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Chang YP, Huang CB, Kao JH, Su TH, Huang SC, Tseng TC, Chen PJ, Liu CJ, Liu CH. Factors associated with pre-treatment hyperferritinemia in patients with chronic hepatitis C virus infection. Sci Rep 2024; 14:19219. [PMID: 39160295 PMCID: PMC11333767 DOI: 10.1038/s41598-024-70233-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 08/14/2024] [Indexed: 08/21/2024] Open
Abstract
Pre-treatment host and viral factors may affect serum ferritin levels in patients with hepatitis C virus (HCV) infection. We delineated pre-treatment factors associated with hyperferritinemia in these patients. 1682 eligible patients underwent pre-treatment assessment for serum ferritin and various host/viral factors. Univariate and multivariate logistic regression analyses were conducted to evaluate factors associated with hyperferritinemia. Multivariate logistic regression analyses revealed that age > 50 years (adjusted odds ratio [OR]: 1.38 (95% confidence interval [CI] 1.09-1.74), p = 0.008), fibrosis stage ≥ F3 (adjusted OR: 1.36 (95% CI 1.04-1.77), p = 0.02), fibrosis index based on four parameters (FIB-4) > 3.25 (adjusted OR: 1.46 (95% CI 1.11-1.92), p = 0.01), presence of metabolic dysfunction-associated steatotic liver disease (MASLD) (adjusted OR: 1.43 (95% CI 1.21-1.76), p = 0.001), and alanine transaminase (ALT) > 2 folds upper limit of normal (ULN) (adjusted OR: 2.87 (95% CI 2.20-3.75), p < 0.001) were associated hyperferritinemia. The log10 value of HBV or HCV viral load was not associated with the log10 value of ferritin level (Spearman's rank correlation coefficient: - 0.025, p = 0.81 and 0.002, p = 0.92). In conclusion, host factors, rather than viral factors, are associated with hyperferritinemia in patients with HCV.
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Affiliation(s)
- Yu-Ping Chang
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
| | - Chiuan-Bo Huang
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Shang-Chin Huang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
| | - Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 10002, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan.
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Pereira TA, Espósito BP. Can iron chelators ameliorate viral infections? Biometals 2024; 37:289-304. [PMID: 38019378 DOI: 10.1007/s10534-023-00558-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/25/2023] [Indexed: 11/30/2023]
Abstract
The redox reactivity of iron is a double-edged sword for cell functions, being either essential or harmful depending on metal concentration and location. Deregulation of iron homeostasis is associated with several clinical conditions, including viral infections. Clinical studies as well as in silico, in vitro and in vivo models show direct effects of several viruses on iron levels. There is support for the strategy of iron chelation as an alternative therapy to inhibit infection and/or viral replication, on the rationale that iron is required for the synthesis of some viral proteins and genes. In addition, abnormal iron levels can affect signaling immune response. However, other studies report different effects of viral infections on iron homeostasis, depending on the class and genotype of the virus, therefore making it difficult to predict whether iron chelation would have any benefit. This review brings general aspects of the relationship between iron homeostasis and the nonspecific immune response to viral infections, along with its relevance to the progress or inhibition of the inflammatory process, in order to elucidate situations in which the use of iron chelators could be efficient as antivirals.
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Bao H, Wang Y, Xiong H, Xia Y, Cui Z, Liu L. Mechanism of Iron Ion Homeostasis in Intestinal Immunity and Gut Microbiota Remodeling. Int J Mol Sci 2024; 25:727. [PMID: 38255801 PMCID: PMC10815743 DOI: 10.3390/ijms25020727] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/01/2024] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Iron is a vital trace element that plays an important role in humans and other organisms. It plays an active role in the growth, development, and reproduction of bacteria, such as Bifidobacteria. Iron deficiency or excess can negatively affect bacterial hosts. Studies have reported a major role of iron in the human intestine, which is necessary for maintaining body homeostasis and intestinal barrier function. Organisms can maintain their normal activities and regulate some cancer cells in the body by regulating iron excretion and iron-dependent ferroptosis. In addition, iron can modify the interaction between hosts and microorganisms by altering their growth and virulence or by affecting the immune system of the host. Lactic acid bacteria such as Lactobacillus acidophilus (L. acidophilus), Lactobacillus rhamnosus (L. rhamnosus), and Lactobacillus casei (L. casei) were reported to increase trace elements, protect the host intestinal barrier, mitigate intestinal inflammation, and regulate immune function. This review article focuses on the two aspects of the iron and gut and generally summarizes the mechanistic role of iron ions in intestinal immunity and the remodeling of gut microbiota.
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Affiliation(s)
| | | | | | | | - Zhifu Cui
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China; (H.B.); (Y.W.); (H.X.); (Y.X.)
| | - Lingbin Liu
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China; (H.B.); (Y.W.); (H.X.); (Y.X.)
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Wang Y, Shen M, Li Y, Shao J, Zhang F, Guo M, Zhang Z, Zheng S. COVID-19-associated liver injury: Adding fuel to the flame. Cell Biochem Funct 2023; 41:1076-1092. [PMID: 37947373 DOI: 10.1002/cbf.3883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/19/2023] [Accepted: 10/21/2023] [Indexed: 11/12/2023]
Abstract
COVID-19 is mainly characterized by respiratory disorders and progresses to multiple organ involvement in severe cases. With expansion of COVID-19 and SARS-CoV-2 research, correlative liver injury has been revealed. It is speculated that COVID-19 patients exhibited abnormal liver function, as previously observed in the SARS and MERS pandemics. Furthermore, patients with underlying diseases such as chronic liver disease are more susceptible to SARS-CoV-2 and indicate a poor prognosis accompanied by respiratory symptoms, systemic inflammation, or metabolic diseases. Therefore, COVID-19 has the potential to impair liver function, while individuals with preexisting liver disease suffer from much worse infected conditions. COVID-19 related liver injury may be owing to direct cytopathic effect, immune dysfunction, gut-liver axis interaction, and inappropriate medication use. However, discussions on these issues are infancy. Expanding research have revealed that angiotensin converting enzyme 2 (ACE2) expression mediated the combination of virus and target cells, iron metabolism participated in the virus life cycle and the fate of target cells, and amino acid metabolism regulated immune response in the host cells, which are all closely related to liver health. Further exploration holds great significance in elucidating the pathogenesis, facilitating drug development, and advancing clinical treatment of COVID-19-related liver injury. This article provides a review of the clinical and laboratory hepatic characteristics in COVID-19 patients, describes the etiology and impact of liver injury, and discusses potential pathophysiological mechanisms.
