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Iriarte-Gahete M, Tarancon-Diez L, Garrido-Rodríguez V, Leal M, Pacheco YM. Absolute and functional iron deficiency: Biomarkers, impact on immune system, and therapy. Blood Rev 2024; 68:101227. [PMID: 39142965 DOI: 10.1016/j.blre.2024.101227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 08/16/2024]
Abstract
Iron is essential for numerous physiological processes and its deficiency often leads to anemia. Iron deficiency (ID) is a global problem, primarily affecting reproductive-age women and children, especially in developing countries. Diagnosis uses classical biomarkers like ferritin or transferrin saturation. Recent advancements include using soluble transferrin receptor (sTfR) or hepcidin for improved detection and classification of absolute and functional iron deficiencies, though mostly used in research. ID without anemia may present symptoms like asthenia and fatigue, even without relevant clinical consequences. ID impacts not only red-blood cells but also immune system cells, highlighting its importance in global health and immune-related comorbidities. Managing ID, requires addressing its cause and selecting appropriate iron supplementation. Various improved oral and intravenous products are available, but further research is needed to refine treatment strategies. This review updates on absolute and functional iron deficiencies, their relationships with the immune system and advancements in diagnosis and therapies.
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Affiliation(s)
- Marianela Iriarte-Gahete
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain
| | - Laura Tarancon-Diez
- Group of Infections in the Pediatric Population, Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Vanesa Garrido-Rodríguez
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain
| | - Manuel Leal
- Internal Medicine Service, Viamed Santa Ángela de la Cruz Hospital, Seville, Spain
| | - Yolanda María Pacheco
- Immunology Service, Unit of Clinical Laboratories, Institute of Biomedicine of Seville, IBiS / Virgen del Rocío University Hospital / CSIC / University of Seville, Seville, Spain; Universidad Loyola Andalucía, Facultad de Ciencias de la Salud, Campus Sevilla, 41704, Dos Hermanas, Sevilla, Spain.
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2
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Li W, Fu Y, Wang W. A real-world pharmacovigilance study investigating the toxicities of histone deacetylase inhibitors. Ann Hematol 2024; 103:3207-3217. [PMID: 38453702 DOI: 10.1007/s00277-024-05691-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/01/2024] [Indexed: 03/09/2024]
Abstract
Histone deacetylase (HDAC) inhibitors are emerging as promising treatments for hematological malignancies, with potential applications extending to solid tumors in the future. Given their wide-ranging biological effects, there is a pressing need for a thorough understanding of the toxicities linked to HDAC inhibition. In this study, a pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System database. Suspected adverse events linked to HDAC inhibitors were detected through various statistical methodologies, including reporting odds ratio, proportional reporting ratio, information component, and Empirical Bayes Geometric Mean. Our study findings have illuminated that, among the total reported cases examined, gastrointestinal disorders accounted for 13% patients of the cohort, while lymphatic system disorders comprised 8% cases of the cohort, all of which manifested as adverse events induced by HDAC inhibitors. Importantly, the usage of HDAC inhibitors was found to be associated with incidents of atrial fibrillation, heart failure, respiratory failure, hepatic dysfunction, and acute kidney injury. Romidepsin and belinostat demonstrated more pronounced signals of adverse events compared to panobinostat and vorinostat, emphasizing the need for vigilant monitoring of adverse events in this particular population. Furthermore, atrial fibrillation (clinical priority score of 7 points) emerged as the paramount medical event warranting utmost clinical attention. Eventually, multiple adverse events were observe to emerge within the initial and second months following the initiation of treatment. Vigilant monitoring and supportive care strategies are critical in addressing the toxicities associated with HDAC inhibitors, particularly those concerning cardiotoxicity, respiratory toxicity, renal toxicity, and hepatotoxicity.
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Affiliation(s)
- Wenjie Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yiming Fu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Wei Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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3
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Neu C, Beckers C, Frank N, Thomas K, Bartneck M, Simon TP, Mossanen J, Peters K, Singendonk T, Martin L, Marx G, Kraemer S, Zechendorf E. Ribonuclease inhibitor 1 emerges as a potential biomarker and modulates inflammation and iron homeostasis in sepsis. Sci Rep 2024; 14:14972. [PMID: 38951571 PMCID: PMC11217267 DOI: 10.1038/s41598-024-65778-8] [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: 03/01/2024] [Accepted: 06/24/2024] [Indexed: 07/03/2024] Open
Abstract
Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential biomarker for acute kidney injury and mortality in thoracoabdominal aortic aneurysm patients. Our study investigates RNH1 dynamics in sepsis, its links to mortality and organ dysfunction, and the interplay with RNase 1 and RNase 5. Furthermore, we explore RNH1 as a therapeutic target in sepsis-related processes like inflammation, non-canonical inflammasome activation, and iron homeostasis. We showed that RNH1 levels are significantly higher in deceased patients compared to sepsis survivors and correlate with creatine kinase, aspartate and alanine transaminase, bilirubin, serum creatinine and RNase 5, but not RNase 1. RNH1 mitigated LPS-induced TNFα and RNase 5 secretion, and relative mRNA expression of ferroptosis-associated genes HMOX1, FTH1 and HAMP in PBMCs. Monocytes were identified as the predominant type of LPS-positive PBMCs. Exogenous RNH1 attenuated LPS-induced CASP5 expression, while increasing IL-1β secretion in PBMCs and THP-1 macrophages. As RNH1 has contradictory effects on inflammation and non-canonical inflammasome activation, its use as a therapeutic agent is limited. However, RNH1 levels may play a central role in iron homeostasis during sepsis, supporting our clinical observations. Hence, RNH1 shows promise as biomarkers for renal and hepatic dysfunction and hepatocyte injury, and may be useful in predicting the outcome of septic patients.
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Affiliation(s)
- Carolina Neu
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Christian Beckers
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Nadine Frank
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Katharina Thomas
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Matthias Bartneck
- Department of Medicine III, University Hospital RWTH Aachen, 52074, Aachen, Germany
| | - Tim-Philipp Simon
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Jana Mossanen
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Kimmo Peters
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Tobias Singendonk
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Lukas Martin
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Gernot Marx
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Sandra Kraemer
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Elisabeth Zechendorf
- Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
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4
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Sharma R, Zhao W, Zafar Y, Murali AR, Brown KE. Serum hepcidin levels in chronic liver disease: a systematic review and meta-analysis. Clin Chem Lab Med 2024; 62:373-384. [PMID: 37540837 DOI: 10.1515/cclm-2023-0540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/25/2023] [Indexed: 08/06/2023]
Abstract
OBJECTIVES Dysregulation of hepcidin-iron axis is presumed to account for abnormal iron status in patients with chronic liver disease (CLD). Our aim is to determine the effect of specific etiologies of CLD and of cirrhosis on serum hepcidin levels. METHODS PubMed, Embase, Web of Science were searched for studies comparing serum hepcidin levels in patients with CLD to that in controls using enzyme-linked immunosorbent assay. The study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Guidelines. Statistical analysis was carried out with STATA using random effects model to calculate the mean difference (MD) between two groups. RESULTS Hepcidin levels were significantly lower in subjects with hepatitis C virus (16 studies) [MD -1.6 (95 % CI: -2.66 to -0.54), p<0.01] and alcoholic liver disease (3 studies) [MD -0.84 (95 % CI: -1.6 to -0.07), p=0.03] than controls. Serum hepcidin was significantly higher in subjects with non-alcoholic fatty liver disease (12 studies) [MD 0.62 (95 % CI: 0.21 to 1.03), p<0.01], but did not differ in subjects with hepatitis B and controls (eight studies) [MD -0.65 (95 % CI: -1.47 to 0.16), p=0.12]. Hepcidin levels were significantly lower in patients with cirrhosis of any etiology (four studies) [MD -1.02 (CI: -1.59 to -0.45), p<0.01] vs. controls (CI: confidence interval). CONCLUSIONS Serum hepcidin levels are altered in common forms of CLD albeit not in a consistent direction. Additional study is needed to determine how changes in hepcidin levels are related to dysregulation of iron metabolism in CLD.
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Affiliation(s)
- Ruchi Sharma
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Weidan Zhao
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Department of Gastroenterology-Hepatology, SUNY Downstate, Brooklyn, NY, USA
| | - Yousaf Zafar
- University of Mississippi Medical Center, Jackson, MS, USA
| | - Arvind R Murali
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Orlando Health, Orlando, FL, USA
| | - Kyle E Brown
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Iowa City Veterans Administration Medical Center, Iowa City, IA, USA
- Department of Radiation Oncology, Program in Free Radical and Radiation Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Hu Y, He B, Cao Q, Li Y, Tang Y, Cao T, Peng B, Zhou X, Liu S. Crosstalk of ferroptosis and oxidative stress in infectious diseases. Front Mol Biosci 2023; 10:1315935. [PMID: 38131014 PMCID: PMC10733455 DOI: 10.3389/fmolb.2023.1315935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023] Open
Abstract
Ferroptosis is a type of programmed cell death that pathogens can leverage to enhance their replication, transmission, and pathogenicity. Hosts typically combat pathogenic infections by utilizing oxidative stress as a defense mechanism. Nonetheless, some pathogens can trigger considerable oxidative stress while infecting, inducing an intense inflammatory response in the host's immune system and activating cell death. The process of ferroptosis is closely linked to oxidative stress, with their interaction exerting a substantial impact on the outcome of infectious diseases. This article presents an overview of the interrelated mechanisms of both Ferroptosis and oxidative stress in infectious diseases, identifying potential targets for treating such diseases in the context of their interaction.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Shuangquan Liu
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Watson PR, Stollmaier JG, Christianson DW. Crystal structure of histone deacetylase 6 complexed with (R)-lipoic acid, an essential cofactor in central carbon metabolism. J Biol Chem 2023; 299:105228. [PMID: 37703993 PMCID: PMC10622836 DOI: 10.1016/j.jbc.2023.105228] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/28/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023] Open
Abstract
The enzyme cofactor (R)-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of (R)-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of (R)-lipoic acid, (R)-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 Å-resolution X-ray crystal structure of the complex between (R)-dihydrolipoic acid and HDAC6 catalytic domain 2 from Danio rerio, and we report a dissociation constant (KD) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn2+ coordination and S-π interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of (R)-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn2+ ion and the aromatic crevice in the active site of HDAC6.
