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Antypiuk A, Vance SZ, Sharma R, Passos S, Asperti M, Navaneethabalakrishan S, Dürrenberger F, Manolova V, Vinchi F. Genetic iron overload aggravates, and pharmacological iron restriction improves, MDS pathophysiology in a preclinical study. Blood 2025; 145:155-169. [PMID: 39437711 DOI: 10.1182/blood.2024026135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/11/2024] [Accepted: 09/11/2024] [Indexed: 10/25/2024] Open
Abstract
ABSTRACT Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear how iron excess is detrimental for disease pathophysiology. Taking advantage of complementary approaches, we analyzed the impact of iron overload and restriction achieved through genetic activation of ferroportin (FPN) via the C326S mutation (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter FPN, respectively, in a MDS mouse model. Although FPNC326S-induced iron overload did not significantly improve the late stages of erythroid maturation, vamifeport-mediated iron restriction ameliorated anemia and red blood cell maturation in MDS mice, through the reduction of oxidative stress and apoptosis in erythroid progenitors. Iron overload aggravated, and restriction alleviated, reactive oxygen species formation, DNA damage, and cell death in hematopoietic stem and progenitor cells (HSPCs), resulting in altered cell survival and quality. Finally, myeloid bias, indicated by expanded bone marrow myeloid progenitors and circulating immature myeloid blasts, was exacerbated by iron excess and attenuated by iron restriction. Overall, vamifeport treatment resulted in improved anemia and significant survival increment in MDS mice. Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared with single treatments and offers additive beneficial effects in MDS. Our results prove, to our knowledge, for the first time in a preclinical model, that iron plays a pathologic role in transfusion-independent MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.
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Affiliation(s)
- Ada Antypiuk
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - S Zebulon Vance
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - Richa Sharma
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - Sara Passos
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - Michela Asperti
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | | | | | - Francesca Vinchi
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
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2
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Zhou H, Chen J, Fan M, Cai H, Dong Y, Qiu Y, Zhuang Q, Lei Z, Li M, Ding X, Yan P, Lin A, Zheng S, Yan Q. KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2023; 42:5. [PMID: 36600258 DOI: 10.1186/s13046-022-02562-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/06/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a multifactor-driven malignant tumor with rapid progression, which causes the difficulty to substantially improve the prognosis of HCC. Limited understanding of the mechanisms in HCC impedes the development of efficacious therapies. Despite Krüpple-Like factors (KLFs) were reported to be participated in HCC pathogenesis, the function of KLF14 in HCC remains largely unexplored. METHODS We generated KLF14 overexpressed and silenced liver cancer cells, and nude mouse xenograft models for the in vitro and in vivo study. Luciferase reporter assay, ChIP-qPCR, Co-IP, immunofluorescence were performed for mechanism research. The expression of KLF14 in HCC samples was analyzed by quantitative RT-PCR, Western blotting, and immunohistochemistry (IHC) analysis. RESULTS KLF14 was significantly downregulated in human HCC tissues, which was highly correlated with poor prognosis. Inhibition of KLF14 promoted liver cancer cells proliferation and overexpression of KLF14 suppressed cells growth. KLF14 exerts its anti-tumor function by inhibiting Iron-responsive element-binding protein 2 (IRP2), which then causes transferrin receptor-1(TfR1) downregulation and ferritin upregulation on the basis of IRP-IREs system. This then leading to cellular iron deficiency and HCC cells growth suppression in vitro and in vivo. Interestingly, KLF14 suppressed the transcription of IRP2 via recruiting SIRT1 to reduce the histone acetylation of the IRP2 promoter, resulting in iron depletion and cell growth suppression. More important, we found fluphenazine is an activator of KLF14, inhibiting HCC cells growth through inducing iron deficiency. CONCLUSION KLF14 acts as a tumor suppressor which inhibits the proliferation of HCC cells by modulating cellular iron metabolism via the repression of IRP2. We identified Fluphenazine, as an activator of KLF14, could be a potential compound for HCC therapy. Our findings therefore provide an innovative insight into the pathogenesis of HCC and a promising therapeutic target.
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Affiliation(s)
- Hui Zhou
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Junru Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China
| | - Mingjie Fan
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China.,Department of Pediatrics, The First Affiliated Hospital, School of Medicine Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Huajian Cai
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Yufei Dong
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Yue Qiu
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Qianqian Zhuang
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Zhaoying Lei
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Mengyao Li
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Xue Ding
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Peng Yan
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Aifu Lin
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
| | - Qingfeng Yan
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China. .,Department of Pediatrics, The First Affiliated Hospital, School of Medicine Zhejiang University, Hangzhou, 310003, Zhejiang, China. .,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, 310058, Zhejiang, China.
