging (MRI). A comprehensive evaluation of the liver may be performed with the quantification of the degree of hepatic steatosis, liver iron concentration, and liver fibrosis. In addition, MRI of the liver may be used to identify complications of cirrhosis, including portal hypertension, ascites, and the development of hepatocellular carcinoma. In this review article, we discuss the state of the art techniques in liver MRI, namely, magnetic resonance elastography, hepatobiliary phase MRI, and liver fat and iron quantification MRI. The use of these advanced techniques in the management of chronic liver diseases, including non-alcoholic fatty liver disease, will be elaborated.
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Affiliation(s)
- Cher Heng Tan
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, Singapore
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13
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Rudnicka A, Woziwodzka A, Wróblewska A, Rybicka M, Bielawski KP, Sikorska K, Bernat A. Analysis of polymorphism and hepatic expression of duodenal cytochrome b in chronic hepatitis C. J Gastroenterol Hepatol 2017; 32:482-486. [PMID: 27439017 DOI: 10.1111/jgh.13495] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2016] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Pathological iron overload is commonly found in chronic hepatitis C (CHC) patients and considered as a negative prognostic factor of the disease. A single nucleotide polymorphism (SNP) rs884409 in duodenal cytochrome b gene (CYBRD1) is implicated in the pathogenesis of hemochromatosis. In our study we investigated the impact of the CYBRD1 genotype and expression on iron overload in CHC patients. METHODS Liver biopsy specimens and whole blood samples from 243 patients with CHC were included in the study. Iron deposits in hepatocytes, serum markers of iron overload, and expression profile of gene-regulators of iron homeostasis were analyzed. Genotyping and analysis of gene expression of the CYBRD1 were performed. The frequency of SNP and the expression levels of CYBRD1 were compared between the groups of patients with and without markers of iron overload. RESULTS The single nucleotide variant rs884409 G was associated with elevated serum iron levels, increased markers of liver inflammation, and oxidative stress. Hepatic expression of CYBRD1 was associated with the expression of Tfr2, Id1, and HO-1 genes, serum ferritin levels, and with increased iron accumulation in liver. CONCLUSION These results implicate CYBRD1 involvement in iron homeostasis in CHC.
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Affiliation(s)
- Alina Rudnicka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk-Medical University of Gdansk, Gdansk, Poland
| | - Anna Woziwodzka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk-Medical University of Gdansk, Gdansk, Poland
| | - Anna Wróblewska
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk-Medical University of Gdansk, Gdansk, Poland
| | - Magda Rybicka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk-Medical University of Gdansk, Gdansk, Poland
| | - Krzysztof P Bielawski
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk-Medical University of Gdansk, Gdansk, Poland
| | - Katarzyna Sikorska
- Department of Tropical Medicine and Epidemiology, Medical University of Gdansk, Gdynia, Poland.,Department of Infectious Diseases, Medical University of Gdansk, Gdansk, Poland
| | - Agnieszka Bernat
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk-Medical University of Gdansk, Gdansk, Poland
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Natural history of chronic hepatitis C development and progression as a consequence of iron and HFE or TfR1 mutations. EGYPTIAN LIVER JOURNAL 2017. [DOI: 10.1097/01.elx.0000524701.59978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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15
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Sikorska K, Bernat A, Wroblewska A. Molecular pathogenesis and clinical consequences of iron overload in liver cirrhosis. Hepatobiliary Pancreat Dis Int 2016; 15:461-479. [PMID: 27733315 DOI: 10.1016/s1499-3872(16)60135-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. DATA SOURCES PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. RESULTS Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. CONCLUSION Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.
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Affiliation(s)
- Katarzyna Sikorska
- Department of Tropical Medicine and Epidemiology, Medical University of Gdansk, Powstania Styczniowego 9b, 81-519 Gdynia, Poland.
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Moossavi S, Besharat S, Sharafkhah M, Ghanbari R, Sharifi A, Rezanejad P, Pourshams A, Poustchi H, Mohamadkhani A. Inverse Association of Plasma Level of Glutathione Peroxidase with Liver Fibrosis in Chronic Hepatitis B: Potential Role of Iron. Middle East J Dig Dis 2016; 8:122-30. [PMID: 27252819 PMCID: PMC4885611 DOI: 10.15171/mejdd.2016.17] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND
Oxidative stress has a major pathogenic role for liver damage following
chronic hepatitis B. Glutathione peroxidase (Gpx) is necessary in oxidative
state mechanism that is generally down-regulated by Hepatitis B virus (HBV)
infection. On the other hand, disorders of iron homeostasis have been found
out in HBV infected patients. Therefore, the objective of this study was to assess
the interplay of Gpx and serum iron on clinical and virological features of
patients with chronic HBV infection.
METHODS
One hundred and fifty adult, treatment-naïve, patients with chronic hepatitis
B were randomly designated from an ongoing cohort of patients with HBV.
Plasma Gpx1 concentration and HBV DNA quantity were measured. Liver
stiffness was measured by transient elastography.
RESULTS
Serum iron had a positive association with HBV DNA count in the total population.
Serum iron was not associated with liver stiffness. However, HBV DNA
was significantly associated with liver stiffness only in male patients. Serum Gpx
was inversely associated with liver stiffness. Serum iron and Gpx had indirect
effects on liver stiffness via HBV DNA count. We observed dissimilar effects of
serum iron on HBV DNA and Gpx on liver stiffness in male and female patients.
CONCLUSION
We identified interplay of serum iron and Gpx1 in relation to level of liver
fibrosis in patients with chronic hepatitis B. Our results propose that oxidative
stress and serum iron are differentially implicated in the progression of chronic
hepatitis B in male and female patients.
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Affiliation(s)
- Shirin Moossavi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sima Besharat
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Sharafkhah
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Ghanbari
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amrollah Sharifi
- Department of Clinical nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Rezanejad
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Pourshams
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ashraf Mohamadkhani
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Sikorska K. The iron homeostasis network and hepatitis C virus - a new challenge in the era of directly acting antivirals. Virulence 2016; 7:620-2. [PMID: 27196953 DOI: 10.1080/21505594.2016.1191739] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Katarzyna Sikorska
- a Department of Tropical Medicine and Epidemiology , Medical University of Gdańsk , Gdynia , Poland.,b Department of Infectious Diseases , Medical University of Gdańsk , Gdańsk , Poland
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Qian XJ, Zhu YZ, Zhao P, Qi ZT. Entry inhibitors: New advances in HCV treatment. Emerg Microbes Infect 2016; 5:e3. [PMID: 26733381 PMCID: PMC4735057 DOI: 10.1038/emi.2016.3] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 10/28/2015] [Accepted: 11/02/2015] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry.