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Affiliation(s)
- Paris R Watson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Juana Goulart Stollmaier
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - David W Christianson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
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7
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Yang Y, Chen H, Zhang C, Shin HJ, Qian Y, Jung YS. HDAC-Specific Inhibitors Induce the Release of Porcine Epidemic Diarrhea Virus via the COPII-Coated Vesicles. Viruses 2023; 15:1874. [PMID: 37766280 PMCID: PMC10534748 DOI: 10.3390/v15091874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/31/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) is an alpha-coronavirus causing acute diarrhea and high mortality in neonatal suckling piglets, resulting in huge economic losses for the global swine industry. The replication, assembly and cell egression of PEDV, an enveloped RNA virus, are mediated via altered intracellular trafficking. The underlying mechanisms of PEDV secretion are poorly understood. In this study, we found that the histone deacetylase (HDAC)-specific inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), facilitate the secretion of infectious PEDV particles without interfering with its assembly. We found that PEDV N protein and its replicative intermediate dsRNA colocalize with coat protein complex II (COPII)-coated vesicles. We also showed that the colocalization of PEDV and COPII is enhanced by the HDAC-specific inhibitors. In addition, ultrastructural analysis revealed that the HDAC-specific inhibitors promote COPII-coated vesicles carrying PEDV virions and the secretion of COPII-coated vesicles. Consistently, HDAC-specific inhibitors-induced PEDV particle secretion was abolished by Sec24B knockdown, implying that the HDAC-specific inhibitors-mediated COPII-coated vesicles are required for PEDV secretion. Taken together, our findings provide initial evidence suggesting that PEDV virions can assemble in the endoplasmic reticulum (ER) and bud off from the ER in the COPII-coated vesicles. HDAC-specific inhibitors promote PEDV release by hijacking the COPII-coated vesicles.
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Affiliation(s)
- Ying Yang
- One Health Laboratory, Jiangsu Foreign Expert Workstation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Huan Chen
- One Health Laboratory, Jiangsu Foreign Expert Workstation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Caisheng Zhang
- One Health Laboratory, Jiangsu Foreign Expert Workstation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Hyun-Jin Shin
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Yingjuan Qian
- One Health Laboratory, Jiangsu Foreign Expert Workstation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- Jiangsu Key Laboratory for High-Tech Research and Development of Veterinary Biopharmaceuticals, Jiangsu Agri-Animal Husbandry Vocational College, Veterinary Bio-Pharmaceutical, Taizhou 225300, China
| | - Yong-Sam Jung
- One Health Laboratory, Jiangsu Foreign Expert Workstation, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
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8
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Watson PR, Stollmaier JG, Christianson DW. Crystal Structure of Histone Deacetylase 6 Complexed with ( R )-Lipoic Acid, an Essential Cofactor in Central Carbon Metabolism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.08.552419. [PMID: 37609266 PMCID: PMC10441330 DOI: 10.1101/2023.08.08.552419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
The enzyme cofactor ( R )-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of ( R )-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of ( R )-lipoic acid, ( R )-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 Å-resolution X-ray crystal structure of the HDAC6-( R )-dihydrolipoic acid complex, and we report a dissociation constant (K D ) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn 2+ coordination and S-π interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of ( R )-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn 2+ ion and the aromatic crevice in the active site of HDAC6.
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Affiliation(s)
- Paris R. Watson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34 Street, Philadelphia, PA 19104-6323, United States
| | - Juana Goulart Stollmaier
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34 Street, Philadelphia, PA 19104-6323, United States
| | - David W. Christianson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34 Street, Philadelphia, PA 19104-6323, United States
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9
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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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10
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Ohta K, Ito M, Chida T, Nakashima K, Sakai S, Kanegae Y, Kawasaki H, Aoshima T, Takabayashi S, Takahashi H, Kawata K, Shoji I, Sawasaki T, Suda T, Suzuki T. Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation. PLoS Pathog 2023; 19:e1011591. [PMID: 37585449 PMCID: PMC10461841 DOI: 10.1371/journal.ppat.1011591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 08/28/2023] [Accepted: 07/31/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatitis C virus (HCV) is a pathogen characterized not only by its persistent infection leading to the development of cirrhosis and hepatocellular carcinoma (HCC), but also by metabolic disorders such as lipid and iron dysregulation. Elevated iron load is commonly observed in the livers of patients with chronic hepatitis C, and hepatic iron overload is a highly profibrogenic and carcinogenic factor that increases the risk of HCC. However, the underlying mechanisms of elevated iron accumulation in HCV-infected livers remain to be fully elucidated. Here, we observed iron accumulation in cells and liver tissues under HCV infection and in mice expressing viral proteins from recombinant adenoviruses. We established two molecular mechanisms that contribute to increased iron load in cells caused by HCV infection. One is the transcriptional induction of hepcidin, the key hormone for modulating iron homeostasis. The transcription factor cAMP-responsive element-binding protein hepatocyte specific (CREBH), which was activated by HCV infection, not only directly recognizes the hepcidin promoter but also induces bone morphogenetic protein 6 (BMP6) expression, resulting in an activated BMP-SMAD pathway that enhances hepcidin promoter activity. The other is post-translational regulation of the iron-exporting membrane protein ferroportin 1 (FPN1), which is cleaved between residues Cys284 and Ala285 in the intracytoplasmic loop region of the central portion mediated by HCV NS3-4A serine protease. We propose that host transcriptional activation triggered by endoplasmic reticulum stress and FPN1 cleavage by viral protease work in concert to impair iron efflux, leading to iron accumulation in HCV-infected cells.
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Affiliation(s)
- Kazuyoshi Ohta
- 2nd Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
- Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masahiko Ito
- Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takeshi Chida
- Department of Regional Medical Care Support, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kenji Nakashima
- Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Satoshi Sakai
- Department of Molecular Biology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yumi Kanegae
- Core Research Facilities, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan
| | - Hideya Kawasaki
- Institute for NanoSuit Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takuya Aoshima
- Laboratory Animal Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shuji Takabayashi
- Laboratory Animal Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Hirotaka Takahashi
- Division of Cell-Free Science, Proteo-Science Center, Ehime University, Matsuyama, Ehime, Japan
| | - Kazuhito Kawata
- 2nd Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Ikuo Shoji
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Tatsuya Sawasaki
- Division of Cell-Free Science, Proteo-Science Center, Ehime University, Matsuyama, Ehime, Japan
| | - Takafumi Suda
- 2nd Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tetsuro Suzuki
- Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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11
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Formica V, Riondino S, Morelli C, Guerriero S, D'Amore F, Di Grazia A, Del Vecchio Blanco G, Sica G, Arkenau HT, Monteleone G, Roselli M. HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling. Br J Cancer 2023; 129:222-236. [PMID: 37081189 PMCID: PMC10338631 DOI: 10.1038/s41416-023-02266-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/25/2023] [Accepted: 03/30/2023] [Indexed: 04/22/2023] Open
Abstract
Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin. The present review highlights the increasing body of evidence for the pro-tumoral effect of HIF2α and Hepcidin, discusses the possible imbalance in HIF2α, Hepcidin and iron homeostasis during cancer, and explores therapeutic options relying on these pathways as anticancer strategies.
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Affiliation(s)
- Vincenzo Formica
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy.
| | - Silvia Riondino
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Cristina Morelli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
- PhD Program in Systems and Experimental Medicine (XXXV cycle), University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Simona Guerriero
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Federica D'Amore
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Antonio Di Grazia
- Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy
| | | | - Giuseppe Sica
- Department of Surgery, University of Rome Tor Vergata, Rome, Italy
| | | | - Giovanni Monteleone
- Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Mario Roselli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
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12
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MacLennan SA, Marra MA. Oncogenic Viruses and the Epigenome: How Viruses Hijack Epigenetic Mechanisms to Drive Cancer. Int J Mol Sci 2023; 24:ijms24119543. [PMID: 37298494 DOI: 10.3390/ijms24119543] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/26/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
Globally, viral infections substantially contribute to cancer development. Oncogenic viruses are taxonomically heterogeneous and drive cancers using diverse strategies, including epigenomic dysregulation. Here, we discuss how oncogenic viruses disrupt epigenetic homeostasis to drive cancer and focus on how virally mediated dysregulation of host and viral epigenomes impacts the hallmarks of cancer. To illustrate the relationship between epigenetics and viral life cycles, we describe how epigenetic changes facilitate the human papillomavirus (HPV) life cycle and how changes to this process can spur malignancy. We also highlight the clinical impact of virally mediated epigenetic changes on cancer diagnosis, prognosis, and treatment.