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Affiliation(s)
- Yingqian Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min Shen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Yujia Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mei Guo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Kol I, Rishiq A, Cohen M, Kahlon S, Pick O, Dassa L, Stein N, Bar-On Y, Wolf DG, Seidel E, Mandelboim O. CLPTM1L is a GPI-anchoring pathway component targeted by HCMV. J Cell Biol 2023; 222:e202207104. [PMID: 37389656 PMCID: PMC10316631 DOI: 10.1083/jcb.202207104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 04/03/2023] [Accepted: 05/19/2023] [Indexed: 07/01/2023] Open
Abstract
The GPI-anchoring pathway plays important roles in normal development and immune modulation. MHC Class I Polypeptide-related Sequence A (MICA) is a stress-induced ligand, downregulated by human cytomegalovirus (HCMV) to escape immune recognition. Its most prevalent allele, MICA*008, is GPI-anchored via an uncharacterized pathway. Here, we identify cleft lip and palate transmembrane protein 1-like protein (CLPTM1L) as a GPI-anchoring pathway component and show that during infection, the HCMV protein US9 downregulates MICA*008 via CLPTM1L. We show that the expression of some GPI-anchored proteins (CD109, CD59, and MELTF)-but not others (ULBP2, ULBP3)-is CLPTM1L-dependent, and further show that like MICA*008, MELTF is downregulated by US9 via CLPTM1L during infection. Mechanistically, we suggest that CLPTM1L's function depends on its interaction with a free form of PIG-T, normally a part of the GPI transamidase complex. We suggest that US9 inhibits this interaction and thereby downregulates the expression of CLPTM1L-dependent proteins. Altogether, we report on a new GPI-anchoring pathway component that is targeted by HCMV.
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Affiliation(s)
- Inbal Kol
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Ahmed Rishiq
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Mevaseret Cohen
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Shira Kahlon
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Ophir Pick
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Liat Dassa
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Natan Stein
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Yotam Bar-On
- Department of Immunology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Dana G. Wolf
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
- Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Einat Seidel
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Ofer Mandelboim
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
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Wróblewska A, Woziwodzka A, Rybicka M, Bielawski KP, Sikorska K. Polymorphisms Related to Iron Homeostasis Associate with Liver Disease in Chronic Hepatitis C. Viruses 2023; 15:1710. [PMID: 37632052 PMCID: PMC10457817 DOI: 10.3390/v15081710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/01/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
Dysregulation of iron metabolism in chronic hepatitis C (CHC) is a significant risk factor for hepatic cirrhosis and cancer. We studied if known genetic variants related to iron homeostasis associate with liver disease progression in CHC. Retrospective analysis included 249 CHC patients qualified for antiviral therapy between 2004 and 2014. For all patients, nine SNPs within HFE, TFR2, HDAC2, HDAC3, HDAC5, TMPRSS6, and CYBRD1 genes were genotyped. Expression of selected iron-related genes, was determined with qRT-PCR in 124 liver biopsies, and mRNA expression of co-inhibitory receptors (PD-1, Tim3, CTLA4) was measured in 79 liver samples. CYBRD1 rs884409, HDAC5 rs368328, TFR2 rs7385804, and TMPRSS6 rs855791 associated with histopathological changes in liver tissue at baseline. The combination of minor allele in HDAC3 rs976552 and CYBRD1 rs884409 linked with higher prevalence of hepatocellular carcinoma (HCC) during follow up (OR 8.1 CI 2.2-29.2; p = 0.001). Minor allele in HDAC3 rs976552 associated with lower hepatic expression of CTLA4. Tested polymorphisms related to iron homeostasis associate with histopathological changes in the liver. The presence of both HDAC3 rs976552 G and CYBRD1 rs884409 G alleles correlates with HCC occurrence, especially in the group of patients with elevated AST (>129 IU/L). rs976552 in HDAC3 could impact immunological processes associated with carcinogenesis in CHC.
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Affiliation(s)
- Anna Wróblewska
- Laboratory of Photobiology and Molecular Diagnostics, Intercollegiate Faculty of Biotechnology University of Gdansk and Medical University of Gdansk, 80-307 Gdansk, Poland; (A.W.); (A.W.); (M.R.); (K.P.B.)
| | - Anna Woziwodzka
- Laboratory of Photobiology and Molecular Diagnostics, Intercollegiate Faculty of Biotechnology University of Gdansk and Medical University of Gdansk, 80-307 Gdansk, Poland; (A.W.); (A.W.); (M.R.); (K.P.B.)
| | - Magda Rybicka
- Laboratory of Photobiology and Molecular Diagnostics, Intercollegiate Faculty of Biotechnology University of Gdansk and Medical University of Gdansk, 80-307 Gdansk, Poland; (A.W.); (A.W.); (M.R.); (K.P.B.)
| | - Krzysztof P. Bielawski
- Laboratory of Photobiology and Molecular Diagnostics, Intercollegiate Faculty of Biotechnology University of Gdansk and Medical University of Gdansk, 80-307 Gdansk, Poland; (A.W.); (A.W.); (M.R.); (K.P.B.)
| | - Katarzyna Sikorska
- Division of Tropical Medicine and Epidemiology, Faculty of Health Sciences, Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 81-519 Gdynia, Poland
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Low G, Ferguson C, Locas S, Tu W, Manolea F, Sam M, Wilson MP. Multiparametric MR assessment of liver fat, iron, and fibrosis: a concise overview of the liver "Triple Screen". Abdom Radiol (NY) 2023; 48:2060-2073. [PMID: 37041393 DOI: 10.1007/s00261-023-03887-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 04/13/2023]
Abstract
Chronic liver disease (CLD) is a common source of morbidity and mortality worldwide. Non-alcoholic fatty liver disease (NAFLD) serves as a major cause of CLD with a rising annual prevalence. Additionally, iron overload can be both a cause and effect of CLD with a negative synergistic effect when combined with NAFLD. The development of state-of-the-art multiparametric MR solutions has led to a change in the diagnostic paradigm in CLD, shifting from traditional liver biopsy to innovative non-invasive methods for providing accurate and reliable detection and quantification of the disease burden. Novel imaging biomarkers such as MRI-PDFF for fat, R2 and R2* for iron, and liver stiffness for fibrosis provide important information for diagnosis, surveillance, risk stratification, and treatment. In this article, we provide a concise overview of the MR concepts and techniques involved in the detection and quantification of liver fat, iron, and fibrosis including their relative strengths and limitations and discuss a practical abbreviated MR protocol for clinical use that integrates these three MR biomarkers into a single simplified MR assessment. Multiparametric MR techniques provide accurate and reliable non-invasive detection and quantification of liver fat, iron, and fibrosis. These techniques can be combined in a single abbreviated MR "Triple Screen" assessment to offer a more complete metabolic imaging profile of CLD.
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Affiliation(s)
- Gavin Low
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Craig Ferguson
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Stephanie Locas
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Wendy Tu
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Florin Manolea
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Medica Sam
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Mitchell P Wilson
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada.