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Affiliation(s)
- Xi-Jing Qian
- Shanghai Key Laboratory of Medical Biodefense, Department of Microbiology, Second Military Medical University, Shanghai 200433, China
| | - Yong-Zhe Zhu
- Shanghai Key Laboratory of Medical Biodefense, Department of Microbiology, Second Military Medical University, Shanghai 200433, China
| | - Ping Zhao
- Shanghai Key Laboratory of Medical Biodefense, Department of Microbiology, Second Military Medical University, Shanghai 200433, China
| | - Zhong-Tian Qi
- Shanghai Key Laboratory of Medical Biodefense, Department of Microbiology, Second Military Medical University, Shanghai 200433, China
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Nagamine T, Sato K, Kakizaki S, Satoh T, Koka M, Kamiya T. Analysis of Erythrocyte Elements in Chronic Hepatitis C Patients Receiving PegIFN Monotherapy, Dual Therapy, and Triple Therapy using in-air MicroPIXE. THE KITAKANTO MEDICAL JOURNAL 2016; 66:91-102. [DOI: 10.2974/kmj.66.91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Affiliation(s)
| | - Ken Sato
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine
| | - Satoru Kakizaki
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine
| | - Takahiro Satoh
- Takasaki Advanced Radiation Research Institute, Japan Atomic Energy Agency
| | - Masashi Koka
- Takasaki Advanced Radiation Research Institute, Japan Atomic Energy Agency
| | - Tomihiro Kamiya
- Takasaki Advanced Radiation Research Institute, Japan Atomic Energy Agency
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Darwish SF, El-Bakly WM, El-Naga RN, Awad AS, El-Demerdash E. Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: Impact on interferon therapy. Biochem Pharmacol 2015; 98:231-42. [PMID: 26358138 DOI: 10.1016/j.bcp.2015.09.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 09/02/2015] [Indexed: 02/07/2023]
Abstract
Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-β1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response.
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Affiliation(s)
- Samar F Darwish
- Central Administration of Pharmaceutical Affairs, Cairo, Egypt
| | - Wesam M El-Bakly
- Pharmacology & Therapeutic Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Reem N El-Naga
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Azza S Awad
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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Nanba S, Ikeda F, Baba N, Takaguchi K, Senoh T, Nagano T, Seki H, Takeuchi Y, Moritou Y, Yasunaka T, Ohnishi H, Miyake Y, Takaki A, Nouso K, Iwasaki Y, Yamamoto K. Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C. J Clin Pathol 2015; 69:226-33. [PMID: 26290259 DOI: 10.1136/jclinpath-2015-203215] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 07/31/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established. METHODS We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera. RESULTS Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p<0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation. CONCLUSIONS Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients. TRIAL REGISTRATION NUMBER UMIN 000001031.
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Affiliation(s)
- Shintaro Nanba
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Fusao Ikeda
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Nobuyuki Baba
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Koichi Takaguchi
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Tomonori Senoh
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takuya Nagano
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Hiroyuki Seki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yasuto Takeuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuki Moritou
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tetsuya Yasunaka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hideki Ohnishi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yasuhiro Miyake
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiro Nouso
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Kohjima M, Yoshimoto T, Enjoji M, Fukushima N, Fukuizumi K, Nakamura T, Kurokawa M, Fujimori N, Sasaki Y, Shimonaka Y, Murata Y, Koyama S, Kawabe K, Haraguchi K, Sumida Y, Harada N, Kato M, Kotoh K, Nakamuta M. Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver. World J Gastroenterol 2015; 21:3291-3299. [PMID: 25805936 PMCID: PMC4363759 DOI: 10.3748/wjg.v21.i11.3291] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 10/22/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between the iron-metabolism-related gene expression profiles and efficacy of antiviral therapy in chronic hepatitis C patients.
METHODS: The hepatic expression profile of iron-metabolism-related genes was analyzed and its association with virological response to pegylated-interferon plus ribavirin combination therapy was evaluated. A hundred patients with chronic hepatitis C (genotype1b, n = 50; genotype 2, n = 50) were enrolled and retrospectively analyzed. Liver biopsy samples were subjected to quantitative polymerase chain reaction for iron-metabolism-related genes and protein expression (Western blotting analysis) for ferroportin. As a control, normal liver tissue was obtained from 18 living donors of liver transplantation. Serum hepcidin level was measured by sensitive liquid chromatography/electrospray ionization tandem mass spectrometry.
RESULTS: Iron overload is associated with liver damage by increasing oxidative stress and hepatitis C virus (HCV) is reported to induce iron accumulation in hepatocytes in vivo. Conversely, iron administration suppresses HCV replication in vitro. Therefore, the association between HCV infection and iron metabolism remains unclear. Compared with controls, patients had significantly higher gene expression for transferrin, iron-regulatory proteins 1 and 2, divalent metal transporter 1, and ferroportin, but similar for transferrin receptors 1 and 2, and hepcidin. When the expression profiles were compared between sustained virological response (SVR) and non-SVR patients, the former showed significantly lower transcription and protein expression of hepcidin and ferroportin. Expression of hepcidin-regulating genes, BMPR1, BMPR2, and hemojuvelin, was significantly increased, whereas BMP2 was decreased in HCV-infected liver. BMPR2 and hemojuvelin expression was significantly lower in the SVR than non-SVR group. HCV infection affects the expression of iron-metabolism-related genes, leading to iron accumulation in hepatocytes.
CONCLUSION: Decreased expression of hepcidin and ferroportin in SVR patients indicates the importance of hepatocytic iron retention for viral response during pegylated-interferon plus ribavirin treatment.
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Ye T, Wu X, Wu W, Dai C, Yuan J. Ferritin protect shrimp Litopenaeus vannamei from WSSV infection by inhibiting virus replication. FISH & SHELLFISH IMMUNOLOGY 2015; 42:138-143. [PMID: 25449379 DOI: 10.1016/j.fsi.2014.10.039] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 10/20/2014] [Accepted: 10/28/2014] [Indexed: 06/04/2023]
Abstract
Iron is considered as an essential element for all living organisms. Therefore, limiting iron availability may be key part of the host's innate immune response to various pathogens. Ferritin is a major iron storage protein in living cells and plays an important role in iron homeostasis. One way the host can transiently reduce iron bioavailability is by ferritin over expression. In invertebrates, ferritin was found to be up-regulated after pathogens challenge and is considered to be an important element in the innate immune system. This study was designed to investigate the involvement of ferritin in shrimp Litopenaeus vannamei defense against WSSV. We discovered that the viral load of shrimp injected with recombinant ferritin protein was lower than that of control group. The suppression of ferritin by dsRNA increased susceptibility to WSSV with 3-fold high viral copies. The present study documented that ferritin protected shrimp L. vannamei from WSSV by inhibiting virus replication. We presume that ferritin reduce iron availability, leading to inhibit the activity of ribonucleotide reductase and delay the replication of virus genome. This study provided new insights into the understanding of molecular responses and defense mechanisms in shrimp against WSSV.