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Affiliation(s)
- Signe A MacLennan
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada
| | - Marco A Marra
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada
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13
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Haidar Z, Fatema K, Shoily SS, Sajib AA. Disease-associated metabolic pathways affected by heavy metals and metalloid. Toxicol Rep 2023; 10:554-570. [PMID: 37396849 PMCID: PMC10313886 DOI: 10.1016/j.toxrep.2023.04.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/21/2023] [Accepted: 04/23/2023] [Indexed: 07/04/2023] Open
Abstract
Increased exposure to environmental heavy metals and metalloids and their associated toxicities has become a major threat to human health. Hence, the association of these metals and metalloids with chronic, age-related metabolic disorders has gained much interest. The underlying molecular mechanisms that mediate these effects are often complex and incompletely understood. In this review, we summarize the currently known disease-associated metabolic and signaling pathways that are altered following different heavy metals and metalloids exposure, alongside a brief summary of the mechanisms of their impacts. The main focus of this study is to explore how these affected pathways are associated with chronic multifactorial diseases including diabetes, cardiovascular diseases, cancer, neurodegeneration, inflammation, and allergic responses upon exposure to arsenic (As), cadmium (Cd), chromium (Cr), iron (Fe), mercury (Hg), nickel (Ni), and vanadium (V). Although there is considerable overlap among the different heavy metals and metalloids-affected cellular pathways, these affect distinct metabolic pathways as well. The common pathways may be explored further to find common targets for treatment of the associated pathologic conditions.
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14
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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15
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Hino K, Yanatori I, Hara Y, Nishina S. Iron and liver cancer: an inseparable connection. FEBS J 2022; 289:7810-7829. [PMID: 34543507 DOI: 10.1111/febs.16208] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/17/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023]
Abstract
Iron is an essential element for all organisms. Iron-containing proteins play critical roles in cellular functions. The biological importance of iron is largely attributable to its chemical properties as a transitional metal. However, an excess of 'free' reactive iron damages the macromolecular components of cells and cellular DNA through the production of harmful free radicals. On the contrary, most of the body's excess iron is stored in the liver. Not only hereditary haemochromatosis but also some liver diseases with mild-to-moderate hepatic iron accumulation, such as chronic hepatitis C, alcoholic liver disease and nonalcoholic steatohepatitis, are associated with a high risk for liver cancer development. These findings have attracted attention to the causative and promotive roles of iron in the development of liver cancer. In the last decade, accumulating evidence regarding molecules regulating iron metabolism or iron-related cell death programmes such as ferroptosis has shed light on the relationship between hepatic iron accumulation and hepatocarcinogenesis. In this review, we briefly present the current molecular understanding of iron regulation in the liver. Next, we describe the mechanisms underlying dysregulated iron metabolism depending on the aetiology of liver diseases. Finally, we discuss the causative and promotive roles of iron in cancer development.
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Affiliation(s)
- Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Izumi Yanatori
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Sohji Nishina
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
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16
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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17
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Hsu CC, Senussi NH, Fertrin KY, Kowdley KV. Iron overload disorders. Hepatol Commun 2022; 6:1842-1854. [PMID: 35699322 PMCID: PMC9315134 DOI: 10.1002/hep4.2012] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/06/2022] [Accepted: 04/16/2022] [Indexed: 01/19/2023] Open
Abstract
Iron overload disorders represent a variety of conditions that lead to increased total body iron stores and resultant end-organ damage. An elevated ferritin and transferrin-iron saturation can be commonly encountered in the evaluation of elevated liver enzymes. Confirmatory homeostatic iron regulator (HFE) genetic testing for C282Y and H63D, mutations most encountered in hereditary hemochromatosis, should be pursued in evaluation of hyperferritinemia. Magnetic resonance imaging with quantitative assessment of iron content or liver biopsy (especially if liver disease is a cause of iron overload) should be used as appropriate. A secondary cause for iron overload should be considered if HFE genetic testing is negative for the C282Y homozygous or C282Y/H63D compound heterozygous mutations. Differential diagnosis of secondary iron overload includes hematologic disorders, iatrogenic causes, or chronic liver diseases. More common hematologic disorders include thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency. If iron overload has been excluded, evaluation for causes of hyperferritinemia should be pursued. Causes of hyperferritinemia include chronic liver disease, malignancy, infections, kidney failure, and rheumatic conditions, such as adult-onset Still's disease or hemophagocytic lymphohistiocytosis. In this review, we describe the diagnostic testing of patients with suspected hereditary hemochromatosis, the evaluation of patients with elevated serum ferritin levels, and signs of secondary overload and treatment options for those with secondary iron overload.
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Affiliation(s)
- Christine C Hsu
- Medstar Georgetown University HospitalMedstar Georgetown Transplant InstituteWashingtonDistrict of ColumbiaUSA
| | - Nizar H Senussi
- Gastroenterology and HepatologyUniversity of New MexicoAlbuquerqueNew MexicoUSA
| | - Kleber Y Fertrin
- Division of HematologyDepartment of MedicineUniversity of WashingtonWashingtonUSA
| | - Kris V Kowdley
- Liver Institute Northwest and Elson S. Floyd College of MedicineWashington State UniversityWashingtonUSA
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18
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Manzoor S, Khalid M, Idrees M. P2X4 receptors mediate induction of antioxidants, fibrogenic cytokines and ECM transcripts; in presence of replicating HCV in in vitro setting: An insight into role of P2X4 in fibrosis. PLoS One 2022; 17:e0259727. [PMID: 35594248 PMCID: PMC9122194 DOI: 10.1371/journal.pone.0259727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/02/2022] [Indexed: 11/19/2022] Open
Abstract
Background & aims
Major HCV infections lead to chronic hepatitis, which results in progressive liver disease including fibrosis, cirrhosis and eventually hepatocellular carcinoma (HCC). P2X4 and P2X7 are most widely distributed receptors on hepatocytes.
Methods
Full length P2X4 (1.7kb) (Rattus norvegicus) was sub cloned in mammalian expression vector pcDNA3.1+. Two stable cell lines 293T/P2X4 (experimental) and 293T/ NV or null vector (control) were established. Both cell lines were inoculated with high viral titers human HCV sera and control human sera. Successfully infected cells harvested on day 5 and day 9 of post infection were used for further studies.
Results
The results revealed a significant increase in gene expression of P2X4 on day 5 and day 9 Post -infection in cells infected with HCV sera compared with cells inoculated with control sera. Quantitative real time PCR analysis revealed that HO-1 was significantly upregulated in presence of P2X4 in HCV infected cells (P2X4/HCV) when compared with control NV/HCV cells. A significant decrease was observed in expression of Cu/ZnSOD in presence of P2X4 in HCV infected cells compared to control NV/HCV cells. However, expression of both antioxidants was observed unaltered in cells harvested on day 9 post infection. Gene expression of angiotensin II significantly increased in HCV infected cells in presence of P2X4 on day 5 and day 9 of post infection when compared with control NV/HCV cells. A significant increase in gene expression of TNF-α and TGF-β was observed in HCV infected cells in presence of P2X4 on day 9 post infection in comparison with control (NV/HCV cells). However, gene expression of adipokine leptin was not affected in both experimental (P2X4/HCV) and control (NV/HCV) groups on day 5 and day 9 of post infection. Extracellular matrix proteins, laminin and elastin genes expression also significantly increased in presence of P2X4 (HCV/P2X4) on day 9 of post-infection compared to control group NV/HCV cells.
Conclusion
In conclusion, these findings constitute the evidence that P2X4 receptors in the presence of HCV play a significant role in the regulation of key antioxidant enzymes (HO-1, Cu/ZnSOD), in the induction of proinflammatory. cytokine (TNF-α), profibrotic cytokine (TGF-β) vasoactive cytokine (angiotensin II). P2X4 also increases the expression of extracellular matrix proteins (laminin and elastin) in the presence of HCV.
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Affiliation(s)
- Sobia Manzoor
- Center of Excellence in Molecular Biology (CEMB), University of Punjab, Lahore, Pakistan
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST), Islamabad, Pakistan
- * E-mail: ,
| | - Madiha Khalid
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science and Technology (NUST), Islamabad, Pakistan
| | - Muhammad Idrees
- Center of Excellence in Molecular Biology (CEMB), University of Punjab, Lahore, Pakistan
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19
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Murphy SA, Mapes NJ, Dua D, Kaur B. Histone modifiers at the crossroads of oncolytic and oncogenic viruses. Mol Ther 2022; 30:2153-2162. [PMID: 35143960 DOI: 10.1016/j.ymthe.2022.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 12/18/2021] [Accepted: 02/04/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer is a disease caused by loss of regulatory processes that control cell cycle, resulting in increased proliferation. The loss of control can deregulate both tumor suppressors and oncogenes. Apart from cell intrinsic gene mutations and environmental factors, infection by cancer-causing viruses also induces changes that lead to malignant transformation. This can be caused by both expression of oncogenic viral proteins and also by changes in cellular genes and proteins that affect the epigenome. Thus, these epigenetic modifiers are good therapeutic targets, and several epigenetic inhibitors are approved for the treatment of different cancers. In addition to small molecule drugs, biological therapies such as antibodies and viral therapies are also increasingly being used to treat cancer. An HSV-1 derived oncolytic virus is currently approved by the US FDA and the European Medicines Agency. Similarly, an adenovirus-based therapeutic is approved for use in China for some cancer types. Since viruses can affect cellular epigenetics, the interaction of epigenome-targeting drugs with oncogenic and oncolytic viruses is a highly significant area of investigation. Here we will review the current knowledge about the impact of using epigenetic drugs in tumors positive for oncogenic viruses or as therapeutic combinations with oncolytic viruses.
