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Normalizing serum hepcidin but not α-1-antitrypsin level during effective treatment of chronic hepatitis C. Clin Exp Hepatol 2017; 3:203-208. [PMID: 29260001 PMCID: PMC5734587 DOI: 10.5114/ceh.2017.71573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 09/01/2017] [Indexed: 11/23/2022] Open
Abstract
Aim of the study We investigated the impact of pegylated interferon α-2 in combination with ribavirin (PEG-IFNα/RBV) treatment on hepcidin and α-1-antitrypsin concentrations in the serum of patients with chronic hepatitis C. Material and methods We measured serum concentrations of hepcidin, prohepcidin and α-1-antitrypsin by enzyme-linked immunosorbent assays in patients with chronic hepatitis C before and during antiviral therapy. Results Hepcidin concentrations were increased in both genotype 1b and 3a hepatitis C virus (HCV) infected patients as compared with the control group. During treatment of patients infected with genotype 1b HCV hepcidin levels gradually declined, reaching significantly lower values at the treatment termination than before therapy. Treatment responders showed an increased concentration of hepcidin at week 4 of therapy and a subsequent decrease to values significantly lower than observed among non-responders at week 48 of treatment. α-1-antitrypsin concentration was not affected by the treatment efficacy. Conclusions Successful therapy of patients persistently infected with HCV was associated with restoration of serum hepcidin concentration to values similar to the control group. Differential dynamics of hepcidin during PEG-IFNα/RBV therapy in responders and non-responders might indicate the direct influence of viral eradication on iron homeostasis.
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Wróblewska A, Bernat A, Woziwodzka A, Markiewicz J, Romanowski T, Bielawski KP, Smiatacz T, Sikorska K. Interferon lambda polymorphisms associate with body iron indices and hepatic expression of interferon-responsive long non-coding RNA in chronic hepatitis C. Clin Exp Med 2017; 17:225-232. [PMID: 27125837 PMCID: PMC5403869 DOI: 10.1007/s10238-016-0423-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 04/18/2016] [Indexed: 12/21/2022]
Abstract
Single nucleotide polymorphisms (SNPs) within DNA region containing interferon lambda 3 (IFNL3) and IFNL4 genes are prognostic factors of treatment response in chronic hepatitis C (CHC). Iron overload, frequently diagnosed in CHC, is associated with unfavorable disease course and a risk of carcinogenesis. Its etiology and relationship with the immune response in CHC are not fully explained. Our aim was to determine whether IFNL polymorphisms in CHC patients associate with body iron indices, and whether they are linked with hepatic expression of genes involved in iron homeostasis and IFN signaling. For 192 CHC patients, four SNPs within IFNL3-IFNL4 region (rs12979860, rs368234815, rs8099917, rs12980275) were genotyped. In 185 liver biopsies, histopathological analyses were performed. Expression of five mRNAs and three long non-coding RNAs (lncRNAs) was determined with qRT-PCR in 105 liver samples. Rs12979860 TT or rs8099917 GG genotypes as well as markers of serum and hepatocyte iron overload associated with higher activity of gamma-glutamyl transpeptidase and liver steatosis. The presence of two minor alleles in any of the tested SNPs predisposed to abnormally high serum iron concentration and correlated with higher hepatic expression of lncRNA NRIR. On the other hand, homozygosity in any major allele associated with higher viral load. Patients bearing rs12979860 CC genotype had lower hepatic expression of hepcidin (HAMP; P = 0.03). HAMP mRNA level positively correlated with serum iron indices and degree of hepatocyte iron deposits. IFNL polymorphisms influence regulatory pathways of cellular response to IFN and affect body iron balance in chronic hepatitis C virus infection.
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Affiliation(s)
- Anna Wróblewska
- Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland
| | - Agnieszka Bernat
- Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland
| | - Anna Woziwodzka
- Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland
| | - Joanna Markiewicz
- Department of Infectious Diseases, Pomeranian Center of Infectious Diseases, Smoluchowskiego 18, 80-214, Gdańsk, Poland
| | - Tomasz Romanowski
- Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland
| | - Krzysztof P Bielawski
- Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology UG and MUG, Abrahama 58, 80-307, Gdańsk, Poland
| | - Tomasz Smiatacz
- Department of Infectious Diseases, Medical University of Gdansk, Smoluchowskiego 18, 80-214, Gdańsk, Poland
| | - Katarzyna Sikorska
- Department of Infectious Diseases, Medical University of Gdansk, Smoluchowskiego 18, 80-214, Gdańsk, Poland.
- Department of Tropical Medicine and Epidemiology, Medical University of Gdansk, Powstania Styczniowego 9b, 81-519, Gdynia, Poland.
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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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Ivanov AV, Bartosch B, Smirnova OA, Isaguliants MG, Kochetkov SN. HCV and oxidative stress in the liver. Viruses 2013; 5:439-469. [PMID: 23358390 PMCID: PMC3640510 DOI: 10.3390/v5020439] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 12/26/2012] [Accepted: 01/17/2013] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) is the etiological agent accounting for chronic liver disease in approximately 2-3% of the population worldwide. HCV infection often leads to liver fibrosis and cirrhosis, various metabolic alterations including steatosis, insulin and interferon resistance or iron overload, and development of hepatocellular carcinoma or non-Hodgkin lymphoma. Multiple molecular mechanisms that trigger the emergence and development of each of these pathogenic processes have been identified so far. One of these involves marked induction of a reactive oxygen species (ROS) in infected cells leading to oxidative stress. To date, markers of oxidative stress were observed both in chronic hepatitis C patients and in various in vitro systems, including replicons or stable cell lines expressing viral proteins. The search for ROS sources in HCV-infected cells revealed several mechanisms of ROS production and thus a number of cellular proteins have become targets for future studies. Furthermore, during last several years it has been shown that HCV modifies antioxidant defense mechanisms. The aim of this review is to summarize the present state of art in the field and to try to predict directions for future studies.