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Affiliation(s)
- Ting Ye
- College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Xiaoting Wu
- Food Science College, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Wenlin Wu
- Department of Biology, Quanzhou Normal University, Quanzhou 362000, China.
| | - Congjie Dai
- Department of Biology, Quanzhou Normal University, Quanzhou 362000, China
| | - Jianjun Yuan
- Department of Biology, Quanzhou Normal University, Quanzhou 362000, China
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Montaldo C, Mattei S, Baiocchini A, Rotiroti N, Del Nonno F, Pucillo LP, Cozzolino AM, Battistelli C, Amicone L, Ippolito G, van Noort V, Conigliaro A, Alonzi T, Tripodi M, Mancone C. Spike-in SILAC proteomic approach reveals the vitronectin as an early molecular signature of liver fibrosis in hepatitis C infections with hepatic iron overload. Proteomics 2014; 14:1107-15. [PMID: 24616218 DOI: 10.1002/pmic.201300422] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/08/2014] [Accepted: 01/09/2014] [Indexed: 01/06/2023]
Abstract
Hepatitis C virus (HCV)-induced iron overload has been shown to promote liver fibrosis, steatosis, and hepatocellular carcinoma. The zonal-restricted histological distribution of pathological iron deposits has hampered the attempt to perform large-scale in vivo molecular investigations on the comorbidity between iron and HCV. Diagnostic and prognostic markers are not yet available to assess iron overload-induced liver fibrogenesis and progression in HCV infections. Here, by means of Spike-in SILAC proteomic approach, we first unveiled a specific membrane protein expression signature of HCV cell cultures in the presence of iron overload. Computational analysis of proteomic dataset highlighted the hepatocytic vitronectin expression as the most promising specific biomarker for iron-associated fibrogenesis in HCV infections. Next, the robustness of our in vitro findings was challenged in human liver biopsies by immunohistochemistry and yielded two major results: (i) hepatocytic vitronectin expression is associated to liver fibrogenesis in HCV-infected patients with iron overload; (ii) hepatic vitronectin expression was found to discriminate also the transition between mild to moderate fibrosis in HCV-infected patients without iron overload.
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Affiliation(s)
- Claudia Montaldo
- Department of Cellular Biotechnologies and Haematology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy; "L. Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy
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Sikorska K, Romanowski T, Stalke P, Izycka Swieszewska E, Bielawski KP. Association of hepcidin mRNA expression with hepatocyte iron accumulation and effects of antiviral therapy in chronic hepatitis C infection. HEPATITIS MONTHLY 2014; 14:e21184. [PMID: 25598789 PMCID: PMC4286710 DOI: 10.5812/hepatmon.21184] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 08/18/2014] [Accepted: 09/13/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Iron overload is frequently observed in patients with chronic hepatitis C (CHC) and is associated with the increased risk of liver fibrosis and carcinogenesis. Hepcidin is a regulator of iron homeostasis and a component of innate immunity. Based on experimental studies, iron overload might be a result of low hepcidin synthesis in CHC. OBJECTIVES The aim of this case-control study was to assess hepcidin mRNA expression in liver tissue of patients with CHC in terms of iron metabolism parameters, hemochromatosis (HFE) gene mutations, disease activity, and efficacy of antiviral treatment with pegylated interferon and ribavirin. PATIENTS AND METHODS A total of 31 patients with CHC, who were qualified for antiviral therapy, were compared with 19 patients with chronic hepatitis B (CHB). In both groups, liver function tests and serum iron parameters were assayed and hepcidin mRNA expression was measured in liver specimens using real time PCR with normalization to reference genes mRNA of stable expression. RESULTS Patients with CHC had lower hepcidin mRNA expression and more frequently iron deposits in hepatocytes than subjects with CHB did. In CHC group, hepcidin mRNA expression was positively correlated with alanine aminotransferase activity and serum iron concentration. Low expression of hepcidin had no correlation with tissue iron overload in those with CHC. In univariate analysis, HCV viral load and efficacy of antiviral treatment were not significantly associated with hepcidin mRNA expression. CONCLUSIONS Further studies on the role of hepcidin in pathogenesis of CHC are needed to assess the potency of its use in antiviral treatment.
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Affiliation(s)
- Katarzyna Sikorska
- Department of Infectious Diseases, Medical University of
Gdansk, Gdansk, Poland
- Corresponding Author: Katarzyna Sikorska, Department
of Infectious Diseases, Medical University of Gdansk, Gdansk, Poland. Tel: +48-583412887,
Fax: +48-5834128287, E-mail:
| | - Tomasz Romanowski
- Department of Biotechnology, Intercollegiate Faculty of
Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland
| | - Piotr Stalke
- Department of Infectious Diseases, Medical University of
Gdansk, Gdansk, Poland
| | - Ewa Izycka Swieszewska
- Department of Pathology and Neuropathology, Medical
University of Gdansk, Gdansk, Poland
| | - Krzysztof Piotr Bielawski
- Department of Biotechnology, Intercollegiate Faculty of
Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland
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26
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Sikorska K, Bernat A. Iron homeostasis and its regulators over the course of chronic hepatitis C. Future Virol 2014. [DOI: 10.2217/fvl.14.63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
ABSTRACT: Chronic infection with HCV has been diagnosed in approximately 170 million people worldwide. It is an important cause of chronic, progressive liver fibrosis. Late consequences of chronic HCV infection, including liver cirrhosis and hepatocellular carcinoma, have become the major indications for liver transplantation in developed countries. Particular attention is being paid to iron accumulation in chronic hepatitis C and its relation to the current antiviral therapy's efficacy and safety, risk of exacerbation of oxidative stress, development of metabolic disorders and hepatocarcinogenesis. HCV infection disrupts the synthesis of hepcidin, which regulates extracellular iron content. This article discusses the impact of iron on HCV multiplication and the involvement of impaired iron homeostasis in chronic hepatitis C in terms of the pathogenesis of insulin resistance, fatty liver and hepatocarcinogenesis.
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Affiliation(s)
- Katarzyna Sikorska
- Department of Infectious Diseases, Medical University of Gdansk. 80-214 Gdansk, Smoluchowskiego 18, Poland
| | - Agnieszka Bernat
- Intercollegiate Faculty of Biotechnology, University of Gdansk & Medical University of Gdansk. 80-822 Gdansk, Kladki 24, Poland
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Liu Y, Lv Q, Gao J, Long L, Duan Z, Liang H, Shen T, Lu F. Coinfection with HIV-1 alleviates iron accumulation in patients with chronic hepatitis C virus infection. PLoS One 2014; 9:e98039. [PMID: 24927015 PMCID: PMC4057081 DOI: 10.1371/journal.pone.0098039] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 04/27/2014] [Indexed: 12/20/2022] Open
Abstract
Most chronically-infected hepatitis C virus (HCV) patients have increased levels of iron in the liver. Iron overload reduces sustained responses to antiviral therapy, leading to more rapid progression to liver cirrhosis and the development of hepatocellular carcinoma. However, it is still unclear how HIV-1 infection affects iron status in patients chronically infected with HCV. The present study recruited 227 patients from a village in central China. These patients were either monoinfected with HCV (n = 129) or coinfected with HCV/HIV-1 (n = 98). Healthy controls (n = 84) were also recruited from the same village. Indicators of iron status, such as serum levels of iron, ferritin, and transferrin, total iron-binding capacity (TIBC), transferrin saturation (Tfs), and hepcidin, were analyzed and compared across the three groups. The results showed that serum levels of iron (p = 0.001) and ferritin (p = 0.009) and the Tfs (p = 0.002) were significantly higher in HCV-monoinfected patients than in the healthy controls; however, there were no differences in iron levels and Tfs between HCV/HIV-1 coinfected patients and healthy controls. Additionally, although serum hepcidin levels in HCV-monoinfected and HCV/HIV-1-coinfected patients were lower (p<0.001) than those in health controls, the levels in coinfected patients were higher (p = 0.025) than those in HCV-monoinfected patients. Serum iron and ferritin levels in HCV-monoinfected patients were positively correlated with serum ALT/AST. Serum transferrin levels were negatively correlated with ALT/AST levels. The levels of iron in the serum of coinfected patients with a CD4+T-cell count <500/µl were lower than those in patients with a CD4+T-cell count ≥500/µl, whereas serum hepcidin levels showed the opposite trend. Taken together, these results suggest that coinfection with HIV-1 alleviates iron accumulation caused by chronic HCV infection. Our study indicated that determining the status of serum iron and other iron-associated parameters will be helpful to understand the complexity of alternations in iron distribution in HCV/HIV-1-coinfected patients.