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Affiliation(s)
- Sara A Murphy
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030;; University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030
| | - Norman John Mapes
- Center for Biomedical Engineering and Rehabilitation Sciences, Louisiana Tech University, Ruston, LA 71270
| | | | - Balveen Kaur
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030;.
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20
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Goel D, Srivastava A, Aledo-Serrano Á, Krishnan A, Vohora D. Pharmacotherapy for SARS-CoV-2 and Seizures for Drug Repurposing Presumed on Mechanistic Targets. Curr Mol Pharmacol 2022; 15:832-845. [PMID: 34645381 DOI: 10.2174/1874467214666211013122528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/16/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022]
Abstract
The currently circulating novel SARS-CoV-2 coronavirus disease (COVID-19) has brought the whole world to a standstill. Recent studies have deciphered the viral genome structure, epidemiology and are in the process of unveiling multiple mechanisms of pathogenesis. Apart from atypical pneumonia and lung disease manifestations, this disease has also been found to be associated with neurological symptoms, which include dizziness, headache, stroke, or seizures, among others. However, a possible direct or indirect association between SARS-CoV-2 and seizures is still not clear. In any manner, it may be of interest to analyze the drugs being used for viral infection in the background of epilepsy or vice versa. To identify the most credible drug candidate for COVID-19 in persons with epilepsy or COVID-19 patients experiencing seizures. A literature search for original and review articles was performed, and further, the Comparative Toxicogenomics Database was used to unearth the most credible drug candidate. Our search based on common mechanistic targets affecting SARS-CoV-2 and seizures revealed ivermectin, dexamethasone, anakinra, and tocilizumab for protection against both COVID-19 and seizures. Amongst the antiseizure medications, we found valproic acid as the most probable pharmacotherapy for COVID-19 patients experiencing seizures. These findings would hopefully provide the basis for initiating further studies on the pathogenesis and drug targeting strategies for this emerging infection accompanied with seizures or in people with epilepsy.
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Affiliation(s)
- Divya Goel
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Ankit Srivastava
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Delhi110007, India
| | - Ángel Aledo-Serrano
- Epilepsy Program, Neurology Department, Ruber Internacional Hospital, Madrid, Spain
| | - Anuja Krishnan
- Department of Molecular Medicine, School of Interdisciplinary Sciences, Jamia Hamdard, New Delhi, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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21
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Ali RAA, Al-Mayali ZK, Al-Kraity WRH. Relation between iron status and hemoglobin in hepatitis patient with diabetes undergo hemodialysis. 3RD INTERNATIONAL SCIENTIFIC CONFERENCE OF ALKAFEEL UNIVERSITY (ISCKU 2021) 2022. [DOI: 10.1063/5.0067430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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22
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Zhu Z, Yin J, Dawsey SM, Liu B, Freedman ND, Yin L, Taylor PR, Cui J, Fan J, Liu Y, Chen W, Qiao Y, Abnet CC. Association between serum ferritin, incident primary liver cancer, and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: A nested case-control study. J Gastroenterol Hepatol 2021; 36:3410-3417. [PMID: 34106490 PMCID: PMC8655023 DOI: 10.1111/jgh.15571] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 05/09/2021] [Accepted: 06/07/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Previous studies suggest that serum ferritin may be associated with higher risk of liver cancer. However, additional studies of the association are needed. It is also not clear whether serum ferritin is associated with mortality from chronic liver disease (CLD). METHODS We performed a nested case-control study in the Linxian Nutrition Intervention Trials. Baseline serum ferritin was measured for 226 incident primary liver cancer cases, 281 CLD mortalities diagnosed, and 1061 age-matched, gender-matched, and trial-matched controls. We used multivariable logistic regression models to calculate odds ratios and 95% confidence intervals. Subgroup analysis and interaction tests were performed by age, gender, alcohol drinking, hepatitis B virus seropositivity (HBV+)/hepatitis C virus seropositivity (HCV+), and trial. RESULTS Participants with serum ferritin in the highest quartile, as compared with those in the lowest quartile, had an increased risk of CLD mortality (odds ratio = 1.72, 95% confidence interval = 1.12, 2.64, P-trend < 0.01). Moreover, the association with higher serum ferritin was stronger among alcohol drinkers and those who were HCV+ (P-interaction < 0.05). For incident liver cancer, risk estimates were above one but were not statistically significant. CONCLUSION In this study, higher levels of serum ferritin at baseline were associated with subsequent mortality from CLD, particularly if combined with alcohol drinking or viral hepatitis. Further work is warranted to confirm our findings.
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Affiliation(s)
- Zhikai Zhu
- Department of Cancer Epidemiology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
- School of Health Policy and Management, School of Health Policy and Management, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jian Yin
- Department of Cancer Epidemiology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Sanford M. Dawsey
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA
| | - Bin Liu
- Department of Cancer Epidemiology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Neal D. Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA
| | - Liangyu Yin
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Department of Clinical Nutrition, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing 400042, China
| | - Philip R. Taylor
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA
| | - Jianfeng Cui
- Department of Cancer Epidemiology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Jinhu Fan
- Department of Cancer Epidemiology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Yuanli Liu
- School of Health Policy and Management, School of Health Policy and Management, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Wen Chen
- Department of Cancer Epidemiology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Youlin Qiao
- Department of Cancer Epidemiology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Christian C. Abnet
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA
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23
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Abstract
Introduction: Oxidative stress underlies the pathophysiology of various etiologies of chronic liver disease and contributes to the development of hepatocarcinogenesis.Areas covered: This review focuses on the impact of oxidative stress in various etiologies of chronic liver disease such as alcoholic liver disease (ALD), nonalcoholic steatohepatitis (NASH), hepatitis B virus (HBV), and hepatitis C virus (HCV) infection. The efficacy of antioxidants in laboratory, animal, and clinical studies in chronic liver disease is also reviewed.Expert opinion: Currently, there are limited targeted pharmacotherapeutics for NASH and no pharmacotherapeutics for ALD and antioxidant supplementation may be useful in these conditions to improve liver function and reverse fibrosis. Antioxidants may also be used in patients with HBV or HCV infection to supplement antiviral therapies. Specific genotypes of antioxidant and prooxidant genes render patients more susceptible to liver cirrhosis and hepatocellular carcinoma while other individual characteristics like age, genotype, and metabolomic profiling can influence the efficacy of antioxidants on CLD. More research needs to be done to establish the safety, efficacy, and dosage of antioxidants and to establish the ideal patient profile that will benefit the most from antioxidant treatment.
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Affiliation(s)
- Sophia Seen
- Tan Tock Seng Hospital, Singapore, Singapore
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Shawki MA, Elsayed NS, Mantawy EM, Said RS. Promising drug repurposing approach targeted for cytokine storm implicated in SARS-CoV-2 complications. Immunopharmacol Immunotoxicol 2021; 43:395-409. [PMID: 34057871 PMCID: PMC8171013 DOI: 10.1080/08923973.2021.1931302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/04/2021] [Indexed: 12/16/2022]
Abstract
A global threat has emerged in 2019 due to the rapid spread of Coronavirus disease (COVID-19). As of January 2021, the number of cases worldwide reached 103 million cases and 2.22 million deaths which were confirmed as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This global pandemic galvanized the scientific community to study the causative virus (SARS-CoV2) pathogenesis, transmission, and clinical symptoms. Remarkably, the most common complication associated with this disease is the cytokine storm which is responsible for COVID-19 mortality. Thus, targeting the cytokine storm with new medications is needed to hamper COVID-19 complications where the most prominent strategy for the treatment is drug repurposing. Through this strategy, several steps are skipped especially those required for testing drug safety and thus may help in reducing the dissemination of this pandemic. Accordingly, the aim of this review is to outline the pathogenesis, clinical features, and immune complications of SARS-CoV2 in addition to suggesting several repurposed drugs with their plausible mechanism of action for possible management of severe COVID-19 cases.