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3
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Isidori A, Loscocco F, Visani G, Chiarucci M, Musto P, Kubasch AS, Platzbecker U, Vinchi F. Iron Toxicity and Chelation Therapy in Hematopoietic Stem Cell Transplant. Transplant Cell Ther 2021; 27:371-379. [PMID: 33969823 DOI: 10.1016/j.jtct.2020.11.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/25/2020] [Accepted: 11/25/2020] [Indexed: 01/19/2023]
Abstract
Many patients with hematologic malignancies receive RBC transfusion support, which often causes systemic and tissue iron toxicity. Because of their compromised bone marrow function, hematopoietic stem cell transplant (HSCT) recipients are especially vulnerable to excess iron levels. Iron toxicity may compromise transplant engraftment and eventually promote relapse by mediating oxidative and genotoxic stress in hematopoietic stem cells (HSCs) and further impairing the already dysfunctional bone marrow microenvironment in HSCT recipients. Iron toxicity is thought to be primarily mediated by its ability to induce reactive oxygen species and trigger inflammation. Elevated iron levels in the bone marrow can decrease the number of HSCs and progenitor cells, as well as their clonogenic potential, alter mesenchymal stem cell differentiation, and inhibit the expression of chemokines and adhesion molecules involved in hematopoiesis. In vivo, in vitro, and clinical studies support the concept that iron chelation therapy may limit iron toxicity in the bone marrow and promote hematologic improvement and engraftment in HSCT recipients. This review will provide an overview of the current knowledge of the detrimental impact of iron toxicity in the setting of HSCT in patients with hematologic malignancies and the use of iron restriction approaches to improve transplant outcome.
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Affiliation(s)
- Alessandro Isidori
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy.
| | - Federica Loscocco
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
| | - Giuseppe Visani
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
| | - Martina Chiarucci
- Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy
| | - Pellegrino Musto
- Unit of Hematology and Stem Cell Transplantation, Department of Emergency and Organ Transplantation, "Aldo Moro" University School of Medicine, AOU Consorziale Policlinico, Bari, Italy
| | - Anne-Sophie Kubasch
- Department of Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany
| | - Uwe Platzbecker
- Department of Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany
| | - Francesca Vinchi
- Iron Research Program, Lindsley Kimball Research Institute, New York Blood Center, New York, New York; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
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4
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Fibach E. The Redox Balance and Membrane Shedding in RBC Production, Maturation, and Senescence. Front Physiol 2021; 12:604738. [PMID: 33664673 PMCID: PMC7920951 DOI: 10.3389/fphys.2021.604738] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/18/2021] [Indexed: 12/25/2022] Open
Abstract
Membrane shedding in the form of extracellular vesicles plays a key role in normal physiology and pathology. Partial disturbance of the membrane-cytoskeleton linkage and increased in the intracellular Ca content are considered to be mechanisms underlying the process, but it is questionable whether they constitute the primary initiating steps. Homeostasis of the redox system, which depends on the equilibrium between oxidants and antioxidants, is crucial for many cellular processes. Excess oxidative power results in oxidative stress, which affects many cellular components, including the membrane. Accumulating evidence suggests that oxidative stress indirectly affects membrane shedding most probably by affecting the membrane-cytoskeleton and the Ca content. In red blood cells (RBCs), changes in both the redox system and membrane shedding occur throughout their life-from birth-their production in the bone marrow, to death-aging in the peripheral blood and removal by macrophages in sites of the reticuloendothelial system. Both oxidative stress and membrane shedding are disturbed in diseases affecting the RBC, such as the hereditary and acquired hemolytic anemias (i.e., thalassemia, sickle cell anemia, and autoimmune hemolytic anemia). Herein, I review some data-based and hypothetical possibilities that await experimental confirmation regarding some aspects of the interaction between the redox system and membrane shedding and its role in the normal physiology and pathology of RBCs.
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Affiliation(s)
- Eitan Fibach
- Department of Hematology, Hadassah University Hospital, Jerusalem, Israel
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5
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Iron overload and its impact on outcome of patients with hematological diseases. Mol Aspects Med 2020; 75:100868. [PMID: 32620237 DOI: 10.1016/j.mam.2020.100868] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/27/2020] [Accepted: 05/27/2020] [Indexed: 01/19/2023]
Abstract
Systemic iron overload (SIO) is a common challenge in patients with hematological diseases and develops as a result of ineffective erythropoiesis, multiple red blood cell (RBC) transfusions and disease-specific therapies. Iron homeostasis is tightly regulated as there is no physiological pathway to excrete iron from the body. Excess iron is, therefore, stored in tissues like liver, heart and bone marrow and can lead to progressive organ damage. The presence of free iron in the form of non-transferrin bound iron (NTBI) is especially detrimental. Reactive oxygen species can also cause stromal damage in the bone marrow and promote leukemic cell growth in vitro. In acute leukemias and myelodysplastic syndromes outcome is worse in patients with SIO compared to patients without. Especially in patients undergoing allogeneic HSCT presence of NTBI before or during transplant has been shown to negatively affect non-relapse mortality and overall survival. Although the mechanisms, of how these effects are mediated by SIO are not very well understood monitoring of iron status by serum markers and imaging techniques is, therefore, mandatory especially in these patients. Whether peri-interventional iron chelation may improve outcome of these patients is part of current clinical research.