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Zheng H, Yang F, Deng K, Wei J, Liu Z, Zheng YC, Xu H. Relationship between iron overload caused by abnormal hepcidin expression and liver disease: A review. Medicine (Baltimore) 2023; 102:e33225. [PMID: 36930080 PMCID: PMC10019217 DOI: 10.1097/md.0000000000033225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/16/2023] [Indexed: 03/18/2023] Open
Abstract
Iron is essential to organisms, the liver plays a vital role in its storage. Under pathological conditions, iron uptake by the intestine or hepatocytes increases, allowing excess iron to accumulate in liver cells. When the expression of hepcidin is abnormal, iron homeostasis in humans cannot be regulated, and resulting in iron overload. Hepcidin also regulates the release of iron from siderophores, thereby regulating the concentration of iron in plasma. Important factors related to hepcidin and systemic iron homeostasis include plasma iron concentration, body iron storage, infection, inflammation, and erythropoietin. This review summarizes the mechanism and regulation of iron overload caused by hepcidin, as well as related liver diseases caused by iron overload and treatment.
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Affiliation(s)
- Haoran Zheng
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Fan Yang
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Kaige Deng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Jiaxin Wei
- Department of Emergency, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhenting Liu
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
| | - Yong-Chang Zheng
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Haifeng Xu
- Division of Liver Surgery, Department of Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
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Keikha M, Kamali H, Ghazvini K, Karbalaei M. Antimicrobial peptides: natural or synthetic defense peptides against HBV and HCV infections. Virusdisease 2022; 33:445-455. [PMID: 36447811 PMCID: PMC9701303 DOI: 10.1007/s13337-022-00790-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 08/22/2022] [Indexed: 11/12/2022] Open
Abstract
According to the literature, treatment of HCV and HBV infections faces challenges due to problems such as the emergence of drug-resistant mutants, the high cost of treatment, and the side effects of current antiviral therapy. Antimicrobial peptides (AMPs), a group of small peptides, are a part of the immune system and are considered as an alternative treatment for microbial infections. These peptides are water-soluble with amphiphilic (hydrophilic and hydrophobic surfaces) characteristics. AMPs are produced by a wide range of organisms including both prokaryotic and eukaryotic cells. The antiviral mechanisms of AMPs include inhibiting virus entry, inhibiting intracellular virus replication, inhibiting intracellular viral packaging, and inducing immune responses. In addition, AMPs are a new generation of antiviral biomolecules that have very low toxicity for human host cells, particularly liver cell lines. AMPs can be considered as one of the most important strategies for developing new adjuvant drugs in the treatment of HBV and HCV infections. In the present study, several groups of AMPs (with a net positive charge) such as Human cathelicidin, Claudin-1, Defensins, Hepcidin, Lactoferrin, Casein, Plectasin, Micrococcin P1, Scorpion venom, and Synthetic peptides were reviewed with antiviral properties against HBV and HCV.
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Affiliation(s)
- Masoud Keikha
- Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Kamali
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kiarash Ghazvini
- Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Karbalaei
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
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10
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Zhou S, Li H, Li S. The Associations of Iron Related Biomarkers with Risk, Clinical Severity and Mortality in SARS-CoV-2 Patients: A Meta-Analysis. Nutrients 2022; 14:3406. [PMID: 36014912 PMCID: PMC9416650 DOI: 10.3390/nu14163406] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/04/2022] [Accepted: 08/07/2022] [Indexed: 11/22/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly around the world and has led to millions of infections and deaths. Growing evidence indicates that iron metabolism is associated with COVID-19 progression, and iron-related biomarkers have great potential for detecting these diseases. However, the results of previous studies are conflicting, and there is not consistent numerical magnitude relationship between those biomarkers and COVID-19. Thereby, we aimed to integrate the results of current studies and to further explore their relationships through a meta-analysis. We searched peer-reviewed literature in PubMed, Scopus and Web of Science up to 31 May 2022. A random effects model was used for pooling standard mean difference (SMD) and the calculation of the corresponding 95% confidence interval (CI). I2 was used to evaluate heterogeneity among studies. A total of 72 eligible articles were included in the meta-analysis. It was found that the ferritin levels of patients increased with the severity of the disease, whereas their serum iron levels and hemoglobin levels showed opposite trends. In addition, non-survivors had higher ferritin levels (SMD (95%CI): 1.121 (0.854, 1.388); Z = 8.22 p for Z < 0.001; I2 = 95.7%, p for I2 < 0.001), lower serum iron levels (SMD (95%CI): −0.483 (−0.597, −0.368), Z = 8.27, p for Z < 0.001; I2 = 0.9%, p for I2 =0.423) and significantly lower TIBC levels (SMD (95%CI): −0.612 (−0.900, −0.324), Z = 4.16, p for Z < 0.001; I2 = 71%, p for I2 = 0.016) than survivors. This meta-analysis demonstrates that ferritin, serum iron, hemoglobin and total iron banding capacity (TIBC) levels are strongly associated with the risk, severity and mortality of COVID-19, providing strong evidence for their potential in predicting disease occurrence and progression.
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Affiliation(s)
| | | | - Shiru Li
- Department of Epidemiology and Health Statistics, School of Public Health, Qingdao University, Qingdao 266071, China
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11
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Xiong H, Zhang C, Han L, Xu T, Saeed K, Han J, Liu J, Klaassen CD, Gonzalez FJ, Lu Y, Zhang Y. Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron-induced hepatotoxicity. Hepatology 2022; 76:387-403. [PMID: 34870866 DOI: 10.1002/hep.32270] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 11/23/2021] [Accepted: 12/04/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS Iron overload (IO) is a frequent finding in the general population. As the major iron storage site, the liver is subject to iron toxicity. Farnesoid X receptor (FXR) regulates bile acid metabolism and is implicated in various liver diseases. We aimed to determine whether FXR plays a role in regulating iron hepatotoxicity. APPROACH AND RESULTS Human and mouse hepatocytes were treated with ferric ammonium citrate or iron dextran (FeDx). Mice were orally administered ferrous sulfate or injected i.p. with FeDx. Wild-type and Fxr-/- mice were fed an iron-rich diet for 1 or 5 weeks. Mice fed an iron-rich diet were coadministered the FXR agonist, GW4064. Forced expression of FXR was carried out with recombinant adeno-associated virus 1 week before iron-rich diet feeding. Serum levels of bile acids and fibroblast growth factor 19 (FGF19) were quantified in adults with hyperferritinemia and children with β-thalassemia. The data demonstrated that iron suppressed FXR expression and signaling in human and mouse hepatocytes as well as in mouse liver and intestine. FXR deficiency potentiated iron hepatotoxicity, accompanied with hepatic steatosis as well as dysregulated iron and bile acid homeostasis. FXR negatively regulated iron-regulatory proteins 1 and 2 and prevented hepatic iron accumulation. Forced FXR expression and ligand activation significantly suppressed iron hepatotoxicity in iron-fed mice. The FXR agonist, GW4064, almost completely restored dysregulated bile acid signaling and metabolic syndrome in iron-fed mice. Conjugated primary bile acids were increased and FGF19 was decreased in serum of adults with hyperferritinemia and children with β-thalassemia. CONCLUSIONS FXR plays a pivotal role in regulating iron homeostasis and protects mice against iron hepatotoxicity. Targeting FXR may represent a therapeutic strategy for IO-associated chronic liver diseases.