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Affiliation(s)
- May Ahmed Shawki
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Noha Salah Elsayed
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Eman M. Mantawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Riham S. Said
- Department of Drug Radiation Research, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
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Jiang S, Guo T, Guo S, Gao J, Ni Y, Ma W, Zhao R. Chronic Variable Stress Induces Hepatic Fe(II) Deposition by Up-Regulating ZIP14 Expression via miR-181 Family Pathway in Rats. BIOLOGY 2021; 10:biology10070653. [PMID: 34356508 PMCID: PMC8301360 DOI: 10.3390/biology10070653] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/25/2021] [Accepted: 07/09/2021] [Indexed: 12/17/2022]
Abstract
Simple Summary Modern intensive production methods attract accusations of poor animal welfare due to long-term exposure to stressors including high temperature, persistent humidity and overcrowding. Stress can be defined as any condition that threatens the physiological homoeostasis and hypothalamic-pituitary-adrenal (HPA) axis responses that tend to restore the prior stable status of the organism. Uncontrollable and unpredictable sources of stress can cause various forms of damage to the liver, which is the central mediator of systemic iron balance. Iron, notably, is an essential element for maintaining health in virtually all organisms. We found that chronic variable stress can cause weight loss and disorders of the liver iron metabolism in rats, thereby triggering liver oxidative damage. Our results also suggest that the miR-181 family is a potential target for treating iron overload-associated diseases. Abstract It is well-known that hepatic iron dysregulation, which is harmful to health, can be caused by stress. The aim of the study was to evaluate chronic variable stress (CVS) on liver damage, hepatic ferrous iron deposition and its molecular regulatory mechanism in rats. Sprague Dawley rats at seven weeks of age were randomly divided into two groups: a control group (Con) and a CVS group. CVS reduces body weight, but increases the liver-to-body weight ratio. The exposure of rats to CVS increased plasma aspartate aminotransferase (AST), alkaline phosphatase (ALP) and hepatic malondialdehyde (MDA) levels, but decreased glutathione peroxidase (GSH-Px) activity, resulting in liver damage. CVS lowered the total amount of hepatic iron content, but induced hepatic Fe(II) accumulation. CVS up-regulated the expression of transferrin receptor 1 (TFR1) and ZRT/IRT-like protein 14 (ZIP14), but down-regulated ferritin and miR-181 family members. In addition, miR-181 family expression was found to regulate ZIP14 expression in HEK-293T cells by the dual-luciferase reporter system. These results indicate that CVS results in liver damage and induces hepatic Fe(II) accumulation, which is closely associated with the up-regulation of ZIP14 expression via the miR-181 family pathway.
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Affiliation(s)
- Shuxia Jiang
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (S.J.); (T.G.); (S.G.); (J.G.); (Y.N.); (R.Z.)
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China
| | - Taining Guo
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (S.J.); (T.G.); (S.G.); (J.G.); (Y.N.); (R.Z.)
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China
| | - Shihui Guo
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (S.J.); (T.G.); (S.G.); (J.G.); (Y.N.); (R.Z.)
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China
| | - Jiang Gao
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (S.J.); (T.G.); (S.G.); (J.G.); (Y.N.); (R.Z.)
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China
| | - Yingdong Ni
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (S.J.); (T.G.); (S.G.); (J.G.); (Y.N.); (R.Z.)
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China
| | - Wenqiang Ma
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (S.J.); (T.G.); (S.G.); (J.G.); (Y.N.); (R.Z.)
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China
- Correspondence: ; Tel.: +86-25-8439-6413; Fax: +86-25-8439-8669
| | - Ruqian Zhao
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; (S.J.); (T.G.); (S.G.); (J.G.); (Y.N.); (R.Z.)
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China
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Hasan Y, Brown K. Viral eradication restores normal iron status in chronic hepatitis C patients with abnormal iron studies. Ann Hepatol 2021; 19:422-426. [PMID: 32278667 DOI: 10.1016/j.aohep.2020.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Abnormal serum iron studies are seen in a third or more of patients with chronic hepatitis C infection (HCV), where they have been linked to accelerated fibrosis progression and increased risk of hepatocellular carcinoma and sometimes lead to concern for coexisting hereditary hemochromatosis. The aim of this study was to assess the effect of HCV eradication in patients with abnormal serum iron studies prior to treatment with direct-acting antiviral agents (DAAs). PATIENTS HCV-infected subjects with iron studies obtained before and after successful treatment with DAAs were identified (n=27). All had one or more abnormal iron test before treatment. RESULTS Following HCV eradication, serum iron, transferrin-iron saturation and ferritin levels decreased significantly (pre- versus post-treatment, p<0.01 for each). Serum iron and/or transferrin-iron saturations normalized in 16/19 subjects and raised ferritin levels returned to the normal range in 14/18 subjects, including several with pretreatment transferrin-iron saturation >90% and/or serum ferritin >1000ng/mL. Elimination of HCV infection was associated with a significant reduction in post-treatment ferritin levels even among subjects whose ferritin levels were within normal limits at baseline. Risk factors for other conditions associated with abnormal iron status were present in the few cases in which iron studies failed to normalize following DAA treatment. CONCLUSIONS Eradication of HCV infection restores normal iron status in most patients with abnormal iron tests, including those whose baseline parameters are suggestive of hemochromatosis.
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Affiliation(s)
- Yazan Hasan
- Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, United States
| | - Kyle Brown
- Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, United States; Iowa City Veterans Administration Medical Center, Iowa City, IA, United States; Free Radical and Radiation Biology Program, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, United States.
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Bloomer SA, Broadhurst KA, Maleah Mathahs M, Brown KE. Effects of long-term ethanol ingestion on hepatic iron metabolism in two mouse strains. Clin Exp Pharmacol Physiol 2021; 48:534-542. [PMID: 33319364 DOI: 10.1111/1440-1681.13445] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/23/2020] [Accepted: 11/26/2020] [Indexed: 01/21/2023]
Abstract
The mechanisms responsible for dysregulation of iron metabolism in response to ethanol ingestion are poorly understood. Relatively brief ethanol exposures in rodents are associated with reduced hepatic hepcidin expression without increases in hepatic iron content. This study evaluated the effects of long-term ethanol treatment on hepatic iron metabolism in two mouse strains. Ethanol was administered in the drinking water to C57BL/6 and BALB/c mice for up to 11 months. Hepatic histology and iron concentrations (HIC) were assessed, along with expression of relevant genes and proteins by real-time RT-PCR and western blot, respectively. The livers of ethanol-consuming mice of both strains showed mild steatosis without inflammation or fibrosis. Stainable hepatocyte iron was modestly increased in both strains ingesting ethanol, although hepatic iron concentrations were significantly higher only in C57BL/6 mice. Long-term ethanol did not affect hepcidin mRNA (Hamp1 or Hamp2) in either strain, nor was the expression of several oxidative stress-responsive genes (glutamate cysteine ligase, gamma-glutamyl transpeptidase, heme oxygenase-1 and growth differentiation factor 15) altered in response to ethanol, suggesting that oxidative stress and suppression of hepcidin expression in short-term ethanol feeding models may be transient phenomena that resolve as mice adapt to ethanol exposure. This murine model of chronic ethanol ingestion demonstrates modest increases in hepatic iron without changes in hepcidin expression, markers of oxidative stress or significant histologic liver injury. Further investigations are needed to characterize the mechanisms of dysregulated iron metabolism resulting from chronic ethanol ingestion.
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Affiliation(s)
- Steven A Bloomer
- Division of Science and Engineering, Penn State Abington, Abington, PA, USA
| | - Kimberly A Broadhurst
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - M Maleah Mathahs
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Kyle E Brown
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Iowa City Veterans Administration Medical Center, Iowa City, IA, USA
- Program in Free Radical and Radiation Biology, Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Domovitz T, Gal-Tanamy M. Tracking Down the Epigenetic Footprint of HCV-Induced Hepatocarcinogenesis. J Clin Med 2021; 10:jcm10030551. [PMID: 33540858 PMCID: PMC7867330 DOI: 10.3390/jcm10030551] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/17/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of death and morbidity globally and is a leading cause of hepatocellular carcinoma (HCC). Incidence of HCV infections, as well as HCV-related liver diseases, are increasing. Although now, with new direct acting antivirals (DAAs) therapy available, HCV is a curable cancer-associated infectious agent, HCC prevalence is expected to continue to rise because HCC risk still persists after HCV cure. Understanding the factors that lead from HCV infection to HCC pre- and post-cure may open-up opportunities to novel strategies for HCC prevention. Herein, we provide an overview of the reported evidence for the induction of alterations in the transcriptome of host cells via epigenetic dysregulation by HCV infection and describe recent reports linking the residual risk for HCC post-cure with a persistent HCV-induced epigenetic signature. Specifically, we discuss the contribution of the epigenetic changes identified following HCV infection to HCC risk pre- and post-cure, the molecular pathways that are epigenetically altered, the downstream effects on expression of cancer-related genes, the identification of targets to prevent or revert this cancer-inducing epigenetic signature, and the potential contribution of these studies to early prognosis and prevention of HCC as an approach for reducing HCC-related mortality.
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Abstract
Persistent infection with hepatitis C virus (HCV) is a major risk factor for hepatocellular carcinoma (HCC). Accumulating evidence suggests that not only inflammation and subsequent fibrosis but also HCV itself are associated with hepatocarcinogenesis. To date, studies using transgenic mouse and cell-culture models, in which HCV proteins are expressed, indicate the direct pathogenicity of HCV, including oncogenic activity. In particular, the core protein of HCV induces excessive oxidative stress by impairing the mitochondrial electron transfer system by disrupting the function of the molecular chaperone, prohibitin. HCV also modulates intracellular signaling pathways, including mitogen-activated protein kinase, promoting the proliferation of hepatocytes. In addition, HCV induces disorders in lipid and glucose metabolism, thereby accelerating the progression of liver fibrosis and the development of HCC. Due to the development of direct-acting antivirals, which was made possible by basic research, HCV can be eradicated from almost all infected patients. However, such patients can develop HCC long after eradication of HCV, suggesting the genetic and/or epigenetic changes induced by HCV may be persistent. These results enhance our understanding of the role of HCV in hepatocarcinogenesis and will facilitate the development of therapeutic and preventive strategies for HCV-induced HCC.