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6
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Controversies on the Consequences of Iron Overload and Chelation in MDS. Hemasphere 2020; 4:e357. [PMID: 32647792 PMCID: PMC7306315 DOI: 10.1097/hs9.0000000000000357] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/17/2020] [Indexed: 12/15/2022] Open
Abstract
Many patients with MDS are prone to develop systemic and tissue iron overload in part as a consequence of disease-immanent ineffective erythropoiesis. However, chronic red blood cell transfusions, which are part of the supportive care regimen to correct anemia, are the major source of iron overload in MDS. Increased systemic iron levels eventually lead to the saturation of the physiological systemic iron carrier transferrin and the occurrence of non-transferrin-bound iron (NTBI) together with its reactive fraction, the labile plasma iron (LPI). NTBI/LPI-mediated toxicity and tissue iron overload may exert multiple detrimental effects that contribute to the pathogenesis, complications and eventually evolution of MDS. Until recently, the evidence supporting the use of iron chelation in MDS was based on anecdotal reports, uncontrolled clinical trials or prospective registries. Despite not fully conclusive, these and more recent studies, including the TELESTO trial, unravel an overall adverse action of iron overload and therapeutic benefit of chelation, ranging from improved hematological outcome, reduced transfusion dependence and superior survival of iron-loaded MDS patients. The still limited and somehow controversial experimental and clinical data available from preclinical studies and randomized trials highlight the need for further investigation to fully elucidate the mechanisms underlying the pathological impact of iron overload-mediated toxicity as well as the effect of classic and novel iron restriction approaches in MDS. This review aims at providing an overview of the current clinical and translational debated landscape about the consequences of iron overload and chelation in the setting of MDS.
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7
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Leitch HA, Gattermann N. Hematologic improvement with iron chelation therapy in myelodysplastic syndromes: Clinical data, potential mechanisms, and outstanding questions. Crit Rev Oncol Hematol 2019; 141:54-72. [DOI: 10.1016/j.critrevonc.2019.06.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 11/25/2018] [Accepted: 06/03/2019] [Indexed: 12/25/2022] Open
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8
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Abstract
Cell oxidative status, which represents the balance between oxidants and antioxidants, is involved in normal functions. Under pathological conditions, there is a shift toward the oxidants, leading to oxidative stress, which is cytotoxic, causing oxidation of cellular components that result in cell death and organ damage. Thalassemia is a hereditary hemolytic anemia caused by mutations in globin genes that cause reduced or complete absence of specific globin chains (commonly, α or β). Although oxidative stress is not the primary etiology of thalassemia, it mediates several of its pathologies. The main causes of oxidative stress in thalassemia are the degradation of the unstable hemoglobin and iron overload-both stimulate the production of excess free radicals. The symptoms aggravated by oxidative stress include increased hemolysis, ineffective erythropoiesis and functional failure of vital organs such as the heart and liver. The oxidative status of each patient is affected by multiple internal and external factors, including genetic makeup, health conditions, nutrition, physical activity, age, and the environment (e.g., air pollution, radiation). In addition, oxidative stress is influenced by the clinical manifestations of the disease (unpaired globin chains, iron overload, anemia, etc.). Application of personalized (theranostics) medicine principles, including diagnostic tests for selecting targeted therapy, is therefore important for optimal treatment of the oxidative stress of these patients. We summarize the role of oxidative stress and the current and potential antioxidative therapeutics in β-thalassemia and describe some methodologies, mostly cellular, that might be helpful for application of a theranostics approach to therapy.
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Affiliation(s)
- Eitan Fibach
- Department of Hematology, Hadassah-Hebrew University Medical Center, Ein-Kerem, POB 12,000, 91120, Jerusalem, Israel.
| | - Mutaz Dana
- Department of Hematology, Hadassah-Hebrew University Medical Center, Ein-Kerem, POB 12,000, 91120, Jerusalem, Israel
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9
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Pietropaoli AP, Henrichs KF, Cholette JM, Spinelli SL, Phipps RP, Refaai MA, Blumberg N. Total plasma heme concentration increases after red blood cell transfusion and predicts mortality in critically ill medical patients. Transfusion 2019; 59:2007-2015. [PMID: 30811035 DOI: 10.1111/trf.15218] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 01/28/2019] [Accepted: 01/29/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Relationships between red blood cell (RBC) transfusion, circulating cell-free heme, and clinical outcomes in critically ill transfusion recipients are incompletely understood. The goal of this study was to determine whether total plasma heme increases after RBC transfusion and predicts mortality in critically ill patients. STUDY DESIGN AND METHODS This was a prospective cohort study of 111 consecutive medical intensive care patients requiring RBC transfusion. Cell-free heme was measured in RBC units before transfusion and in the patients' plasma before and after transfusion. RESULTS Total plasma heme levels increased in response to transfusion, from a median (interquartile range [IQR]) of 35 (26-76) μmol/L to 47 (35-73) μmol/L (p < 0.001). Posttransfusion total plasma heme was higher in nonsurvivors (54 [35-136] μmol/L) versus survivors (44 [31-65] μmol/L, p = 0.03). Posttransfusion total plasma heme predicted hospital mortality (odds ratio [95% confidence interval] per quartile increase in posttransfusion plasma heme, 1.76 [1.17-2.66]; p = 0.007). Posttransfusion total plasma heme was not correlated with RBC unit storage duration and weakly correlated with RBC unit cell-free heme concentration. CONCLUSIONS Total plasma heme concentration increases in critically ill patients after RBC transfusion and is independently associated with mortality. This transfusion-associated increase in total plasma heme is not fully explained by RBC unit storage age or cell-free heme content. Additional studies are warranted to define mechanisms of transfusion-related plasma heme accumulation and test prevention strategies.