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Affiliation(s)
- Yuan Liu
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China
- Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Henan, China
| | - Quanjun Lv
- Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Henan, China
| | - Jian Gao
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China
| | - Lu Long
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China
| | - Zhaojun Duan
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China
| | - Hua Liang
- State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China
| | - Tao Shen
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China
- * E-mail:
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China
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Carreño V. Review article: management of chronic hepatitis C in patients with contraindications to anti-viral therapy. Aliment Pharmacol Ther 2014; 39:148-62. [PMID: 24279580 DOI: 10.1111/apt.12562] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 08/13/2013] [Accepted: 11/05/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND There are patients with chronic hepatitis C who are not eligible for the current interferon-based therapies or refuse to be treated due to secondary effects. AIM To provide information on alternative treatments for the management of these patients. METHODS A PubMed search was performed to identify relevant literature. Search terms included hepatitis C virus, anti-inflammatory treatment, antioxidant, natural products and alternative treatment, alone or in combination. Additional publications were identified using the references cited by primary and review articles. RESULTS Several approaches, such as iron depletion (phlebotomy), treatment with ursodeoxycholic acid or glycyrrhizin, have anti-inflammatory and/or anti-fibrotic effects. Life interventions like weight loss, exercise and coffee consumption are associated with a biochemical improvement. Other alternatives (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) do not have any beneficial effect or need to be tested in larger clinical studies. CONCLUSION There are therapeutic strategies and lifestyle interventions that can be used to improve liver damage in patients with chronic hepatitis C who cannot receive or refuse interferon-based treatments.
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Affiliation(s)
- V Carreño
- Fundación Estudio Hepatitis Virales, Madrid, Spain
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Arciello M, Gori M, Balsano C. Mitochondrial dysfunctions and altered metals homeostasis: new weapons to counteract HCV-related oxidative stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:971024. [PMID: 24371505 PMCID: PMC3859171 DOI: 10.1155/2013/971024] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 10/18/2013] [Accepted: 10/28/2013] [Indexed: 02/06/2023]
Abstract
The hepatitis C virus (HCV) infection produces several pathological effects in host organism through a wide number of molecular/metabolic pathways. Today it is worldwide accepted that oxidative stress actively participates in HCV pathology, even if the antioxidant therapies adopted until now were scarcely effective. HCV causes oxidative stress by a variety of processes, such as activation of prooxidant enzymes, weakening of antioxidant defenses, organelle damage, and metals unbalance. A focal point, in HCV-related oxidative stress onset, is the mitochondrial failure. These organelles, known to be the "power plants" of cells, have a central role in energy production, metabolism, and metals homeostasis, mainly copper and iron. Furthermore, mitochondria are direct viral targets, because many HCV proteins associate with them. They are the main intracellular free radicals producers and targets. Mitochondrial dysfunctions play a key role in the metal imbalance. This event, today overlooked, is involved in oxidative stress exacerbation and may play a role in HCV life cycle. In this review, we summarize the role of mitochondria and metals in HCV-related oxidative stress, highlighting the need to consider their deregulation in the HCV-related liver damage and in the antiviral management of patients.
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Affiliation(s)
- Mario Arciello
- Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Via del Policlinico 155, 00161 Rome, Italy
- Francesco Balsano Foundation, Via G.B. Martini 6, 00198 Rome, Italy
| | - Manuele Gori
- Francesco Balsano Foundation, Via G.B. Martini 6, 00198 Rome, Italy
| | - Clara Balsano
- Francesco Balsano Foundation, Via G.B. Martini 6, 00198 Rome, Italy
- Institute of Molecular Biology and Pathology (IBPM); CNR, Piazzale Aldo Moro 7, 00185 Rome, Italy
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Vagu C, Sultana C, Ruta S. Serum iron markers in patients with chronic hepatitis C infection. HEPATITIS MONTHLY 2013; 13:e13136. [PMID: 24348638 PMCID: PMC3842519 DOI: 10.5812/hepatmon.13136] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 09/12/2013] [Accepted: 09/23/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury. OBJECTIVES The aim of this study was to investigate the possible correlations between iron metabolism serum markers, HCV viral load, and liver disease severity in treatment-naive patients with chronic hepatitis C infection. PATIENTS AND METHODS Eighty five patients with untreated hepatitis C chronic infection were investigated. RESULTS Twenty one patients (24.7%) had elevated serum iron levels, and 29 subjects (34.1%) had severe liver fibrosis. Significantly elevated levels of serum iron (P < 0.05) and ferritin (P < 0.001), associated with lower levels of TIBC (P < 0.05) were detected in patients with severe fibrosis compared to no/mild fibrosis. Severe necroinflammatory activity was also significantly correlated with serum iron (P < 0.001), TIBC (P < 0.05), and ferritin levels (P < 0.001). Using multiple linear regression analysis, serum levels of ferritin and transferrin were the independent variables selected as being good predictors for advanced fibrosis and severe necroinflammatory activity. No significant correlations were detected between HCV viral load and iron markers. CONCLUSIONS This study revealed that serum iron markers (especially ferritin and transferrin) might be used as surrogate markers for both liver fibrosis and necroinflammatory activity.Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury.