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Affiliation(s)
- Hui Xiong
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Lifeng Han
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tong Xu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Khawar Saeed
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Jing Han
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Jing Liu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Curtis D Klaassen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Yuanfu Lu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
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12
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SMAD proteins: Mediators of diverse outcomes during infection. Eur J Cell Biol 2022; 101:151204. [DOI: 10.1016/j.ejcb.2022.151204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 11/19/2022] Open
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13
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Pandrangi SL, Chittineedi P, Chikati R, Lingareddy JR, Nagoor M, Ponnada SK. Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer. Am J Cancer Res 2022; 12:974-985. [PMID: 35411219 PMCID: PMC8984875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 02/10/2022] [Indexed: 06/14/2023] Open
Abstract
Iron is the most abundant metal in the human body. No independent life forms on earth can survive without iron. However, excess iron is closely associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Therefore, it is speculated that iron might play a dual role in cells, by both stimulating cell growth and causing cell death. Dietary iron is absorbed by the intestinal enterocytes in the form of ferrous ion which forms cLIP. Excess iron stored in the form of Ferritin serves as a reservoir under iron depletion conditions. Ferroptosis, is an iron-dependent non-mutational form of cell death process and is suppressed by iron-binding compounds such as deferoxamine. Blocking transferrin-mediated iron import or recycling of iron-containing storage proteins (i.e., ferritin) also attenuates ferroptosis, consistent with the iron-dependent nature of this process. Unsurprisingly, ferroptosis also plays a role in the development of cancer and maybe a beneficial strategy for anticancer treatment. Different lines of evidence suggest that ferroptosis plays a crucial role in the suppression of tumorigenesis. In this review, we have discussed the pros and cons of iron accumulation, utilization and, its role in cell proliferation, ferroptosis and pathophysiology of cancer.
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Affiliation(s)
- Santhi Latha Pandrangi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM (Deemed to be) UniversityVisakhapatnam 530045, India
| | - Prasanthi Chittineedi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM (Deemed to be) UniversityVisakhapatnam 530045, India
| | | | - Joji Reddy Lingareddy
- Department of Biotechnology, Loyola AcademyOld Alwal, Secunderabad, Telangana 500010, India
| | | | - Suresh Kumar Ponnada
- Department of Biotechnology, Loyola AcademyOld Alwal, Secunderabad, Telangana 500010, India
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14
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Li H, Hu L, Wang L, Wang Y, Shao M, Chen Y, Wu W, Wang L. Iron Activates cGAS-STING Signaling and Promotes Hepatic Inflammation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:2211-2220. [PMID: 35133148 DOI: 10.1021/acs.jafc.1c06681] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Iron deposition and chronic inflammation are associated with chronic liver diseases, such as alcoholic liver disease, nonalcoholic fatty liver disease, and chronic hepatitis B and C. However, the relationship between iron deposition and chronic inflammation in these diseases is still unclear. In the current study, we aimed to investigate the effect of iron on chronic inflammation in HepG2 cells and mice liver. We demonstrated that iron treatment enhanced the expression of cGAS, STING, and their downstream targets, including TBK1, IRF-3, and NF-κB in HepG2 cells and mice liver. We also found that treatment of HepG2 cells and mice with ferric ammonium citrate increased the expression of inflammatory cytokines, such as IFN-β. Finally, we found that genes involved in iron metabolism and the STING signaling pathway were up-regulated in liver cancer tissues, and the survival time of patients with high expression of these genes in tumor tissues was significantly shortened. These results suggest that iron overload may promote the progress of the chronic liver disease by activating cGAS-STING-mediated chronic inflammation, which provides a new idea for the development of drugs for the treatment of the chronic liver disease.
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Affiliation(s)
- Hailang Li
- Department of Pharmacy, Xiamen Medical College, Xiamen 361023, China
| | - Ling Hu
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Liwen Wang
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Yixuan Wang
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Meiqi Shao
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
| | - Yupei Chen
- Department of Pharmacy, Xiamen Medical College, Xiamen 361023, China
| | - Wenlin Wu
- Department of Biotechnology, Quanzhou Normal University, Quanzhou 362000, China
- Fujian Province Key Laboratory for the Development of Bioactive Material from Marine Algae, Quanzhou Normal University, Quanzhou 362000, China
| | - Lei Wang
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
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15
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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16
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Dawood RM, El-Meguid MA, Elrobe W, Salum GM, Zayed N, Mousa S, Medhat E. Significance of Hereditary Hemochromatosis Gene (HFE) Mutations in Chronic Hepatitis C and Hepatocellular Carcinoma Patients in Egypt: A Pilot Study. Asian Pac J Cancer Prev 2021; 22:2837-2845. [PMID: 34582652 PMCID: PMC8850884 DOI: 10.31557/apjcp.2021.22.9.2837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/12/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Hereditary hemochromatosis is a genetic disease defined by enhanced overloading of iron and associated with Chronic Hepatitis C (CHC). This study aims to evaluate the correlation of the HFE gene mutations on Egyptian CHC with liver disease progression and the risk of HCC development. METHODS The HFE mutations (C282Y and H63D) were genotyped on 100 CHC patients and 50 healthy individuals by a hybridization assay. The serum iron content was also measured for all subjects. RESULTS A significant elevation of the serum iron, ferritin, and TIBC in HCV-infected patients (p≤0.05). The H63D mutation was detected in 23% of the all studied samples. The serum iron and the H63D heterozygosity were correlated significantly between non-cirrhotic and cirrhotic without HCC patients. CONCLUSION The H63D heterozygosity might have a potential role in iron accumulation. Moreover, HFE mutations did not tend to be associated with an increased risk of HCC in cirrhotic patients.
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Affiliation(s)
- Reham M Dawood
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt.