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Affiliation(s)
- Anthony P Pietropaoli
- Department of Medicine, Division of Pulmonary & Critical Care Medicine, University of Rochester Medical Center, Rochester, New York
| | - Kelly F Henrichs
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
| | - Jill M Cholette
- Department of Pediatrics, University of Rochester Medical Center, Rochester, New York
| | - Sherry L Spinelli
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
| | - Richard P Phipps
- Department of Medicine, Division of Pulmonary & Critical Care Medicine, University of Rochester Medical Center, Rochester, New York.,Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.,Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, New York
| | - Majed A Refaai
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
| | - Neil Blumberg
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
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10
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Lumsden AL, Rogers JT, Majd S, Newman M, Sutherland GT, Verdile G, Lardelli M. Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease. Front Neurosci 2018; 12:533. [PMID: 30150923 PMCID: PMC6099262 DOI: 10.3389/fnins.2018.00533] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022] Open
Abstract
The overwhelming majority of dominant mutations causing early onset familial Alzheimer’s disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid β (Aβ). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer’s disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship – the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer’s disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a “Stress Threshold Change of State” model of Alzheimer’s disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia.
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Affiliation(s)
- Amanda L Lumsden
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Jack T Rogers
- Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, Massachusetts General Hospital (East), Harvard Medical School, Harvard University, Charlestown, MA, United States
| | - Shohreh Majd
- Neuronal Injury and Repair Laboratory, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Morgan Newman
- Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Greg T Sutherland
- Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Giuseppe Verdile
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
| | - Michael Lardelli
- Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
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11
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Zacharski LR, Shamayeva G, Chow BK. Iron reduction response and demographic differences between diabetics and non-diabetics with cardiovascular disease entered into a controlled clinical trial. Metallomics 2018; 10:264-277. [DOI: 10.1039/c7mt00282c] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Filings of elemental iron separated magnetically from a homogenate of breakfast cereal implicated in the risk of cardiovascular disease and diabetes.
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Affiliation(s)
- Leo R. Zacharski
- Veterans Affairs New England Health Care System
- Research Service (151)
- VA Medical Center
- White River Jct
- USA
| | - Galina Shamayeva
- Veterans Affairs Cooperative Studies Program Coordinating Center
- Veterans Affairs Palo Alto Health Care System
- Palo Alto
- USA
| | - Bruce K. Chow
- Veterans Affairs Cooperative Studies Program Coordinating Center
- Veterans Affairs Palo Alto Health Care System
- Palo Alto
- USA
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12
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Abstract
Thalassemia (thal) is an autosomal recessive, hereditary, chronic hemolytic anemia due to a partial or complete deficiency in the synthesis of α-globin chains (α-thal) or β-globin chains (β-thal) that compose the major adult hemoglobin (α 2β 2). It is caused by one or more mutations in the corresponding genes. The unpaired globin chains are unstable; they precipitate intracellularly, resulting in hemolysis, premature destruction of red blood cell [RBC] precursors in the bone marrow, and a short life-span of mature RBCs in the circulation. The state of anemia is treated by frequent RBC transfusions. This therapy results in the accumulation of iron (iron overload), a condition that is exacerbated by the breakdown products of hemoglobin (heme and iron) and the increased iron uptake for the chronic accelerated, but ineffective, RBC production. Iron catalyzes the generation of reactive oxygen species, which in excess are toxic, causing damage to vital organs such as the heart and liver and the endocrine system. Herein, we review recent findings regarding the pathophysiology underlying the major symptoms of β-thal and potential therapeutic modalities for the amelioration of its complications, as well as new modalities that may provide a cure for the disease.