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Affiliation(s)
- Codruta Vagu
- Discipline of Biochemistry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Camelia Sultana
- Department of Virology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Emergent Diseases Department, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
| | - Simona Ruta
- Department of Virology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Emergent Diseases Department, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
- Corresponding author: Simona Ruta, Stefan S. Nicolau Institute of Virology, 285 Mihai Bravu Bvd, Bucharest, Romania. Tel/Fax: +40-213242590, E-mail:
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Baggio G, Corsini A, Floreani A, Giannini S, Zagonel V. Gender medicine: a task for the third millennium. Clin Chem Lab Med 2013; 51:713-27. [PMID: 23515103 DOI: 10.1515/cclm-2012-0849] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 02/18/2013] [Indexed: 01/07/2023]
Abstract
Gender-specific medicine is the study of how diseases differ between men and women in terms of prevention, clinical signs, therapeutic approach, prognosis, psychological and social impact. It is a neglected dimension of medicine. In this review we like to point out some major issues in five enormous fields of medicine: cardiovascular diseases (CVDs), pharmacology, oncology, liver diseases and osteoporosis. CVDs have been studied in the last decades mainly in men, but they are the first cause of mortality and disability in women. Risk factors for CVD have different impacts in men and women; clinical manifestations of CVD and the influence of drugs on CVD have lot of gender differences. Sex-related differences in pharmacokinetics and pharmacodynamics are also emerging. These differences have obvious relevance to the efficacy and side effect profiles of various medications in the two sexes. This evidence should be considered for drug development as well as before starting any therapy. Gender disparity in cancer incidence, aggressiveness and prognosis has been observed for a variety of cancers and, even if partially known, is underestimated in clinical practice for the treatment of the major types of cancer. It is necessary to systematize and encode all the known data for each type of tumor on gender differences, to identify where this variable has to be considered for the purposes of the prognosis, the choice of treatment and possible toxicity. Clinical data suggest that men and women exhibit differences regarding the epidemiology and the progression of certain liver diseases, i.e., autoimmune conditions, genetic hemochromatosis, non-alcoholic steatohepatitis and chronic hepatitis C. Numerous hypotheses have been formulated to justify this sex imbalance including sex hormones, reproductive and genetic factors. Nevertheless, none of these hypothesis has thus far gathered enough convincing evidence and in most cases the evidence is conflicting. Osteoporosis is an important public health problem both in women and men. On the whole, far more epidemiologic, diagnostic and therapeutic studies have been carried out in women than in men. In clinical practice, if this disease remains underestimated in women, patients' and physicians' awareness is even lower for male osteoporosis, for which diagnostic and therapeutic strategies are at present less defined. In conclusion this review emphasizes the urgency of basic science and clinical research to increase our understanding of the gender differences of diseases.
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Affiliation(s)
- Giovannella Baggio
- Internal Medicine Unit, Azienda Ospedaliera di Padova, Via Giustiniani 2, Padua 35125, Italy.
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Identification of transferrin receptor 1 as a hepatitis C virus entry factor. Proc Natl Acad Sci U S A 2013; 110:10777-82. [PMID: 23754414 DOI: 10.1073/pnas.1301764110] [Citation(s) in RCA: 164] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a liver tropic pathogen that affects ∼170 million people worldwide and causes liver pathologies including fibrosis, cirrhosis, steatosis, iron overload, and hepatocellular carcinoma. As part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis, we found that HCV alters expression of the iron uptake receptor transferrin receptor 1 (TfR1). After further investigation, we found that TfR1 mediates HCV entry. Specifically, functional studies showed that TfR1 knockdown and antibody blocking inhibit HCV cell culture (HCVcc) infection. Blocking cell surface TfR1 also inhibited HCV pseudoparticle (HCVpp) infection, demonstrating that TfR1 acts at the level of HCV glycoprotein-dependent entry. Likewise, a TfR1 small-molecule inhibitor that causes internalization of surface TfR1 resulted in a decrease in HCVcc and HCVpp infection. In kinetic studies, TfR1 antibody blocking lost its inhibitory activity after anti-CD81 blocking, suggesting that TfR1 acts during HCV entry at a postbinding step after CD81. In contrast, viral spread assays indicated that HCV cell-to-cell spread is less dependent on TfR1. Interestingly, silencing of the TfR1 trafficking protein, a TfR-1 specific adaptor protein required for TfR1 internalization, also inhibited HCVcc infection. On the basis of these results, we conclude that TfR1 plays a role in HCV infection at the level of glycoprotein-mediated entry, acts after CD81, and possibly is involved in HCV particle internalization.
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Lv W, Yan F, Zeng M, Zhang J, Yuan Y, Ma J. Value of abdominal susceptibility-weighted magnetic resonance imaging for quantitative assessment of hepatic iron deposition in patients with chronic hepatitis B: comparison with serum iron markers. J Int Med Res 2013; 40:1005-15. [PMID: 22906273 DOI: 10.1177/147323001204000319] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To assess hepatic iron deposition quantitatively in patients with chronic hepatitis B (HBV) infection, using abdominal susceptibility-weighted magnetic resonance imaging (SWI). METHODS Patients with HBV infection and healthy controls underwent abdominal SWI and were assessed for serum iron markers. Phase values were measured and five grades of hepatic iron deposition were described by SWI. RESULTS Patients with HBV infection (n = 327) and healthy controls (n = 50) were prospectively enrolled. In total, 77 (25.4%) patients with HBV infection had hepatic iron deposition as determined by SWI. Phase values were significantly different between patients with hepatic iron deposition compared with patients without hepatic iron deposition or controls, and were significantly different across different grades of hepatic iron deposition. Serum iron, ferritin, transferrin and transferrin saturation were significantly higher in patients with, versus those without, hepatic iron deposition. Only serum ferritin was significantly different across different grades of hepatic iron deposition, and there was a low inverse correlation between serum ferritin and phase values. CONCLUSIONS Compared with serum iron markers, abdominal SWI may represent a powerful tool to assess hepatic iron deposition quantitatively in patients with chronic HBV infection.
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Affiliation(s)
- W Lv
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
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Role of hyaluronic acid, its degrading enzymes, degradation products, and ferritin in the assessment of fibrosis stage in Egyptian patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2013; 25:69-76. [PMID: 23011038 DOI: 10.1097/meg.0b013e3283594924] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Liver biopsy is considered a gold standard for fibrosis staging, but it has a high risk of morbidity. Therefore, there is an interest in developing noninvasive markers for the prediction of liver fibrosis stages. METHODS Hyaluronic acid, ferritin, N-acetyl-β-D-glucosaminidase, β-glucuronidase, glucosamine, aspartate transaminase, and alanine transaminase were assayed in 210 individuals with chronic hepatitis C infection. Statistical analysis was carried out by logistic regression and receiver-operating characteristic curves. RESULTS The best linear combination of only significant blood markers was used for the determination of the fibrosis discriminant score; score=[1.64 (numerical constant)-0.002×hyaluronic acid (pg/l)-2.68×β-glucuronidase (µmol/ml/min)-0.026×glucosamine (µg/dl)-0.001×ferritin-0.033 (ng/ml)×aspartate transaminase/alanine transaminase]. The selected fibrosis discriminant score function correctly classified 81% of patients with severe liver fibrosis at a discriminant cut-off score=0.55 (i.e. less than 0.55 indicated mild liver fibrosis and greater than 0.55 indicated severe liver fibrosis), with a sensitivity of 100% and a specificity of 73%. CONCLUSION A simple fibrosis index can be useful to select hepatitis C virus-infected patients with a very low risk of significant fibrosis in whom the protocol of liver biopsies may be avoided.
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Abstract
The biological differences between males and females advocate the ultimate need for gender-specific medicine. The variation in response to viral infection as well as therapy among different genders makes it very intriguing to reveal the responsible factors for causing this discrepancy. HCV is one of the most noxious infectious diseases, however the impact of gender on the response to HCV has received negligible attention in the literature. The controversial studies concerning the effect of gender on the outcome of interferon-based therapy urge a need to judge the gender discrepancy in host factors responsible for both interferon release and action. The main aim of this review is to disentangle the interplay between sex hormones and several viral and host factors responsible for viral clearance in an attempt to clarify the role of gender in modulating the response to HCV as well as interferon-based therapy.