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt.
| | - Walied Elrobe
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Ghada M Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt.
| | - Naglaa Zayed
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Sherief Mousa
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Eman Medhat
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
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17
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Foka P, Dimitriadis A, Karamichali E, Kochlios E, Eliadis P, Valiakou V, Koskinas J, Mamalaki A, Georgopoulou U. HCV-Induced Immunometabolic Crosstalk in a Triple-Cell Co-Culture Model Capable of Simulating Systemic Iron Homeostasis. Cells 2021; 10:2251. [PMID: 34571900 PMCID: PMC8465420 DOI: 10.3390/cells10092251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/26/2021] [Accepted: 08/26/2021] [Indexed: 11/16/2022] Open
Abstract
Iron is crucial to the regulation of the host innate immune system and the outcome of many infections. Hepatitis C virus (HCV), one of the major viral human pathogens that depends on iron to complete its life cycle, is highly skilled in evading the immune system. This study presents the construction and validation of a physiologically relevant triple-cell co-culture model that was used to investigate the input of iron in HCV infection and the interplay between HCV, iron, and determinants of host innate immunity. We recorded the expression patterns of key proteins of iron homeostasis involved in iron import, export and storage and examined their relation to the iron regulatory hormone hepcidin in hepatocytes, enterocytes and macrophages in the presence and absence of HCV. We then assessed the transcriptional profiles of pro-inflammatory cytokines Interleukin-6 (IL-6) and interleukin-15 (IL-15) and anti-inflammatory interleukin-10 (IL-10) under normal or iron-depleted conditions and determined how these were affected by infection. Our data suggest the presence of a link between iron homeostasis and innate immunity unfolding among liver, intestine, and macrophages, which could participate in the deregulation of innate immune responses observed in early HCV infection. Coupled with iron-assisted enhanced viral propagation, such a mechanism may be important for the establishment of viral persistence and the ensuing chronic liver disease.
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Affiliation(s)
- Pelagia Foka
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
| | - Alexios Dimitriadis
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - Eirini Karamichali
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
| | - Emmanouil Kochlios
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
| | - Petros Eliadis
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - Vaia Valiakou
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - John Koskinas
- 2nd Department of Internal Medicine, Hippokration Hospital, Medical School of Athens, 11527 Athens, Greece;
| | - Avgi Mamalaki
- Molecular Biology and Immunobiotechnology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (A.D.); (P.E.); (V.V.); (A.M.)
| | - Urania Georgopoulou
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521 Athens, Greece; (E.K.); (E.K.); (U.G.)
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18
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Evolution of ferritin levels in hepatitis C patients treated with antivirals. Sci Rep 2020; 10:19744. [PMID: 33184464 PMCID: PMC7661708 DOI: 10.1038/s41598-020-76871-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
The evolution of ferritin levels in hepatitis C virus (HCV)-infected patients with sustained virological responses (SVRs) following various therapy regimens remains elusive. An 8-year prospective cohort study of 1194 HCV-infected patients [interferon-based therapy (n = 620), direct-acting antiviral agent (DAA) therapy (n = 355)] was conducted. At baseline, sex, alanine aminotransferase (ALT), triglycerides, homeostatic model assessment of insulin resistance (HOMA-IR), estimated glomerular filtration rate (eGFR), hemoglobin, iron/total iron-binding capacity (Fe/TIBC) and IFNL3-rs12979860 genotypes were associated with ferritin levels. At 24 weeks posttherapy, ALT, triglycerides, total cholesterol, eGFR, Fe/TIBC and the therapy regimen were associated with ferritin levels in SVR patients. Among interferon-treated patients, ferritin levels increased at 24 weeks posttherapy, regardless of SVR, and 24-week posttherapy ferritin levels were higher in non-SVR patients (n = 111) than in SVR patients (n = 509); ferritin levels began decreasing at 3 years posttherapy and were lower than pretherapy levels since 4 years posttherapy in SVR patients. Among DAA-treated SVR patients (n = 350), ferritin levels decreased and remained stable since 24 weeks posttherapy. ALT, triglycerides, eGFR, and Fe/TIBC were HCV-unrelated factors associated with ferritin levels; sex, HOMA-IR, total cholesterol, hemoglobin and IFNL3-rs12979860 genotype were HCV-related factors associated with ferritin levels. In interferon-treated SVR patients, the increased trend of posttherapy ferritin levels was not reversed until 4 years posttherapy. In DAA-treated SVR patients, ferritin levels decreased since 24 weeks posttherapy.
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19
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Zhang Y, Zhang G, Liang Y, Wang H, Wang Q, Zhang Y, Zhang X, Zhang J, Chu L. Potential Mechanisms Underlying the Hepatic–Protective Effects of Danshensu on Iron Overload Mice. Biol Pharm Bull 2020; 43:968-975. [DOI: 10.1248/bpb.b19-01084] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yuanyuan Zhang
- School of Pharmacy, Hebei University of Chinese Medicine
| | - Gaohua Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Yingran Liang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Hongfang Wang
- School of Pharmacy, Hebei University of Chinese Medicine
| | - Qian Wang
- School of Pharmacy, Hebei University of Chinese Medicine
| | - Ying Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Xuan Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Jianping Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Li Chu
- School of Pharmacy, Hebei University of Chinese Medicine
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns
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20
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Abstract
BACKGROUND Disorders of serum iron balance are frequently observed in chronic hepatitis C (CHC) patients. Iron overload as well as iron deficiency anemia are common clinical findings in these patients. Variceal bleeding is also a common complication. To date, no study has discussed the influence of esophageal bleeding on iron status in anemic CHC bleeders. OBJECTIVE Was to study reticulocyte hemoglobin content (CHr) and serum hepcidin levels in anemic CHC and to evaluate the influence of variceal bleeding on patients' iron status. METHODS Serum hepcidin levels and CHr were assessed in 65 early phase CHC patients (20 nonanemic, 23 anemic nonbleeders, and 22 anemic bleeders), and 20 healthy controls; and were compared with the conventional indices of iron deficiency including mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, serum iron, total iron binding capacity, transferrin saturation and ferritin. RESULTS Hepcidin levels were comparable in patients groups, but were significantly lower in patients than in controls (P = 0.01). Child-Pugh class B patients showed significantly lower hepcidin levels than class A patients. CHr levels were comparable in all groups as well as all iron deficiency indices. Patients with ferritin values or less 100 ng/ml and CHr or less 29 pg/cell or Tfsat or less 16% are more likely to have iron deficiency [odds ratio (OR = 3.93, 95% confidence interval (CI) = 2.54-6.08; OR = 10.50, 95% CI = 1.94-56.55, respectively). CONCLUSION Esophageal bleeding has an almost no influence on iron status in CHC patients. Serum hepcidin content is influenced by CHC disease rather than by anemia associated with or without esophageal bleeding and it could be used as a marker of early hepatic insufficiency. Assessing CHr content could add a potential utility in the detection of iron deficiency in CHC patients.