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Affiliation(s)
- Eitan Fibach
- Department of Hematology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
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13
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Gattermann N. Iron overload in myelodysplastic syndromes (MDS). Int J Hematol 2017; 107:55-63. [PMID: 29177643 DOI: 10.1007/s12185-017-2367-1] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 11/08/2017] [Indexed: 01/19/2023]
Abstract
Iron overload (IOL) starts to develop in MDS patients before they become transfusion-dependent because ineffective erythropoiesis suppresses hepcidin production in the liver and thus leads to unrestrained intestinal iron uptake. However, the most important cause of iron overload in MDS is chronic transfusion therapy. While transfusion dependency by itself is a negative prognostic factor reflecting poor bone marrow function, the ensuing transfusional iron overload has an additional dose-dependent negative impact on the survival of patients with lower risk MDS. Cardiac dysfunction appears to be important in this context, as a consequence of chronic anemia, age-related cardiac comorbidity, and iron overload. Another potential problem is iron-related endothelial dysfunction. There is some evidence that with increasing age, high circulating iron levels worsen the atherosclerotic phenotype. Transfusional IOL also appears to aggravate bone marrow failure in MDS, through unfavorable effects on mesenchymal stromal cells as well a hematopoietic cells, particularly erythroid precursors. Patient series and clinical trials have shown that the iron chelators deferoxamine and deferasirox can improve hematopoiesis in a minority of transfusion-dependent patients. Analyses of registry data suggest that iron chelation provides a survival benefit for patients with MDS, but data from a prospective randomized clinical trial are still lacking.
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Affiliation(s)
- Norbert Gattermann
- Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
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14
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Iron overload in hematological disorders. Presse Med 2017; 46:e296-e305. [PMID: 29174474 DOI: 10.1016/j.lpm.2017.10.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Revised: 07/22/2017] [Accepted: 10/04/2017] [Indexed: 12/20/2022] Open
Abstract
While most common symptom of impairment of iron homeostasis is iron deficiency anemia, some hematological disorders are associated with iron overload (IO). These disorders are related mainly to chronic severe hemolytic anemia, where red blood cells (RBC) or their precursors are destroyed prematurely (hemolyzed), leading to anemia that cannot be compensated by increased production of new RBC. In such cases, IO is mainly due to repeated RBC transfusions and/or increased uptake of iron in the gastrointestinal tract. Normally, iron is present in the plasma and in the cells bound to compounds that render it redox inactive. Iron overload leaves a fraction of the iron free (labile iron pool) and redox active, leading to the generation of excess free radicals such as the reactive oxygen species. This condition upsets the cellular redox balance between oxidants and antioxidants, leading to oxidative stress. The free radicals bind to various cellular components, thereby becoming toxic to vital organs. Oxidative stress may also affect blood cells, such as RBC, platelets and neutrophils, exacerbating the anemia, and causing recurrent infections and thrombotic events, respectively. The toxic effect of IO can be decreased by treating the patients with iron chelators that enter cells, bind free iron and remove it from the body through the urine and feces. Iron toxicity may be also ameliorated by treatment with anti-oxidants that scavenge free radicals and/or correct their damage. The use of iron chelators is widely accepted when started in young patients with severe chronic anemia, but is still debatable as a therapeutic modality for older patients suffering from IO due to myelodysplastic syndromes. It should be noted that in addition to preventing iron toxicity, some compounds with iron chelator activity may also benefit other aspects of hematological disorders. These aspects include stimulation of platelet production, inhibition of leukemic cell proliferation and induction of their differentiation. Compounds with such multiple activities may prove beneficial for at least some patients with leukemia and myelodysplastic syndromes.
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Is the Benefit-Risk Ratio for Patients with Transfusion-Dependent Thalassemia Treated by Unrelated Cord Blood Transplantation Favorable? Int J Mol Sci 2017; 18:ijms18112472. [PMID: 29156642 PMCID: PMC5713438 DOI: 10.3390/ijms18112472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 11/02/2017] [Accepted: 11/17/2017] [Indexed: 01/19/2023] Open
Abstract
Transfusion-dependent thalassemia (TDT) is an inherited disorder characterized by absent or defective production of α- or β-hemoglobin chains. If untreated, the disease invariably culminates in death in early infancy due to cardiac failure or overwhelming infection. Although there is clear evidence of good health-related quality of life and return to normal life style, the choice to undergo hematopoietic stem cell transplantation (HSCT) remains a challenge because of the potential risk of transplant-related mortality (TRM) in TDT. Successful hematopoietic stem cell transplantation may cure the hematological manifestations of TDT, but introduces risks of TRM and morbidity. The low incidence of graft-versus-host disease (GVHD) provides the major rationale for pursuing unrelated cord blood transplantation (CBT). Considerable evidence suggests a lower rate of recurrence after CBT than after transplantation from adult donors. As the TRM, overall survival, and thalassemia-free survival for CBT improve, the utility of this stem cell source will expand to indications that have hitherto rarely used unrelated CBT. This paper summarizes the current progress in understanding the advances in unrelated CBT for thalassemia. Although as yet only in a limited number of patients, the results of unrelated CBT for thalassemia are encouraging.