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Affiliation(s)
- Radwa Y Mekky
- The Molecular Pathology Research Group, Department of Pharmacology and Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames 11835, Cairo, Egypt
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Coelho-Borges S, Cheinquer H, Wolff FH, Cheinquer N, Krug L, Ashton-Prolla P. Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin. ARQUIVOS DE GASTROENTEROLOGIA 2012; 49:9-13. [PMID: 22481680 DOI: 10.1590/s0004-28032012000100003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 08/10/2011] [Indexed: 12/15/2022]
Abstract
CONTEXT Abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis C and are associated with a lower response rate to interferon therapy. OBJECTIVE To determine if the presence of HFE gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis C patients with elevated serum ferritin. METHODS A total of 44 treatment naÏve patients with histologically demonstrated chronic hepatitis C, all infected with hepatitis C virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/mL were treated with interferon (3 MU, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. RESULTS Sustained virological response was defined as negative qualitative HCV-RNA more than 24 weeks after the end of treatment. Serum HCV-RNA was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 IU/mL. HFE gene mutation was detected using restriction-enzyme digestion with RsaI (C282Y mutation analysis) and BclI (H63D mutation analysis) in 16 (37%) patients, all heterozygous (11 H63D, 2 C282Y and 3 both). Sustained virological response was achieved in 0 of 16 patients with HFE gene mutations and 11 (41%) of 27 patients without HFE gene mutations (P = 0.002; exact Fisher test). CONCLUSION Heterozigozity for H63D and/or C282Y HFE gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis C, non-1 genotype and serum ferritin levels above 500 ng/mL.
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Li SH, Zhao H, Ren YY, Liu YZ, Song G, Ding P, Ding YP, Wang GQ. The H63D mutation of the hemochromatosis gene is associated with sustained virological response in chronic hepatitis C patients treated with interferon-based therapy: a meta-analysis. TOHOKU J EXP MED 2012; 226:293-9. [PMID: 22499121 DOI: 10.1620/tjem.226.293] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
The hemochromatosis (HFE) gene encodes the HFE protein that regulates iron absorption. HFE mutations lead to the hemochromatosis disease of excessive iron absorption. HFE mutations may also influence the sustained virologic response (SVR, long-term virus suppression) in chronic hepatitis C patients treated with interferon-based antiviral therapy. We performed a meta-analysis of all English and Chinese language studies of HFE mutations and SVR in interferon-treated chronic hepatitis C patients indexed in the Medline, PubMed, Embase, and China National Knowledge Infrastructure databases to November 2011. Seven studies involving 605 patients with HFE mutations (homozygous or heterozygous mutation of C282Y, H63D or S65C) and 1279 with wild-type HFE (no mutation of C282Y, H63D or S65C for both alleles) were analyzed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the fixed- or random-effect models. HFE mutations were associated with significantly higher SVR rate (vs. wild-type: OR = 1.56, 95% CI: 1.23-1.97, P < 0.001), indicating that mutation carriers were likely to achieve SVR in response to interferon-based antiviral therapy. Stratification analysis by HFE mutation type revealed that the H63D mutation was associated with a significantly higher SVR rate (OR = 1.60, 95% CI: 1.09-2.34, P = 0.020), while the C282Y mutation was not (OR = 1.19, 95% CI: 0.71-1.98, P = 0.510). Our meta-analysis results indicate that the H63D mutation in HFE is associated with a higher SVR rate in chronic hepatitis C patients treated with interferon-based antiviral therapy.
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Affiliation(s)
- Shi-Hong Li
- Department of Infectious Diseases, Peking University First Hospital, Beijing, P.R. China
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Ryan JD, Altamura S, Devitt E, Mullins S, Lawless MW, Muckenthaler MU, Crowe J. Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C. Hepatology 2012; 56:492-500. [PMID: 22334511 DOI: 10.1002/hep.25666] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2011] [Accepted: 02/09/2012] [Indexed: 12/27/2022]
Abstract
UNLABELLED Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important role in innate immunity, we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥ 2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor. CONCLUSION Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients.
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Affiliation(s)
- John D Ryan
- Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland.
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Tabatabaei SV, Alavian SM, Keshvari M, Behnava B, Miri SM, Karimi Elizee P, Zamani F, Amini Kafiabad S, Gharehbaghian A, Hajibeigy B, Lankarani KB. Low dose ribavirin for treatment of hepatitis C virus infected thalassemia major patients; new indications for combination therapy. HEPATITIS MONTHLY 2012; 12:372-81. [PMID: 22879826 PMCID: PMC3412553 DOI: 10.5812/hepatmon.6592] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 05/15/2012] [Accepted: 05/30/2012] [Indexed: 02/05/2023]
Abstract
BACKGROUND Treatment guidelines contraindicate ribavirin for treatment of hepatitis C virus (HCV) infection in thalassemia major patients. Nevertheless, the current evidence suggests that ribavirin might be tolerated by these patients. OBJECTIVES Despite this evidence, low dose ribavirin combination therapy has not been compared with peginterferon monotherapy in these patients so far. PATIENTS AND METHODS Two hundred eighty thalassemia patients with detectable HCV-RNA PCR (≥ 50 IU/mL) and liver histology consistent with chronic HCV infection were self-assigned to receive peginterferon alfa-2a (n = 81) monotherapy or its combination therapy with ribavirin, 600-800 mg QD, according to hemoglobin levels (n = 199). Treatment experienced patients were eligible for this study. RESULTS Sustained virological response (SVR) was significantly higher in patients who received ribavirin (51 % vs. 38 % P = 0.02). In multivariate regression, OR of ribavirin for prediction of SVR was 2.2 (95 % CI 1.24-3.91). The SVR was significantly higher in the ribavirin group in subgroups of patients with more than 24 years of age, elevated ALT, ferritin < 2006 ng/mL, previous treatment failure, genotype 1, positive history of splenectomy, fibrosis score of 0-4 HAI and viral load < 600,000 IU/mL. Treatment discontinuations due to the safety concerns were comparable between the treatment groups (6.5 and 8 %). Furthermore, transfusion intervals were almost halved in patients who received low dose ribavirin. CONCLUSIONS According to the present study, adult thalassemia patients with HCV infection can be treated successfully with low dose ribavirin. Hence, we strongly advise combination therapy in thalassemia patients with aforementioned clinical characteristics. Moreover, ribavirin does not seem to be beneficial in thalassemia patients below 18 years of age.