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Affiliation(s)
- Alexander V. Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow 119991, Russia; E-Mails: (A.I.); (O.S.); (S.K.)
| | - Birke Bartosch
- CRCL, INSERM U1052, CNRS 5286, Université de Lyon, 151, Cours A Thomas 69424 Lyon Cedex France; E-Mail:
| | - Olga A. Smirnova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow 119991, Russia; E-Mails: (A.I.); (O.S.); (S.K.)
| | - Maria G. Isaguliants
- Department of Molecular Biology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16 17177 Stockholm, Sweden; E-Mail:
- D.I. Ivanovsky Institute of Virology, Gamaleya Str. 16, 123098 Moscow, Russia; E-Mail:
| | - Sergey N. Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow 119991, Russia; E-Mails: (A.I.); (O.S.); (S.K.)
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Kell DB. Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples. Arch Toxicol 2010; 84:825-89. [PMID: 20967426 PMCID: PMC2988997 DOI: 10.1007/s00204-010-0577-x] [Citation(s) in RCA: 266] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 07/14/2010] [Indexed: 12/11/2022]
Abstract
Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.
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Affiliation(s)
- Douglas B Kell
- School of Chemistry and the Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7DN, UK.
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Jaroszewicz J, Rogalska M, Flisiak I, Flisiak R. Successful antiviral therapy is associated with a decrease of serum prohepcidin in chronic hepatitis C. World J Gastroenterol 2010; 16:1747-52. [PMID: 20380007 PMCID: PMC2852823 DOI: 10.3748/wjg.v16.i14.1747] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess serum concentrations of prohepcidin in chronic hepatitis C individuals and evaluate their associations with disease activity and efficacy of pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy.
METHODS: Prohepcidin was measured in sera of 53 chronic hepatitis C patients. Concentrations of prohepcidin and other iron metabolism markers were analyzed at 9 time points before, during and after the end of antiviral therapy.
RESULTS: In hepatitis C virus (HCV) genotype 1-infected individuals, a gradual decrease of prohepcidin during antiviral therapy was observed in responders (88.8 ± 14.7 ng/mL before therapy vs 60.6 ± 0.3 ng/mL in the 48th wk, P = 0.04). In contrast, no decrease was observed in non-responders. A similar association was observed in HCV genotype 3a individuals, with a statistically significant decline in serum prohepcidin only in the responder group (99.5 ± 5.2 ng/mL at baseline vs 72.7 ± 6.1 ng/mL in the 24th wk, P = 0.01). Moreover, HCV-RNA at week 12 of therapy was positively correlated with baseline (R = 0.63, P < 0.005) and week 12 (R = 0.60, P = 0.01) serum prohepcidin concentrations in HCV genotype 1 infection.
CONCLUSION: Successful PEG-IFN/RBV therapy results in a decline of serum prohepcidin concentration in chronic hepatitis C, which may suggest a direct effect of HCV on iron metabolism at the prohormonal level of hepcidin.
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Sugimoto R, Fujita N, Tomosugi N, Hara N, Miyachi H, Tanaka H, Takeo M, Nakagawa N, Iwasa M, Kobayashi Y, Kaito M, Takei Y. Impaired regulation of serum hepcidin during phlebotomy in patients with chronic hepatitis C. Hepatol Res 2009; 39:619-24. [PMID: 19260996 DOI: 10.1111/j.1872-034x.2009.00497.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM This study was conducted to determine the clinical relevance of hepcidin, a recently identified key iron regulatory hormone, in patients with chronic hepatitis C virus (C-HCV). METHODS Serum hepcidin levels were measured in 9 C-HCV patients by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS), and compared to those of healthy controls. Sequential changes of hepcidin were also investigated during phlebotomy. RESULTS Serum hepcidin and ferritin were significantly higher in C-HCV than in controls (P = 0.0002), these two variables were strongly related to each other (r = 0.658; P < 0.01), and phlebotomy significantly decreased serum hepcidin in C-HCV (P = 0.0007); all these results recollect the hepcidin response to iron signal. Hepcidin/ferritin ratio, an index of the appropriateness of hepcidin expression relative to iron overload, was significantly lower in C-HCV than in controls (0.33 +/- 0.41 vs. 0.73 +/- 0.36, P = 0.0068). This relative impairment of hepcidin expression was not reversible after phlebotomy (P = NS). CONCLUSIONS Although the hepcidin expression responds to iron conditions in C-HCV, this response is relatively limited. This relative impairment of hepcidin expression may be relevant to disease progression, and thus correction of its regulation may be beneficial for these iron-overloaded C-HCV patients.
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Affiliation(s)
- Ryosuke Sugimoto
- Department of Gastroenterology and Hepatology, Division of Clinical Medicine and Biomedical Science, Institute of Medical Sciences, Mie University Graduate School of Medicine, Mie
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