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Unraveling the mechanisms behind iron overload and ineffective hematopoiesis in myelodysplastic syndromes. Leuk Res 2017; 62:108-115. [DOI: 10.1016/j.leukres.2017.10.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/22/2017] [Accepted: 10/02/2017] [Indexed: 01/06/2023]
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Musto P, Maurillo L, Simeon V, Poloni A, Finelli C, Balleari E, Ricco A, Rivellini F, Cortelezzi A, Tarantini G, Villani O, Mansueto G, Milella MR, Scapicchio D, Marziano G, Breccia M, Niscola P, Sanna A, Clissa C, Voso MT, Fenu S, Venditti A, Santini V, Angelucci E, Levis A. Iron-chelating therapy with deferasirox in transfusion-dependent, higher risk myelodysplastic syndromes: a retrospective, multicentre study. Br J Haematol 2017; 177:741-750. [PMID: 28419408 DOI: 10.1111/bjh.14621] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 12/27/2016] [Indexed: 01/19/2023]
Abstract
Iron chelation is controversial in higher risk myelodysplastic syndromes (HR-MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion-dependent, intermediate-to-very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty-six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375-2500 mg) for a median of 11 months (range 0·4-75). Eight patients (16%) showed grade 2-3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 μg/l at baseline to 1100 μg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR-MDS are comparable, in terms of safety and efficacy, with those observed in lower-risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR-MDS patients.
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Affiliation(s)
- Pellegrino Musto
- Scientific Direction, IRCCS-CROB, "Referral Cancer Centre of Basilicata", Rionero In Vulture (Pz), Italy
| | - Luca Maurillo
- Haematology, Department of Biomedicine and Prevention, "Tor Vergata" University, Rome, Italy
| | - Vittorio Simeon
- Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, "Referral Cancer Centre of Basilicata", Rionero In Vulture (Pz), Italy
| | - Antonella Poloni
- Haematology Clinic, Department of Clinic and Molecular Sciences, "Università Politecnica delle Marche", Ancona, Italy
| | - Carlo Finelli
- "Seràgnoli Institute of Haematology", University School of Medicine, Bologna, Italy
| | - Enrico Balleari
- Department of Haematology and Oncology, IRCCS AOU San Martino - IST, Genova, Italy
| | - Alessandra Ricco
- Department of Emergency and Organ Transplantation, Haematology Section, University of Bari, Bari, Italy
| | | | - Agostino Cortelezzi
- Department of Oncology and Haemato-Oncology, University of Milan and Haematology Unit, "Fondazione IRCCS Ca' Granda, Ospedale Maggiore" Policlinico, Milan, Italy
| | | | - Oreste Villani
- Department of Onco-Haematology, IRCCS-CROB, "Referral Cancer Centre of Basilicata", Rionero in Vulture (Pz), Italy
| | - Giovanna Mansueto
- Department of Onco-Haematology, IRCCS-CROB, "Referral Cancer Centre of Basilicata", Rionero in Vulture (Pz), Italy
| | - Maria R Milella
- Pharmacy Unit, IRCCS-CROB, "Referral Cancer Centre of Basilicata", Rionero In Vulture (Pz), Italy
| | - Daniele Scapicchio
- Management Control Unit, IRCCS-CROB, "Referral Cancer Centre of Basilicata", Rionero In Vulture (Pz), Italy
| | - Gioacchino Marziano
- Scientific Direction, IRCCS-CROB, "Referral Cancer Centre of Basilicata", Rionero In Vulture (Pz), Italy
| | - Massimo Breccia
- Department of Cellular Biotechnologies and Haematology, "La Sapienza" University, Rome, Italy
| | | | - Alessandro Sanna
- Haematology, University of Florence, AOU Careggi, Florence, Italy
| | - Cristina Clissa
- Haematology and Haematopoietic Stem Cell Transplant Centre, AORMN, Pesaro, Italy
| | - Maria T Voso
- Haematology, Department of Biomedicine and Prevention, "Tor Vergata" University, Rome, Italy
| | - Susanna Fenu
- Haematology, "San Giovanni" Hospital, Rome, Italy
| | - Adriano Venditti
- Haematology, Department of Biomedicine and Prevention, "Tor Vergata" University, Rome, Italy
| | - Valeria Santini
- Haematology, University of Florence, AOU Careggi, Florence, Italy
| | - Emanuele Angelucci
- Department of Haematology and Oncology, IRCCS AOU San Martino - IST, Genova, Italy
| | - Alessandro Levis
- FISM, Fondazione Italiana Sindromi Mielodisplastiche, Alessandria, Italy
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Kontoghiorghe CN, Kontoghiorghes GJ. New developments and controversies in iron metabolism and iron chelation therapy. World J Methodol 2016; 6:1-19. [PMID: 27019793 PMCID: PMC4804243 DOI: 10.5662/wjm.v6.i1.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 11/17/2015] [Accepted: 12/17/2015] [Indexed: 02/06/2023] Open
Abstract
Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.