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Affiliation(s)
- Seyed Vahid Tabatabaei
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Seyed-Moayed Alavian, Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah Hospital, Mollasadra Ave., Vanak Sq. P.O. Box: 14155-3651, Tehran, IR Iran. Tel.: +98-2188067114, Fax: +98-2188067114, E-mail:
| | - Maryam Keshvari
- Iranian Blood Transfusion Organization Research Centre (IBTO), Tehran, IR Iran
| | - Bita Behnava
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyyed Mohammad Miri
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Pegah Karimi Elizee
- Iranian Blood Transfusion Organization Research Centre (IBTO), Tehran, IR Iran
| | - Farhad Zamani
- Liver Disease Research Center, Iran University of Medical Sciences, Tehran, IR Iran
| | | | - Ahmad Gharehbaghian
- Iranian Blood Transfusion Organization Research Centre (IBTO), Tehran, IR Iran
| | - Bashir Hajibeigy
- Iranian Blood Transfusion Organization Research Centre (IBTO), Tehran, IR Iran
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Ishizu Y, Katano Y, Honda T, Hayashi K, Ishigami M, Itoh A, Hirooka Y, Nakano I, Goto H. Clinical impact of HFE mutations in Japanese patients with chronic hepatitis C. J Gastroenterol Hepatol 2012; 27:1112-6. [PMID: 22098610 DOI: 10.1111/j.1440-1746.2011.06976.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM HFE mutations, a common cause of hereditary hemochromatosis (HH), are reportedly associated with hepatic iron overload, severe liver fibrosis, and good response to interferon treatment in European patients with chronic hepatitis C (CHC). HH shows ethnicity-based differences and little is known about the effects of HH mutations on CHC in the Japanese. Thus, the aim of this study was to clarify the clinical influence of HFE mutations in Japanese CHC patients. METHODS In a total of 251 patients with CHC, we analyzed the frequencies of H63D and S65C mutations in the HFE gene, and the influence of these mutations on clinical parameters and response to pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin therapy. RESULTS Fourteen patients (5.6%) carried the H63D mutation; all were heterozygotes. No S65C mutations were found. Only hemoglobin levels in the H63D heterozygotes were higher than in wild-type patients. Eleven of 14 H63D heterozygotes achieved sustained virological response (SVR). On univariate analysis, factors associated with SVR were interleukin 28B (IL28B) polymorphism, age, hepatitis C virus (HCV) genotype, HCV viral load, white blood cell count, stage of fibrosis and H63D mutation. All patients with both TT genotype in IL28B (rs8099917) and H63D mutation in HFE (n = 10) achieved SVR. CONCLUSIONS The H63D mutation has little impact on the clinical characteristics of CHC, but is related to favorable response to PEG-IFN plus ribavirin therapy, particularly in patients with the TT allele in IL28B.
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Affiliation(s)
- Yoji Ishizu
- Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Wang Q, Liu Y, An D, Diao H, Xu W, He X, Sun R, Wei L, Li L. Regulation of hepatitis C virus translation initiation by iron: role of eIF3 and La protein. Virus Res 2012; 167:302-9. [PMID: 22634302 DOI: 10.1016/j.virusres.2012.05.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 05/16/2012] [Accepted: 05/17/2012] [Indexed: 12/18/2022]
Abstract
Eukaryotic initiation factors (eIFs) are required for encoding polyprotein of hepatitis C virus (HCV) which is mediated by an internal ribosome-entry site (IRES). Iron overload, a common finding among HCV patients, may be correlated with HCV pathology, but the underlying molecular mechanisms are poorly understood. In this study, we investigated the possible relationship among iron status, eIFs and HCV IRES-mediated translation in vitro. Using bicistronic reporter gene constructs carrying HCV IRES sequence, we found that the levels of intracellular iron were positively associated with the HCV IRES-dependent translation initiation in Huh-7 cells. RT-PCR method showed that iron treatment specifically increased the levels of eIF3A mRNA and La mRNA, whereas iron chelation reduced them. Western blots also confirmed that iron-dependent changes in eIF3A mRNA and La mRNA affected the expression of their proteins. Moreover, antisense phosphorothioate oligodeoxynucleotides to eIF3A and La successfully suppressed the levels of eIF3A and La protein and significantly reduced iron-dependent HCV translation. Taken together, our results suggest that iron promotes the translation initiation of HCV by stimulating the expression of eIF3A and La proteins. Inhibition of eIF3A and La proteins substantially repressed iron-dependent HCV translation, a beneficial effect that may have significant clinical implications.
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Affiliation(s)
- Qiang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou 310003, China
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Liu Y, An D, Sun R, Jin L, Wang Q. Inhibition of translation initiation factors might be the potential therapeutic targets for HCV patients with hepatic iron overload. Med Hypotheses 2011; 78:142-3. [PMID: 22047986 DOI: 10.1016/j.mehy.2011.10.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2011] [Accepted: 10/11/2011] [Indexed: 12/21/2022]
Abstract
Standard therapy, interferon-alpha (IFN-α) and ribavirin, remains the only available option for treatment of patients with hepatitis C virus (HCV) infection. However, iron overload, a common finding among HCV patients, have a poor response to treatment with current therapy. These data suggest that both host and viral factors are involved in the determination of the outcome of the therapy. Currently, novel antiviral compounds focus on the development of indirect antiviral drugs. The process of the viral translation is considered as the potential therapeutic targets. Coincidentally, study has found that hepatic iron load enhances the levels of eukaryotic initiation factor 3 (eIF3), which is essential for HCV translation. Reversely, iron chelation could reduce eIF3 p170 translation. Our hypothesis is that iron overload may specifically enhance cellular eIFs. As a result, the cellular mechanisms, in patients with iron overload, are utilized for translating viral mRNA into protein. Thus, treatment strategies that target eIFs should be an exceptionally good candidate therapeutic method for HCV patients with hepatic iron overload.
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Affiliation(s)
- Yiping Liu
- Center of Hygiene Assessment, Institute of Disease Prevention and Control, Academy of Military Medical Sciences, Beijing 100071, China.
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Ackerman Z, Pappo O, Ben-Dov IZ. The prognostic value of changes in serum ferritin levels during therapy for hepatitis C virus infection. J Med Virol 2011; 83:1262-8. [PMID: 21567428 DOI: 10.1002/jmv.22093] [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: 01/14/2023]
Abstract
An increase in serum ferritin levels during combined interferon-ribavirin treatment in chronic patients infected with hepatitis C virus (HCV) can occur. A study was conducted to determine whether observing the kinetics of serum ferritin levels during antiviral therapy, may assist in predicting the rate of sustained virological response. The kinetics of serum ferritin levels during antiviral therapy in treatment-naive, adherent patients with chronic HCV who had early virological response were characterized. Thirteen patients achieved sustained virological response (group 1) while eight patients did not (group 2). Pre-treatment serum ferritin levels were higher in group 2 patients. During antiviral therapy, serum ferritin levels increased in both groups. On treatment, the median increase (compared to baseline) and the calculated rate of the increase in serum ferritin levels was higher in group 1 patients (874% vs. 272%, P < 0.05, 63%/week vs. 13%/week, P = 0.024, respectively). Red blood cell lysis did not contribute to the increase in serum ferritin level. Post-treatment (1st month) serum ferritin levels in group 1 patients were lower than in group 2 patients. In addition, the degree of decline in the 1st month serum ferritin levels (from peak levels) in group 1 patients was higher (76% vs. 49%, P = 0.039). Measuring serum ferritin levels during antiviral therapy in HCV patients who had an early virological response may assist in predicting sustained virological response.