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Bao Y, Tong L, Song B, Liu G, Zhu Q, Lu X, Zhang J, Lu YF, Wen H, Tian Y, Sun Y, Zhu WG. UNG2 deacetylation confers cancer cell resistance to hydrogen peroxide-induced cytotoxicity. Free Radic Biol Med 2020; 160:403-417. [PMID: 32649985 DOI: 10.1016/j.freeradbiomed.2020.06.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 05/29/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023]
Abstract
Cancer therapeutics produce reactive oxygen species (ROS) that damage the cancer genome and lead to cell death. However, cancer cells can resist ROS-induced cytotoxicity and survive. We show that nuclear-localized uracil-DNA N-glycosylase isoform 2 (UNG2) has a critical role in preventing ROS-induced DNA damage and enabling cancer-cell resistance. Under physiological conditions, UNG2 is targeted for rapid degradation via an interaction with the E3 ligase UHRF1. In response to ROS, however, UNG2 protein in cancer cells exhibits a remarkably extended half-life. Upon ROS exposure, UNG2 is deacetylated at lysine 78 by histone deacetylases, which prevents the UNG2-UHRF1 interaction. Accumulated UNG2 protein can thus excise the base damaged by ROS and enable the cell to survive these otherwise toxic conditions. Consequently, combining HDAC inhibitors (to permit UNG2 degradation) with genotoxic agents (to produce cytotoxic cellular levels of ROS) leads to a robust synergistic killing effect in cancer cells in vitro. Altogether, these data support the application of a novel approach to cancer treatment based on promoting UNG2 degradation by altering its acetylation status using an HDAC inhibitor.
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Affiliation(s)
- Yantao Bao
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China; International Cancer Center, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Lili Tong
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Boyan Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Ge Liu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Qian Zhu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Xiaopeng Lu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Jun Zhang
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Ya-Fei Lu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - He Wen
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Yuan Tian
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China
| | - Yujie Sun
- Department of Cell Biology, Nanjing Medical University, Nanjing, 211166, China
| | - Wei-Guo Zhu
- Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China; International Cancer Center, Shenzhen University School of Medicine, Shenzhen, 518055, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China; Shenzhen Bay Laboratory, Shenzhen University School of Medicine, Shenzhen, 518055, China.
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Martín-González C, Pelazas-González R, Fernández-Rodríguez C, Alemán-Valls R, Martínez-Riera A, Ortega-Toledo P, García-Rodríguez A, Rodríguez-Gaspar M, González-Reimers E. Ferritin and liver fibrosis among patients with chronic hepatitis C virus infection. J Trace Elem Med Biol 2020; 61:126542. [PMID: 32417635 DOI: 10.1016/j.jtemb.2020.126542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/29/2020] [Accepted: 04/27/2020] [Indexed: 12/25/2022]
Abstract
INTRODUCTION In chronic hepatitis C virus (HCV) infection there is increased iron absorption leading to iron overload, a fact that may promote ferritin synthesis. Theoretically, increased ferritin should promote ongoing liver fibrosis but disparate results have been described. OBJECTIVE We analyze the behavior of iron metabolism- related variables, comparing them with fibrosis and inflammatory activity in liver biopsy in HCV infected patients. PATIENTS AND METHODS We analyzed among 90 HCV patients subjected to liver biopsy prior to antiviral treatment the relationships of serum levels of iron, ferritin, transferrin, transferrin saturation index (TSI) and total iron binding capacity (TIBC) with liver fibrosis and histological severity, assessed by Metavir-f, Metavir-a and Knodell indices, as well as with liver function, and also compared the aforementioned iron metabolism- related variables with 34 controls. RESULTS Patients showed higher values of sideremia (T = 2.04; p = 0.044) and transferrin (T = 2.29; p = 0.004) compared with controls; but not ferritin, that was significantly higher among the 33 patients who also consumed alcohol (Z = 2.05; p = 0.041). Most patients showed a well preserved liver function (86 cases, Child A). Patients with Child B or C showed higher ferritin levels (Z = 2.68; p = 0.007) and TSI (Z = 2.41; p = 0.016), but lower transferrin and TIBC (Z = 3.25; p = 0.001) than Child A patients. Transferrin and TIBC were directly related to albumin (ρ = 0.24; p = 0.026), whereas bilirubin showed direct relationships with iron (ρ = 0.25; p = 0.016), TSI (ρ = 0.39; p < 0.001) and ferritin (ρ = 0.36; p < 0.001). Both ferritin (ρ = -0.22; p = 0.04) and TSI (ρ = -0.25; p = 0.016) were related to platelet count. No relationships were observed between iron variables and Knodell index, but serum iron, serum transferrin, and TSI were directly related to Metavir-f score (ρ = 0.28; p = 0.009, ρ = 0.22; p = 0.044, and ρ = 0.22; p = 0.044, in this order). CONCLUSION Alterations of iron related variables are relatively subtle in our series of 90 well compensated HCV patients. Serum ferritin was not related to liver fibrosis and increases only when alcoholism co-exists with HCV infection.
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Affiliation(s)
- Candelaria Martín-González
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain.
| | - Ricardo Pelazas-González
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain
| | - Camino Fernández-Rodríguez
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain
| | - Remedios Alemán-Valls
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain
| | - Antonio Martínez-Riera
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain
| | - Paula Ortega-Toledo
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain
| | - Alen García-Rodríguez
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain
| | - Melchor Rodríguez-Gaspar
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain.
| | - Emilio González-Reimers
- Servicio de Medicina Interna. Hospital Universitario de Canarias. Universidad de La Laguna. Tenerife, Canary Islands, Spain.
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A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin. Int J Mol Sci 2020; 21:ijms21155516. [PMID: 32752233 PMCID: PMC7432483 DOI: 10.3390/ijms21155516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 01/02/2023] Open
Abstract
Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies.
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Himoto T, Masaki T. Current Trends of Essential Trace Elements in Patients with Chronic Liver Diseases. Nutrients 2020; 12:nu12072084. [PMID: 32674425 PMCID: PMC7400835 DOI: 10.3390/nu12072084] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/16/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Essential trace elements play crucial roles in the maintenance of health, since they are involved in many metabolic pathways. A deficiency or an excess of some trace elements, including zinc, selenium, iron, and copper, frequently causes these metabolic disorders such as impaired glucose tolerance and dyslipidemia. The liver largely regulates most of the metabolism of trace elements, and accordingly, an impairment of liver functions can result in numerous metabolic disorders. The administration or depletion of these trace elements can improve such metabolic disorders and liver dysfunction. Recent advances in molecular biological techniques have helped to elucidate the putative mechanisms by which liver disorders evoke metabolic abnormalities that are due to deficiencies or excesses of these trace elements. A genome-wide association study revealed that a genetic polymorphism affected the metabolism of a specific trace element. Gut dysbiosis was also responsible for impairment of the metabolism of a trace element. This review focuses on the current trends of four trace elements in chronic liver diseases, including chronic hepatitis, liver cirrhosis, nonalcoholic fatty liver disease, and autoimmune liver diseases. The novel mechanisms by which the trace elements participated in the pathogenesis of the chronic liver diseases are also mentioned.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan
- Correspondence: ; Tel.: +81-87-870-1240; Fax: +81-87-870-1202
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0123, Japan;
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Feng S, Daw JN, Chen QM. Histone deacetylase inhibitors prevent H 2O 2 from inducing stress granule formation. Curr Res Toxicol 2020; 1:141-148. [PMID: 34345843 PMCID: PMC8320627 DOI: 10.1016/j.crtox.2020.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/02/2020] [Accepted: 10/20/2020] [Indexed: 12/27/2022] Open
Abstract
Reactive Oxygen Species (ROS) are generated as by-products of aerobic metabolism. The production of ROS increases during xenobiotic stress and under multiple pathological conditions. Although ROS are considered harmful historically, mounting evidence recently indicates a signaling function of ROS, preceding to and regulating transcriptional or post-transcriptional events, contributing to cell death or cell survival and adaptation. Among the cellular defense mechanisms activated by ROS is formation of stress granules (SGs). The stalled translational apparatus, together with mRNA, aggregates into microscopically detectable and molecularly dynamic granules. We found that with H2O2, the dose most potent for inducing SGs in HeLa cells is 400-600 μM. With 200 μM H2O2, 2 h treatment induced the highest percentage of cells containing SGs. Whether ROS signaling pathways regulate the formation of SGs was tested using pharmacological inhibitors. We probed the potential role of PI3K, MAPKs, PKC or histone deacetylation in SG formation. Using deferoxamine as a positive control, we found a lack of inhibitory effect of wortmannin, LY-294002, JNK-I, SB-202190, PD-98059, or H89 when the percentage of cells containing SGs was counted. About 35% inhibition was observed with HDAC6 inhibitor Tubastatin A, whereas general HDAC inhibitor Trichostatin A provided a complete inhibition of SG formation. Our data point to the need of investigating the role of HDACs in SG formation during oxidative stress.
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Affiliation(s)
- Siyuan Feng
- Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson AZ85721, USA
| | - Jennifer Nichole Daw
- Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson AZ85721, USA
| | - Qin M. Chen
- Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson AZ85721, USA
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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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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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DUAN L, YIN X, MENG H, FANG X, MIN J, WANG F. [Progress on epigenetic regulation of iron homeostasis]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020; 49:58-70. [PMID: 32621410 PMCID: PMC8800797 DOI: 10.3785/j.issn.1008-9292.2020.02.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(DMT1), transferrin receptor 1(TFR1), transferrin receptor 2(TFR2), ferroportin(FPN), hepcidin(HAMP), hemojuvelin(HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 (BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.