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Angelucci E, Pilo F. Management of iron overload before, during, and after hematopoietic stem cell transplantation for thalassemia major. Ann N Y Acad Sci 2016; 1368:115-21. [PMID: 26999450 DOI: 10.1111/nyas.13027] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/20/2016] [Accepted: 01/22/2016] [Indexed: 12/21/2022]
Abstract
Solid evidence has established the negative impact of high iron burden and related tissue damage on the outcome of hemopoietic stem cell transplantation for thalassemia major. Recent improvements in our knowledge of iron metabolism have been focused on elevated non-transferrin-bound iron and labile plasma iron levels in the peritransplantation period as potential contributors to tissue toxicity and subsequent adverse transplant outcome. As mouse models have shown, iron overload can injure bone marrow hematopoiesis by increasing reactive oxygen species. The Pesaro experience, conducted in the deferoxamine-only era, clearly defined three iron-related factors (liver fibrosis, hepatomegaly, and quality of lifelong chelation) as significantly affecting transplant outcome. The detrimental effect of iron has only been clarified in recent years. Active interventional strategies are ongoing. Although successful hematopoietic stem cell transplantation clinically resolves the thalassemia marrow defect, patients still remain carriers of iron overload and of all the clinical complications acquired during prior years of transfusion therapy. Therefore, adequate "iron diagnosis" and management is mandatory after hemopoietic stem cell transplantation. In transplanted thalassemia patients, body iron should be returned to within the normal range. Phlebotomy is the gold standard to reduce iron burden; though deferoxamine is a proven, acceptable alternative, clinical investigations on deferasirox are ongoing.
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Affiliation(s)
- Emanuele Angelucci
- Unità Operativa Ematologia e Centro Trapianti, Ospedale Oncologico di Riferimento Regionale "Armando Businco,", Azienda Ospedaliera di Rilievo Nazionale "Brotzu,", Cagliari, Italy
| | - Federica Pilo
- Unità Operativa Ematologia e Centro Trapianti, Ospedale Oncologico di Riferimento Regionale "Armando Businco,", Azienda Ospedaliera di Rilievo Nazionale "Brotzu,", Cagliari, Italy
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20
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Abstract
Decreased serum and increased hepatic iron uptake is the hallmark of acute-phase (AP) response. Iron uptake is controlled by iron transport proteins such as transferrin receptors (TfRs) and lipocalin 2 (LCN-2). The current study aimed to understand the regulation of iron uptake in primary culture hepatocytes in the presence/absence of AP mediators. Rat hepatocytes were stimulated with different concentrations of iron alone (0.01, 0.1, 0.5 mM) and AP cytokines (interleukin 6 [IL-6], IL-1β, tumor necrosis factor α) in the presence/absence of iron (FeCl3: 0.1 mM). Hepatocytes were harvested at different time points (0, 6, 12, 24 h). Total mRNA and proteins were extracted for reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot. A significant iron uptake was detected with 0.1 mM iron administration with a maximum (133.37 ± 4.82 µg/g of protein) at 24 h compared with control and other iron concentrations. This uptake was further enhanced in the presence of AP cytokines with a maximum iron uptake (481 ± 25.81 µg/g of protein) after concomitant administration of IL-6 + iron to cultured hepatocytes. Concomitantly, gene expression of LCN-2 and ferritin subunits (light- and heavy-chain ferritin subunits) was upregulated by iron or/and AP cytokines with a maximum at 24 h both at mRNA and protein levels. In contrast, a decreased TfR1 level was detected by IL-6 and iron alone, whereas combination of iron and AP cytokines (mainly IL-6) abrogated the downregulation of TfR1. An increase in LCN-2 release into the supernatant of cultured hepatocytes was observed after addition of iron/AP cytokines into the medium. This increase in secretion was further enhanced by combination of IL-6 + iron. In conclusion, iron uptake is tightly controlled by already present iron concentration in the culture. This uptake can be further enhanced by AP cytokines, mainly by IL-6.
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Pinto JP, Arezes J, Dias V, Oliveira S, Vieira I, Costa M, Vos M, Carlsson A, Rikers Y, Rangel M, Porto G. Physiological implications of NTBI uptake by T lymphocytes. Front Pharmacol 2014; 5:24. [PMID: 24616700 PMCID: PMC3935319 DOI: 10.3389/fphar.2014.00024] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 02/11/2014] [Indexed: 12/29/2022] Open
Abstract
In iron overload disorders a significant fraction of the total iron circulates in the plasma as low molecular weight complexes not bound to transferrin, known as non-transferrin-bound iron (NTBI). By catalyzing the formation of free radicals, NTBI accumulation results in oxidative stress and cellular damage, being a major cause of organ toxicity. NTBI is rapidly and preferentially cleared from circulation by the liver and the myocardium, the main disease targets in iron overload conditions. We have recently demonstrated that human peripheral blood T lymphocytes take up NTBI in vitro, with a pattern that resembles that of hepatocytes. Since T lymphocytes constitute a numerically important component of the circulating cell pool, these findings support a putative role for this cell type in the systemic protection against iron toxicity. Here we tested the hypothesis that the circulating peripheral blood T lymphocyte pool constitutes an important storage compartment for NTBI and is thus a modifier of NTBI deposition in target organs. First we show that NTBI uptake by human T lymphocytes increases the expression of the iron-storage protein ferritin and of the iron exporter ferroportin via an IRE-dependent mechanism. NTBI retention by T lymphocytes is shown to be critically controlled by the hepcidin-mediated modulation of ferroportin both in vitro and in vivo. Finally, the protective effect of T lymphocytes was tested by analyzing the patterns of iron accumulation in the T lymphocyte-deficient mouse model Foxn1nu before and after reconstitution with T lymphocytes by adoptive transfer. The results confirmed a significant increase of liver and pancreas iron accumulation in T lymphocyte-deficient mice. NTBI accumulation in the liver and spleen was prevented by reconstitution with syngeneic T lymphocytes. Altogether, our results demonstrate that T lymphocytes are important components of a circulating “NTBI storage compartment” and show its physiological relevance as a modifier of tissue iron overload.