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Affiliation(s)
- Zvi Ackerman
- Department of Medicine, Mount Scopus Campus, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
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Jafroodi M, Asadi R, Heydarzadeh A, Besharati S. Effect of hepatic iron concentration and viral factors in chronic hepatitis C-infected patients with thalassemia major, treated with interferon and ribavirin. Int J Gen Med 2011; 4:529-33. [PMID: 21845061 PMCID: PMC3150176 DOI: 10.2147/ijgm.s19643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Indexed: 01/22/2023] Open
Abstract
Background: Beta thalassemia major patients are vulnerable to transfusion-transmitted infection, especially hepatitis C virus (HCV), and iron overload. These comorbidities lead to cirrhosis and hepatocellular carcinoma in these patients. In order to prevent these complications, treatment of HCV infection and regular iron chelating seems to be necessary. The aim of this study was to evaluate the effect of hepatic iron concentration (HIC) and viral factors on the sustained virological response (SVR) in chronic HCV-infected patients, with beta thalassemia major being treated with interferon and ribavirin. Materials and methods: We enrolled 30 patients with thalassemia major and chronic HCV who were referred to the Hematology Clinic of Guilan University of Medical Sciences, between December 2002 and April 2006. HIC was measured by atomic absorption spectroscopy before treatment. The viral factors (viral load, genotype) and HIC were compared between those who achieved a SVR and nonresponders. Results: Mean age of the 30 thalassemic patients, was 22.56 ± 4.28 years (14–30 years). Most patients were male (56.7%). Genotype 1a was seen in 24 (80%) cases. SVR was achieved in 15 patients (50%). There were no significant correlations between HIC (P = 1.00), viral load (P = 0.414), HCV genotype (P = 0.068), and SVR. No difference was observed in viral load (P = 0.669) and HIC (P = 0.654) between responders and nonresponders. Conclusion: HIC, HCV viral load, and HCV genotype were not correlated with virological response, and it seems that there is no need to postpone antiviral treatment for more vigorous iron chelating therapy.
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Affiliation(s)
- Maryam Jafroodi
- Department of Hematology, Gulian University of Medical Sciences, Rasht, Guilan, Iran
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Ryan JD, Crowe J. Hepatocyte iron accumulation: a new string to ribavirin's antiviral bow? J Hepatol 2011; 55:237-8; author reply 238. [PMID: 21349299 DOI: 10.1016/j.jhep.2011.01.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 01/28/2011] [Indexed: 02/05/2023]
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Abstract
BACKGROUND Increased liver iron stores may contribute to the progression of liver injury and fibrosis, and are associated with a higher risk of hepatocellular carcinoma development. Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients. HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins. This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis. METHODS Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases. Liver function tests and serum iron markers were assessed in both groups. All patients were screened for HFE mutations (C282Y, H63D, S65C). Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes. RESULTS The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis. There were no differences in the prevalence of all HFE mutations in both groups. In patients with a diagnosis of hepatocellular carcinoma, no significant associations with iron disorders and HFE gene mutations were found. CONCLUSIONS Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations. Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis. As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease, there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.
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Bartolomei G, Cevik RE, Marcello A. Modulation of hepatitis C virus replication by iron and hepcidin in Huh7 hepatocytes. J Gen Virol 2011; 92:2072-2081. [PMID: 21593278 DOI: 10.1099/vir.0.032706-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Several clinical observations point to an intricate crosstalk between iron (Fe) metabolism and chronic hepatitis C virus (HCV) infection. In this study, we wanted to investigate the molecular control that Fe levels exert on HCV replication at the hepatocyte level. In keeping with previous observations we confirmed that supra-physiological intracellular Fe induced by haemin treatment down-modulated HCV replication from subgenomic replicons. We also found that RNAi-mediated knockdown of the key Fe modulator hepcidin increased intracellular ferritin and inhibited HCV replication. Conversely, HCV replication did not modulate ferritin content in hepatocytes. Finally, we demonstrated that hepcidin is modulated at the mRNA level by alpha interferon through STAT3. We propose that in Huh7 cells hepcidin modulation leads to an unfavourable intracellular environment for HCV replication. These data may therefore contribute to a better understanding of the complex interplay between HCV and cellular physiology during infection.
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Affiliation(s)
- Giody Bartolomei
- Laboratory of Molecular Virology of the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Recep Emrah Cevik
- Laboratory of Molecular Virology of the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Alessandro Marcello
- Laboratory of Molecular Virology of the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
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Schwarz P, Strnad P, von Figura G, Janetzko A, Krayenbühl P, Adler G, Kulaksiz H. A novel monoclonal antibody immunoassay for the detection of human serum hepcidin. J Gastroenterol 2011; 46:648-56. [PMID: 21136275 DOI: 10.1007/s00535-010-0344-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 10/18/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepcidin is a liver-derived peptide hormone regulating iron metabolism. Changes in the expression of hepcidin are known to be the key pathogenic factors in hereditary hemochromatosis and are associated with infection and inflammation. To better understand the hormone's function in human disease, we aimed to establish an immunoassay to determine hepcidin concentrations in serum. METHODS Monoclonal antibodies mHK(8) and mHK(9) were generated and characterized by dot blot, Western blot, and immunofluorescence. A competitive enzyme-linked immunosorbent assay (ELISA) was established with mHK(9). RESULTS Both antibodies recognized hepcidin, by dot blot and Western blot, respectively. In human liver, mHK(8)/(9) showed an immunofluorescence staining pattern in hepatocytes identical to that of established prohepcidin antibodies. The developed immunoassay with mHK(9), reliably detecting mature hepcidin in serum over a large concentration range (0.9-140 ng ml⁻¹), showed high sensitivity and precision (intra-/interassay coefficients of variation: 4-5 and 7-11%; mean linearity: 85-112%; mean recovery: 87-114%). To test the clinical functionality of the developed assay we measured hepcidin serum concentrations in healthy volunteers, hepatitis C virus (HCV) patients, and two groups of hemochromatotic patients undergoing phlebotomy. The assay distinguished low hepcidin level in HCV and homozygous hemochromatosis patients from normal-range controls and compound heterozygous hemochromatosis patients. In healthy subjects and HCV patients, hepcidin levels were correlated with iron and transferrin saturation; no correlation was observed in the hemochromatotic patients. CONCLUSION We developed a monoclonal antibody ELISA that quantifies serum hepcidin levels with high sensitivity, robustness, and reliability of detection. The hepcidin ELISA should help to enhance our understanding of hepcidin-related human disorders.
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Affiliation(s)
- Peggy Schwarz
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany
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Sirlin CB, Reeder SB. Magnetic resonance imaging quantification of liver iron. Magn Reson Imaging Clin N Am 2011; 18:359-81, ix. [PMID: 21094445 DOI: 10.1016/j.mric.2010.08.014] [Citation(s) in RCA: 144] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Iron overload is the histologic hallmark of hereditary hemochromatosis and transfusional hemosiderosis but also may occur in chronic hepatopathies. This article provides an overview of iron deposition and diseases where liver iron overload is clinically relevant. Next, this article reviews why quantitative noninvasive biomarkers of liver iron would be beneficial. Finally, we describe current state-of-the-art methods for quantifying iron with MR imaging and review remaining challenges and unsolved problems.
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Affiliation(s)
- Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California San Diego, 408 Dickinson Street, San Diego, CA 92103-8226, USA.
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