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21
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Barton JC, Barton JC, Adams PC. Prevalence and characteristics of anti-HCV positivity and chronic hepatitis C virus infection in HFE p.C282Y homozygotes. Ann Hepatol 2020; 18:354-359. [PMID: 31056361 DOI: 10.1016/j.aohep.2018.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/30/2018] [Accepted: 11/28/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Observations of hepatitis C virus (HCV) infection in adults with hemochromatosis are limited. MATERIALS AND METHODS We determined associations of serum ferritin (SF) with anti-HCV in non-Hispanic white North American adults in a post-screening examination. Cases included p.C282Y homozygotes (regardless of screening transferrin saturation (TS) and SF) and participants (regardless of HFE genotype) with high screening TS/SF. Controls included participants without p.C282Y or p.H63D who had normal screening TS/SF. Participants with elevated alanine aminotransferase underwent anti-HCV testing. We determined prevalence of chronic HCV infection in consecutive Alabama and Ontario referred adults with HFE p.C282Y homozygosity. RESULTS In post-screening participants, anti-HCV prevalence was 0.3% [95% CI: 0.02, 2.2] in 294 p.C282Y homozygotes, 9.5% [7.2, 12.3] in 560 Cases without p.C282Y homozygosity, and 0.7% [0.2, 2.3] in 403 Controls. Anti-HCV was detected in 7.2% of 745 participants with and 0.8% of 512 participants without elevated SF (odds ratio 9.9 [3.6, 27.6]; p<0.0001). Chronic HCV infection prevalence in 961 referred patients was 1.0% (10/961) [95% confidence interval (CI): 0.5, 2.0]. Ten patients with chronic HCV infection had median age 45y (range 29-67) and median SF 1163μg/L (range 303-2001). Five of eight (62.5%) patients had biopsy-proven cirrhosis. CONCLUSIONS Odds ratio of anti-HCV was increased in post-screening participants with elevated SF. Prevalence of anti-HCV in post-screening participants with HFE p.C282Y homozygosity and chronic HCV infection in referred adults with HFE p.C282Y homozygosity in North America is similar to that of Control participants with HFE wt/wt and normal screening TS/SF.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, Birmingham, AL, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | | | - Paul C Adams
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
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22
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Sevastianos VA, Voulgaris TA, Dourakis SP. Hepatitis C, systemic inflammation and oxidative stress: correlations with metabolic diseases. Expert Rev Gastroenterol Hepatol 2020; 14:27-37. [PMID: 31868062 DOI: 10.1080/17474124.2020.1708191] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Hepatitis C chronic infection has long been correlated with numerous systemic diseases, such as diabetes mellitus and hepatic steatosis. Recent studies have also revealed an association with atherosclerosis.Areas covered: An analysis is presented on the mechanisms through which the hepatitis C viral infection can lead to a systemic increase in pro-inflammatory markers, especially tumor necrosis factor-a and interleukin-6. The immunological imbalance created may, through different mechanisms, act on the metabolic pathways that contribute to the development of insulin resistance, the accumulation of lipids in the liver, and even the formation of atherosclerotic plaques. Moreover, an additional contributing factor to the above-mentioned metabolic derangements is the unopposed oxidative stress observed in chronic hepatitis C viral infection. The virus itself contributes to the formation of oxidative stress, through alterations in the trace metal homeostasis and its effect on pro-inflammatory cytokines, such as tumor necrosis factor-a.Expert opinion: The scope of this review is to emphasize the importance of the metabolic manifestations of hepatitis C viral infection and to elucidate the pathophysiological mechanisms behind their emergence.
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Affiliation(s)
- Vassilios A Sevastianos
- Department of Internal Medicine and Liver Outpatient Clinic, "Evangelismos" General Hospital, Athens, Greece
| | - Theodoros A Voulgaris
- Department of Internal Medicine and Liver Outpatient Clinic, "Evangelismos" General Hospital, Athens, Greece
| | - Spyros P Dourakis
- Department of Internal Μedicine, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens Ippokrateio, Athens, Greece
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23
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Gupta S, Read SA, Shackel NA, Hebbard L, George J, Ahlenstiel G. The Role of Micronutrients in the Infection and Subsequent Response to Hepatitis C Virus. Cells 2019; 8:E603. [PMID: 31212984 PMCID: PMC6627053 DOI: 10.3390/cells8060603] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/13/2019] [Indexed: 12/13/2022] Open
Abstract
Micronutrient deficiencies develop for a variety of reasons, whether geographic, socioeconomic, nutritional, or as a result of disease pathologies such as chronic viral infection. As micronutrients are essential for a strong immune response, deficiencies can significantly dampen both the innate and the adaptive arms of antiviral immunity. The innate immune response in particular is crucial to protect against hepatitis C virus (HCV), a hepatotropic virus that maintains chronic infection in up to 80% of individuals if left untreated. While many micronutrients are required for HCV replication, an overlapping group of micronutrients are also necessary to enact a potent immune response. As the liver is responsible for the storage and metabolism of many micronutrients, HCV persistence can influence the micronutrients' steady state to benefit viral persistence both directly and by weakening the antiviral response. This review will focus on common micronutrients such as zinc, iron, copper, selenium, vitamin A, vitamin B12, vitamin D and vitamin E. We will explore their role in the pathogenesis of HCV infection and in the response to antiviral therapy. While chronic hepatitis C virus infection drives deficiencies in micronutrients such as zinc, selenium, vitamin A and B12, it also stimulates copper and iron excess; these micronutrients influence antioxidant, inflammatory and immune responses to HCV.
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Affiliation(s)
- Sunil Gupta
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia.
| | - Scott A Read
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia.
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, Australia.
| | - Nicholas A Shackel
- Department of Medicine, University of New South Wales, Kensington, NSW 2052, Australia.
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, Centre for Molecular Therapeutics, James Cook University, Australian Institute of Tropical Health and Medicine, Townsville, QLD 4814, Australia.
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, Australia.
| | - Golo Ahlenstiel
- Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia.
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, Australia.
- Department of Medicine, Blacktown Hospital, Blacktown, NSW 2148, Australia.