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Lim JH, Park YW, Lee SH, Do JY, Kim SH, Han S, Jung HY, Choi JY, Cho JH, Kim CD, Park SH, Kim YL. Association of Hepcidin With Anemia Parameters in Incident Dialysis Patients: Differences Between Dialysis Modalities. Ther Apher Dial 2020; 24:4-16. [PMID: 31090188 DOI: 10.1111/1744-9987.12837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 05/07/2019] [Accepted: 05/13/2019] [Indexed: 11/30/2022]
Abstract
Hepcidin's relationships with other variables are unclear. We evaluated associations of serum hepcidin with clinical parameters in ESRD patients. Ninety-nine incident dialysis patients, including 57 on peritoneal dialysis (PD) and 42 on HD, were prospectively followed for 6 months. Serum hepcidin levels significantly increased during initial 6 months of dialysis. In the multivariate regression model, independent predictors of serum hepcidin levels in ESRD patients before maintenance dialysis were interleukin-6, ferritin, phosphate, iron, and aspartate transaminase. Six months after initiating dialysis, serum hepcidin levels were independently predicted by ferritin, total iron binding capacity (TIBC), and aspartate transaminase in all patients, whereas by ferritin and TIBC in PD patients, and ferritin, TIBC, and 24-h urine volume in HD patients. Serum hepcidin levels are differentially associated with anemia parameters in PD compared with HD patients. Urine volume was an independent predictor of hepcidin levels in early HD patients.
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Affiliation(s)
- Jeong-Hoon Lim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Yeong Woo Park
- Department of Statistics, Kyungpook National University, Daegu, South Korea
| | - Sun Hee Lee
- Division of Nephrology, Kyungpook National University Hospital, Daegu, South Korea
| | - Jun Young Do
- Department of Internal Medicine, Yeungnam University Hospital, Daegu, South Korea
| | - Sung-Ho Kim
- Department of Internal Medicine, Daegu-Fatima Hospital, Daegu, South Korea
| | - Seungyeup Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea
| | - Hee-Yeon Jung
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Ji-Young Choi
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Jang-Hee Cho
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Chan-Duck Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Sun-Hee Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Yong-Lim Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
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Mirzaei H, Ghorbani S, Khanizadeh S, Namdari H, Faghihloo E, Akbari A. Histone deacetylases in virus-associated cancers. Rev Med Virol 2019; 30:e2085. [PMID: 31743548 DOI: 10.1002/rmv.2085] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/31/2019] [Accepted: 09/03/2019] [Indexed: 12/24/2022]
Abstract
Oncogenic viruses are one of the most important causes of cancer worldwide. The pathogens contribute to the establishment of human malignancies by affecting various cellular events. Epigenetic mechanisms, such as histone modification methylation/demethylation, are one of the most critical events manipulated by oncogenic viruses to drive tumorigenesis. Histone modifications are mediated by histone acetylation and deacetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Dysregulation of HDACs activity affects viral tumorigenesis in several ways, such as manipulating tumor suppressor and viral gene expression. The present review aims to describe the vital interactions between both cancer-caused/associated viruses and the HDAC machinery, particularly by focusing on those viruses involved in gastrointestinal tumors, as some of the most common viral-mediated cancers.
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Affiliation(s)
- Habibollah Mirzaei
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.,Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed Ghorbani
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.,Department of Virology, Faculty of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Sayyad Khanizadeh
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.,Department of Virology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Haideh Namdari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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Du Y, Tang G, Yuan W. Suppression of HDAC2 by sodium butyrate alleviates apoptosis of kidney cells in db/db mice and HG‑induced NRK‑52E cells. Int J Mol Med 2019; 45:210-222. [PMID: 31746362 PMCID: PMC6889930 DOI: 10.3892/ijmm.2019.4397] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/18/2019] [Indexed: 01/12/2023] Open
Abstract
Butyrate is short-chain fatty acid, which is produced by intestinal microbiota metabolizing dietary fibers. Butyrate participates in various physiological processes predominantly by activating G-coupled-receptors, inhibiting histone deacetylases (HDACs) and serving as an energy substrate. Previous studies have shown that butyrate plays a protective role in diabetic nephropathy (DN); however, the exact mechanism remains unclear. The present study identified that providing sodium butyrate (NaBu) by gavage relieved renal damage and apoptosis in db/db mice, which is a widely used type 2 DN model. In vitro, NaBu suppressed high glucose (HG)-induced apoptosis in normal rat kidney tubular epithelial (NRK-52E) cells. Of the eleven HDACs (HDAC1-11) studied, only the mRNA expression of HDAC2 was attenuated by NaBu in NRK-52E cells under the HG condition. Overexpression of HDAC2 offset the anti-apoptotic effect of NaBu. NaBu also suppressed HG-induced oxidative stress. Additionally, H2O2 induced an upregulation of HDAC2 in NRK-52E cells, while NaBu inhibited this process. Mechanistically, NaBu acted as an antioxidant in HG-induced NRK-52E cells and suppressed HG-induced apoptosis of NRK-52E cells through inhibiting HDAC2 by virtue of its anti-oxidative property.
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Affiliation(s)
- Yi Du
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Gang Tang
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Weijie Yuan
- Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
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Singal AK. Porphyria cutanea tarda: Recent update. Mol Genet Metab 2019; 128:271-281. [PMID: 30683557 DOI: 10.1016/j.ymgme.2019.01.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 01/05/2019] [Accepted: 01/05/2019] [Indexed: 12/13/2022]
Abstract
Porphyria cutanea tarda (PCT) is the most common human porphyria, due to hepatic deficiency of uroporphyrinogen decarboxylase (UROD), which is acquired in the presence of iron overload and various susceptibility factors, such as alcohol abuse, smoking, hepatitis C virus (HCV) infection, HIV infection, iron overload with HFE gene mutations, use of estrogens, and UROD mutation. Patients with familial or type II PCT due to autosomal dominant UROD mutation also require other susceptibility factors, as the disease phenotype requires hepatic UROD deficiency to below 20% of normal. PCT clinically manifests with increased skin fragility and blistering skin lesions on sun exposed areas. The common age of presentation is 5th to 6th decade and occurs slightly more commonly in males. Although mild liver biochemical profile are common, advanced fibrosis and cirrhosis with hepatocellular carcinoma (HCC) can occasionally develop. Screening for HCC using ultrasound examination is recommended in PCT patients, especially with cirrhosis and advanced fibrosis. PCT is effectively and readily treatable with the use of either repeated phlebotomy or use of 100 mg hydroxychloroquine orally twice a week, and both the treatments are equally effective and safe. With the advent of new or direct antiviral agents for HCV infection, treatment of concomitant HCV has become safer and effective. Data are emerging on the benefit of these drugs as monotherapy for both PCT and HCV. After the achievement of remission of PCT, there remains a potential for relapse, especially when the susceptibility factors are not adequately controlled. Scanty data from retrospective and observational studies shows the relapse rate to be somewhat higher after remission with low-dose hydroxychloroquine as compared to phlebotomy induced remission. Future studies are needed on exploring mechanism of action of 4-aminoquinolines, understanding interaction of HCV and PCT, and relapse of PCT on long-term follow-up.
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Affiliation(s)
- Ashwani K Singal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL, United States.
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42
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Inomata S, Anan A, Yamauchi E, Yamauchi R, Kunimoto H, Takata K, Tanaka T, Yokoyama K, Morihara D, Takeyama Y, Irie M, Shakado S, Sohda T, Sakisaka S. Changes in the Serum Hepcidin-to-ferritin Ratio with Erythroferrone after Hepatitis C Virus Eradication Using Direct-acting Antiviral Agents. Intern Med 2019; 58:2915-2922. [PMID: 31243222 PMCID: PMC6859405 DOI: 10.2169/internalmedicine.2909-19] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective Hepcidin is a master iron regulator hormone produced by the liver, but precise mechanism underlying its involvement in iron overload in hepatitis C virus (HCV) infection remains unclear. We investigated the serum hepcidin levels against iron overload before and after HCV eradication. Methods We prospectively investigated the iron metabolism characteristics in 24 patients with HCV genotype 1b infection before and after treatment. We also assessed the serum erythroferrone (ERFE) levels to investigate its association with iron metabolism changes. Patients were treated with Ledipasvir 90 mg and Sofosbuvir 400 mg once daily for 12 weeks and observed for 12 more weeks in order to evaluate their sustained virological response. Results Serum hepcidin levels at baseline were in the normal range, although serum ferritin levels were increased. After HCV eradication, both serum ferritin and hepcidin levels were significantly decreased at 24 weeks from baseline (p<0.001, p=0.006, respectively). However, the serum hepcidin-to-ferritin ratios were significantly increased (p<0.001). In addition, the serum ERFE levels were significantly decreased (p<0.001). Increases in the serum hepcidin-to-ferritin ratios were correlated with decreases in the serum ERFE levels (ρ=-0.422, p=0.039). Conclusion Serum hepcidin levels were relatively low against ferritin levels in HCV infection. However, after HCV eradication, the serum hepcidin-to-ferritin ratios were increased. These results indicate the improvement of inadequate hepcidin secretion against iron overload after HCV eradication. Downregulation of ERFE may have affected the improvement of iron metabolism.