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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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Mehta KJ, Farnaud SJ, Sharp PA. Iron and liver fibrosis: Mechanistic and clinical aspects. World J Gastroenterol 2019; 25:521-538. [PMID: 30774269 PMCID: PMC6371002 DOI: 10.3748/wjg.v25.i5.521] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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Affiliation(s)
- Kosha J Mehta
- School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
- Division of Human Sciences, School of Applied Sciences, London South Bank University, London SE1 0AA, United Kingdom
| | - Sebastien Je Farnaud
- Faculty Research Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry CV1 2DS, United Kingdom
| | - Paul A Sharp
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, United Kingdom
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Abstract
Objective: The aim of this study was to summarize the interactions between hepatitis C virus (HCV) infection and iron overload, and to understand the mechanisms of iron overload in chronic hepatitis C (CHC) and the role iron plays in HCV life cycle. Data Sources: This review was based on data in articles published in the PubMed databases up to January 28, 2017, with the keywords “hepatitis C virus”, “iron overload”, “iron metabolism”, “hepcidin”, “translation”, and “replication”. Study Selection: Articles related to iron metabolism, iron overload in patients with CHC, or the effects of iron on HCV life cycle were selected for the review. Results: Iron overload is common in patients with CHC. The mechanisms involve decreased hepcidin levels caused by HCV through signal transducer and activator of transcription 3, mitogen-activated protein kinase, or bone morphogenetic protein/SMAD signaling pathways, and the altered expression of other iron-metabolism-related genes. Some studies found that iron increases HCV replication, while other studies found the opposite result. Most of the studies suggest the positive role of iron on HCV translation, the mechanisms of which involve increased expression levels of factors associated with HCV internal ribosome entry site-dependent translation, such as eukaryotic initiation factor 3 and La protein. Conclusion: The growing literature demonstrates that CHC leads to iron overload, and iron affects the HCV life cycle in turn. Further research should be conducted to clarify the mechanism involved in the complicated interaction between iron and HCV.
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Affiliation(s)
- Dong-Mei Zou
- Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Wan-Ling Sun
- Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
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27
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Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis. PLoS One 2017; 12:e0179074. [PMID: 28594937 PMCID: PMC5464635 DOI: 10.1371/journal.pone.0179074] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 05/23/2017] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25–34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87–24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635–0.863) and internal validation cohort (AUC = 0.741; CI 0.558–0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.
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28
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Michels KR, Zhang Z, Bettina AM, Cagnina RE, Stefanova D, Burdick MD, Vaulont S, Nemeth E, Ganz T, Mehrad B. Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia. JCI Insight 2017; 2:e92002. [PMID: 28352667 DOI: 10.1172/jci.insight.92002] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Gram-negative pneumonia is a dangerous illness, and bacterial dissemination to the bloodstream during the infection is strongly associated with death. Antibiotic resistance among the causative pathogens has resulted in diminishing treatment options against this infection. Hepcidin is the master regulator of extracellular iron availability in vertebrates, but its role in the context of host defense is undefined. We hypothesized that hepcidin-mediated depletion of extracellular iron during Gram-negative pneumonia protects the host by limiting dissemination of bacteria to the bloodstream. During experimental pneumonia, hepcidin was induced in the liver in an IL-6-dependent manner and mediated a rapid decline in plasma iron. In contrast, hepcidin-deficient mice developed a paradoxical increase in plasma iron during infection associated with profound susceptibility to bacteremia. Incubation of bacteria with iron-supplemented plasma enhanced bacterial growth in vitro, and systemic administration of iron to WT mice similarly promoted increased susceptibility to bloodstream infection. Finally, treatment with a hepcidin analogue restored hypoferremia in hepcidin-deficient hosts, mediated bacterial control, and improved outcomes. These data show hepcidin induction during pneumonia to be essential to preventing bacterial dissemination by limiting extracellular iron availability. Hepcidin agonists may represent an effective therapy for Gram-negative infections in patients with impaired hepcidin production or signaling.
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Affiliation(s)
| | - Zhimin Zhang
- Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | | | - R Elaine Cagnina
- Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Debora Stefanova
- Departments of Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, California, USA
| | - Marie D Burdick
- Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Sophie Vaulont
- INSERM U1016, Cochin Institute, Descartes University, Paris, France
| | - Elizabeta Nemeth
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Tomas Ganz
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Borna Mehrad
- Departments of Microbiology, Immunology, and Cancer Biology.,Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.,Beirne B. Carter Center for Immunology, University of Virginia, Charlottesville, Virginia, USA
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29
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Affiliation(s)
- Che C. Colpitts
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques and Université de Strasbourg, Strasbourg, France
| | - Thomas F. Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques and Université de Strasbourg and Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hopitaux, Universitaires de Strasbourg, Strasbourg, France
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30
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Milic S, Mikolasevic I, Orlic L, Devcic E, Starcevic-Cizmarevic N, Stimac D, Kapovic M, Ristic S. The Role of Iron and Iron Overload in Chronic Liver Disease. Med Sci Monit 2016; 22:2144-2151. [PMID: 27332079 PMCID: PMC4922827 DOI: 10.12659/msm.896494] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 11/24/2015] [Indexed: 12/13/2022] Open
Abstract
The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models.
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Affiliation(s)
- Sandra Milic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
| | - Ivana Mikolasevic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
- Department of Nephrology, Dialysis and Kidney Transplantation, UHC Rijeka, Rijeka, Croatia
| | - Lidija Orlic
- Department of Nephrology, Dialysis and Kidney Transplantation, UHC Rijeka, Rijeka, Croatia
| | - Edita Devcic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
| | | | - Davor Stimac
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
| | - Miljenko Kapovic
- Department of Biology and Medical Genetics, Faculty of Medicine, Rijeka, Croatia
| | - Smiljana Ristic
- Department of Biology and Medical Genetics, Faculty of Medicine, Rijeka, Croatia
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31
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Zhu L, Chen X, Kong X, Cai YD. Investigation of the roles of trace elements during hepatitis C virus infection using protein-protein interactions and a shortest path algorithm. Biochim Biophys Acta Gen Subj 2016; 1860:2756-68. [PMID: 27208424 DOI: 10.1016/j.bbagen.2016.05.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 05/05/2016] [Accepted: 05/13/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis is a type of infectious disease that induces inflammation of the liver without pinpointing a particular pathogen or pathogenesis. Type C hepatitis, as a type of hepatitis, has been reported to induce cirrhosis and hepatocellular carcinoma within a very short amount of time. It is a great threat to human health. Some studies have revealed that trace elements are associated with infection with and immune rejection against hepatitis C virus (HCV). However, the mechanism underlying this phenomenon is still unclear. METHODS In this study, we aimed to expand our knowledge of this phenomenon by designing a computational method to identify genes that may be related to both HCV and trace element metabolic processes. The searching procedure included three stages. First, a shortest path algorithm was applied to a large network, constructed by protein-protein interactions, to identify potential genes of interest. Second, a permutation test was executed to exclude false discoveries. Finally, some rules based on the betweenness and associations between candidate genes and HCV and trace elements were built to select core genes among the remaining genes. RESULTS 12 lists of genes, corresponding to 12 types of trace elements, were obtained. These genes are deemed to be associated with HCV infection and trace elements metabolism. CONCLUSIONS The analyses indicate that some genes may be related to both HCV and trace element metabolic processes, further confirming the associations between HCV and trace elements. The method was further tested on another set of HCV genes, the results indicate that this method is quite robustness. GENERAL SIGNIFICANCE The newly found genes may partially reveal unknown mechanisms between HCV infection and trace element metabolism. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.