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Affiliation(s)
- Shinjiro Inomata
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
- Meotoiwa Hospital, Japan
| | - Akira Anan
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
- Shiida Clinic, Japan
| | - Eri Yamauchi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Hideo Kunimoto
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Daisuke Morihara
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Yasuaki Takeyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Makoto Irie
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
- Division of Gastroenterology, Fukuoka University Nishijin Hospital, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
| | - Tetsuro Sohda
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
- Department of Hepatology, Red Cross Fukuoka Hospital, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan
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Danilenko NG, Siniauskaya MG, Lukashyk SP, Karpov IA, Davydenko OG. “Double Punch”: Hepatitis C in Patients with Genetic Defects of Iron Metabolism. CYTOL GENET+ 2019. [DOI: 10.3103/s0095452719050062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Kozlov MV, Konduktorov KA, Malikova AZ, Kamarova KA, Shcherbakova AS, Solyev PN, Kochetkov SN. Structural isomers of cinnamic hydroxamic acids block HCV replication via different mechanisms. Eur J Med Chem 2019; 183:111723. [PMID: 31557613 DOI: 10.1016/j.ejmech.2019.111723] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
A set of ortho-, meta- and para-substituted cinnamic hydroxamic acids (CHAs) was synthesized. In each series of structural isomers, a phenyl substituent was linked to an aromatic ring of the parent cinnamic acid via a linker of one to four atoms in length. Using a cell test system with the full-length replicon of hepatitis C virus (HCV), we established a relationship between the suppression of HCV replicon propagation and the inhibition of class I/IIb histone deacetylases (HDACs). Anti-HCV activity correlated with the inhibition of HDAC8 in the case of ortho-CHAs, while in the case of meta-CHAs it correlated with the inhibition of HDAC1/2/3 and HDAC6. The antiviral activity of para-CHAs was many times stronger than that of meta-CHAs with about the same efficiency of HDAC1/2/3/6 inhibition, which indicated the existence of an additional cell target that does not belong to the studied group of HDACs.
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Affiliation(s)
- Maxim V Kozlov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia.
| | - Konstantin A Konduktorov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Alsu Z Malikova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Kamila A Kamarova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Anastasia S Shcherbakova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Pavel N Solyev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
| | - Sergey N Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, Moscow, 119991, Russia
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Hamano H, Ikeda Y, Watanabe H, Horinouchi Y, Izawa-Ishizawa Y, Imanishi M, Zamami Y, Takechi K, Miyamoto L, Ishizawa K, Tsuchiya K, Tamaki T. The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin in chronic kidney disease. Nephrol Dial Transplant 2019; 33:586-597. [PMID: 28992067 DOI: 10.1093/ndt/gfx252] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 06/24/2017] [Indexed: 12/11/2022] Open
Abstract
Background Hepcidin secreted by hepatocytes is a key regulator of iron metabolism throughout the body. Hepcidin concentrations are increased in chronic kidney disease (CKD), contributing to abnormalities in iron metabolism. Levels of indoxyl sulfate (IS), a uremic toxin, are also elevated in CKD. However, the effect of IS accumulation on iron metabolism remains unclear. Methods We used HepG2 cells to determine the mechanism by which IS regulates hepcidin concentrations. We also used a mouse model of adenine-induced CKD. The CKD mice were divided into two groups: one was treated using AST-120 and the other received no treatment. We examined control mice, CKD mice, CKD mice treated using AST-120 and mice treated with IS via drinking water. Results In the in vitro experiments using HepG2 cells, IS increased hepcidin expression in a dose-dependent manner. Silencing of the aryl hydrocarbon receptor (AhR) inhibited IS-induced hepcidin expression. Furthermore, IS induced oxidative stress and antioxidant drugs diminished IS-induced hepcidin expression. Adenine-induced CKD mice demonstrated an increase in hepcidin concentrations; this increase was reduced by AST-120, an oral adsorbent of the uremic toxin. CKD mice showed renal anemia, decreased plasma iron concentration, increased plasma ferritin and increased iron content in the spleen. Ferroportin was decreased in the duodenum and increased in the spleen. These changes were ameliorated by AST-120 treatment. Mice treated by direct IS administration showed hepatic hepcidin upregulation. Conclusions IS affects iron metabolism in CKD by participating in hepcidin regulation via pathways that depend on AhR and oxidative stress.
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Affiliation(s)
- Hirofumi Hamano
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.,Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan
| | - Yasumasa Ikeda
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroaki Watanabe
- Department of Clinical Pharmacology and Therapeutics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yuya Horinouchi
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yuki Izawa-Ishizawa
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Masaki Imanishi
- Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan
| | - Yoshito Zamami
- Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan.,Department of Clinical Pharmacology and Therapeutics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Kenshi Takechi
- Clinical Trial Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan
| | - Licht Miyamoto
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Keisuke Ishizawa
- Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan.,Department of Clinical Pharmacology and Therapeutics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Koichiro Tsuchiya
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Toshiaki Tamaki
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
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Fontanellas A, Ávila MA, Anderson KE, Deybach JC. Current and innovative emerging therapies for porphyrias with hepatic involvement. J Hepatol 2019; 71:422-433. [PMID: 31102718 DOI: 10.1016/j.jhep.2019.05.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/24/2019] [Accepted: 05/03/2019] [Indexed: 01/19/2023]
Abstract
Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.
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Affiliation(s)
- Antonio Fontanellas
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain. Instituto de Salud Carlos III, Spain.
| | - Matías A Ávila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain. Instituto de Salud Carlos III, Spain
| | - Karl E Anderson
- Porphyria Laboratory & Center, Departments of Preventive Medicine and Community Health, and Internal Medicine (Division of Gastroenterology), University of Texas Medical Branch, Galveston, TX, USA
| | - Jean-Charles Deybach
- CRMR Porphyries France, Assistance Publique-Hôpitaux de Paris (AP-HP), University Denis Diderot Paris 7, France; European Porphyria Network (EPNET)
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Sharma S. Role of redox iron towards an increase in mortality among patients: a systemic review and meta-analysis. Blood Res 2019; 54:87-101. [PMID: 31309086 PMCID: PMC6614104 DOI: 10.5045/br.2019.54.2.87] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 11/06/2018] [Accepted: 11/06/2018] [Indexed: 11/25/2022] Open
Abstract
An increase in biochemical concentrations of non-transferrin bound iron (NTBI) within the patients with an increase in serum iron concentration was evaluated with the following objectives: (a) Iron overloading diseases/conditions with free radicle form of ‘iron containing’ reactive oxygen species (ROS) and its imbalance mediated mortality, and (b) Intervention with iron containing drugs in context to increased redox iron concentration and treatment induced mortality. Literature search was done within Pubmed and cochrane review articles. The Redox iron levels are increased during dys-erythropoiesis and among transfusion recipient population and are responsive to iron-chelation therapy. Near expiry ‘stored blood units’ show a significant rise in the ROS level. Iron mediated ROS damage may be estimated by the serum antioxidant level, and show reduction in toxicity with high antioxidant, low pro-oxidant levels. Iron drug therapy causes a significant increase in NTBI and labile iron levels. Hospitalized patients on iron therapy however show a lower mortality rate. Serum ferritin is a mortality indicator among the high-dose iron therapy and transfusion dependent population. The cumulative difference of pre-chelation to post chelation ROS iron level was 0.97 (0.62; 1.32; N=261) among the transfusion dependent subjects and 2.89 (1.81–3.98; N=130) in the post iron therapy ‘iron ROS’ group. In conclusion, iron mediated mortality may not be mediated by redox iron among multi-transfused and iron overloaded patients.
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Affiliation(s)
- Sankalp Sharma
- Department of Transfusion Medicine and Blood Bank, All India Institute of Medical Sciences Raipur, Chhattisgarh, India
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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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Importance of Studying the Levels of Hepcidin and Vitamin D in Egyptian Children with Chronic Hepatitis C. J Transl Int Med 2019; 7:15-21. [PMID: 30997352 PMCID: PMC6463826 DOI: 10.2478/jtim-2019-0004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background and Objective Hepcidin is the key regulator of iron metabolism and is a significant biomarker for systemic inflammatory states. Vitamin D is a powerful immunomodulator and plays a significant role in the inflammatory responses and fibrosis occurring due to hepatitis C virus (HCV) infection. This study assessed the level of vitamin D and serum hepcidin and its expression in peripheral blood of children with chronic hepatitis C (CHC) and correlated them with other serum markers to reflect iron metabolism and liver disease severity. Methods A total of 100 children were included in this study: 50 with HCV infection and 50 healthy controls. Biochemical parameters together with vitamin D, hepcidin, and its expression were all measured. Results The level of hepcidin and its expression together with vitamin D and hepcidin-to-ferritin (H/F) ratios were significantly reduced in patients, but the iron and ferritin levels were higher (P<0.001). Serum hepcidin level showed significant positive correlation with hepcidin expression, HCV titer, iron, ferritin, and H/F ratio (r = 0.43, 0.31, 0.34, 0.28, and 0.91, respectively) but significant negative correlation with vitamin D (r = -0.37). Both hepcidin and ferritin were higher in patients with Child Pugh scores B and C than those with score A (P<0.001). Conclusion Measuring serum hepcidin and its expression together with vitamin D levels in patients may have a prognostic value and is promising in the follow-up of the severity of liver disease.
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