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Affiliation(s)
- LiuCun Zhu
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China
| | - XiJia Chen
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China
| | - Xiangyin Kong
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, People's Republic of China
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai 200444, People's Republic of China.
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32
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Tapia-Paniagua ST, Vidal S, Lobo C, García de la Banda I, Esteban MA, Balebona MC, Moriñigo MA. Dietary administration of the probiotic SpPdp11: Effects on the intestinal microbiota and immune-related gene expression of farmed Solea senegalensis treated with oxytetracycline. FISH & SHELLFISH IMMUNOLOGY 2015; 46:449-458. [PMID: 26190256 DOI: 10.1016/j.fsi.2015.07.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 07/08/2015] [Accepted: 07/14/2015] [Indexed: 06/04/2023]
Abstract
Few antimicrobials are currently authorised in the aquaculture industry to treat infectious diseases. Among them, oxytetracycline (OTC) is one of the first-choice drugs for nearly all bacterial diseases. The objective of this study was to evaluate the effect of the dietary administration of OTC both alone and jointly with the probiotic Shewanella putrefaciens Pdp11 (SpPdp11) on the intestinal microbiota and hepatic expression of genes related to immunity in Senegalese sole (Solea senegalensis) juveniles. The results demonstrated that the richness and diversity of the intestinal microbiota of fish treated with OTC decreased compared with those of the control group but that these effects were lessened by the simultaneous administration of SpPdp11. In addition, specimens that received OTC and SpPdp11 jointly showed a decreased intensity of the Denaturing Gradient Gel Electrophoresis (DGGE) bands related to Vibrio genus and the presence of DGGE bands related to Lactobacillus and Shewanella genera. The relationship among the intestinal microbiota of fish fed with control and OTC diets and the expression of the NADPH oxidase and CASPASE-6 genes was demonstrated by a Principal Components Analysis (PCA) carried out in this study. In contrast, a close relationship between the transcription of genes, such as NKEF, IGF-β, HSP70 and GP96, and the DGGE bands of fish treated jointly with OTC and SpPdp11 was observed in the PCA study. In summary, the results obtained in this study demonstrate that the administration of OTC results in the up-regulation of genes related to apoptosis but that the joint administration of OTC and S. putrefaciens Pdp11 increases the transcription of genes related to antiapoptotic effects and oxidative stress regulation. Further, a clear relationship between these changes and those detected in the intestinal microbiota is established.
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Affiliation(s)
- S T Tapia-Paniagua
- Universidad de Málaga, Departamento de Microbiología, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - S Vidal
- Universidad de Málaga, Departamento de Microbiología, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - C Lobo
- Spanish Institute of Oceanography, Oceanographic Center of Santander, 39080 Santander, Spain
| | - I García de la Banda
- Spanish Institute of Oceanography, Oceanographic Center of Santander, 39080 Santander, Spain
| | - M A Esteban
- Innate Immune System Group, Department of Cell Biology and Histology, Faculty of Biology, Campus Regional de Excelencia Internacional "Campus Mare Nostrum", University of Murcia, 30100 Murcia, Spain
| | - M C Balebona
- Universidad de Málaga, Departamento de Microbiología, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - M A Moriñigo
- Universidad de Málaga, Departamento de Microbiología, Campus de Teatinos s/n, 29071 Málaga, Spain.
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Gonçalves LDR, Campanhon IB, Domingues RR, Paes Leme AF, Soares da Silva MR. Comparative salivary proteome of hepatitis B- and C-infected patients. PLoS One 2014; 9:e113683. [PMID: 25423034 PMCID: PMC4244100 DOI: 10.1371/journal.pone.0113683] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B and C virus (HBV and HCV) infections are an important cause of cirrhosis and hepatocellular carcinoma. The natural history has a prominent latent phase, and infected patients may remain undiagnosed; this situation may lead to the continuing spread of these infections in the community. Compelling reasons exist for using saliva as a diagnostic fluid because it meets the demands of being an inexpensive, noninvasive and easy-to-use diagnostic method. Indeed, comparative analysis of the salivary proteome using mass spectrometry is a promising new strategy for identifying biomarkers. Our goal is to apply an Orbitrap-based quantitative approach to explore the salivary proteome profile in HBV- and HCV-infected patients. In the present study, whole saliva was obtained from 20 healthy, (control) 20 HBV-infected and 20 HCV-infected subjects. Two distinct pools containing saliva from 10 subjects of each group were obtained. The samples were ultracentrifuged and fractionated, and all fractions were hydrolyzed (trypsin) and injected into an LTQ-VELOS ORBITRAP. The identification and analyses of peptides were performed using Proteome Discoverer1.3 and ScaffoldQ + v.3.3.1. From a total of 362 distinct proteins identified, 344 proteins were identified in the HBV, 326 in the HCV and 303 in the control groups. Some blood proteins, such as flavin reductase (which converts biliverdin to bilirubin), were detected only in the HCV group. The data showed a reduced presence of complement C3, ceruloplasmin, alpha(1)-acid glycoprotein and alpha(2)-acid glycoprotein in the hepatitis-infected patients. Peptides of serotransferrin and haptoglobin were less detected in the HCV group. This study provides an integrated perspective of the salivary proteome, which should be further explored in future studies targeting specific disease markers for HBV and HCV infection.
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Affiliation(s)
- Lorena Da Rós Gonçalves
- Department of Biochemistry, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Isabele Batista Campanhon
- Department of Biochemistry, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Kanda T, Nakamoto S, Yasui S, Nakamura M, Miyamura T, Wu S, Jiang X, Arai M, Imazeki F, Yokosuka O. Occurrence and Recurrence of Hepatocellular Carcinoma Were Not Rare Events during Phlebotomy in Older Hepatitis C Virus-Infected Patients. Case Rep Oncol 2014; 7:288-296. [PMID: 24926259 PMCID: PMC4035674 DOI: 10.1159/000362869] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The use of phlebotomy is relatively common for 'difficult-to-treat by antiviral therapies' hepatitis C virus (HCV)-infected patients and for certain patients having chronic liver diseases with an iron overload of the liver. In the present study, we retrospectively analyzed patients treated with phlebotomy and their adverse events. We observed the occurrence and recurrence of hepatocellular carcinoma, and the appearance of ascites in some patients infected with HCV as well as the reduction of serum ferritin and alanine aminotransferase levels. Severe adverse events necessitating a cessation of phlebotomy occurred independently of α-fetoprotein (>10 ng/ml) in patients infected with HCV according to multivariate logistic regression analysis. These findings may serve as a basis for phlebotomy especially in older patients with chronic hepatitis C.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
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