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Affiliation(s)
- Jorge P Pinto
- Molecular and Cellular Biology Division, Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto Porto, Portugal
| | - João Arezes
- Molecular and Cellular Biology Division, Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto Porto, Portugal
| | - Vera Dias
- Molecular and Cellular Biology Division, Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto Porto, Portugal
| | - Susana Oliveira
- Molecular and Cellular Biology Division, Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto Porto, Portugal
| | - Inês Vieira
- Molecular and Cellular Biology Division, Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto Porto, Portugal
| | - Mónica Costa
- Molecular and Cellular Biology Division, Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto Porto, Portugal ; Faculdade de Medicina, Universidade do Porto Porto, Portugal
| | | | | | | | - Maria Rangel
- Chemistry Department, REQUIMTE, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto Porto, Portugal
| | - Graça Porto
- Molecular and Cellular Biology Division, Basic and Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto Porto, Portugal ; Clinical Hematology, CHP-HSA - Santo António General Hospital Porto, Portugal ; Molecular Immunology and Pathology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto Porto, Portugal
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Kolnagou A, Natsiopoulos K, Kleanthous M, Ioannou A, Kontoghiorghes GJ. Liver iron and serum ferritin levels are misleading for estimating cardiac, pancreatic, splenic and total body iron load in thalassemia patients: factors influencing the heterogenic distribution of excess storage iron in organs as identified by MRI T2*. Toxicol Mech Methods 2013; 23:48-56. [PMID: 22943064 DOI: 10.3109/15376516.2012.727198] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A comparative assessment of excess storage iron distribution in the liver, heart, spleen and pancreas of β-thalassemia major (β-ΤΜ) patients has been carried out using magnetic resonance imaging (MRI) relaxation times T2*. The β-ΤΜ patients (8-40 years, 11 males, 9 females) had variable serum ferritin levels (394-5603 μg/L) and were treated with deferoxamine (n = 10), deferiprone (n = 5) and deferoxamine/deferiprone combination (n = 5). MRI T2* assessment revealed that excess iron is not proportionally distributed among the organs but is stored at different concentrations in each organ and the distribution is different for each β-ΤΜ patient. There is random variation in the distribution of excess storage iron from normal to severe levels in each organ among the β-ΤΜ patients by comparison to the same organs of ten normal volunteers. The correlation of serum ferritin with T2* was for spleen (r = -0.81), liver (r = -0.63), pancreas (r = -0.33) and none with heart. Similar trend was observed in the correlation of liver T2* with the T2* of spleen (r = 0.62), pancreas (r = 0.61) and none with heart. These studies contradict previous assumptions that serum ferritin and liver iron concentration is proportional to the total body iron stores in β-ΤΜ and especially cardiac iron load. The random variation in the concentration of iron in the organs of β-ΤΜ patients appears to be related to the chelation protocol, organ function, genetic, dietary, pharmacological and other factors. Monitoring of the iron load for all the organs is recommended for each β-ΤΜ patient.
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Affiliation(s)
- Annita Kolnagou
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus
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Koba M, Słomka A, Bączek T, Marszałł MP, Żekanowska E. Ability to determine the desferrioxamine-chelatable iron fractions of nontransferrin-bound iron using HPLC. J Sep Sci 2013; 36:665-9. [DOI: 10.1002/jssc.201200683] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 10/26/2012] [Accepted: 10/26/2012] [Indexed: 02/06/2023]
Affiliation(s)
- Marcin Koba
- Department of Toxicology, Faculty of Pharmacy; Collegium Medicum of Nicolaus Copernicus University; Bydgoszcz Poland
| | - Artur Słomka
- Department of Pathophysiology, Faculty of Pharmacy; Collegium Medicum of Nicolaus Copernicus University; Bydgoszcz Poland
| | - Tomasz Bączek
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy; Medical University of Gdańsk; Gdańsk Poland
| | - Michał P. Marszałł
- Department of Medicinal Chemistry, Faculty of Pharmacy; Collegium Medicum of Nicolaus Copernicus University; Bydgoszcz Poland
| | - Ewa Żekanowska
- Department of Pathophysiology, Faculty of Pharmacy; Collegium Medicum of Nicolaus Copernicus University; Bydgoszcz Poland
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Ścibior A, Adamczyk A, Gołębiowska D, Niedźwiecka I. Effect of 12-week vanadate and magnesium co-administration on chosen haematological parameters as well as on some indices of iron and copper metabolism and biomarkers of oxidative stress in rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2012; 34:235-252. [PMID: 22561110 DOI: 10.1016/j.etap.2012.04.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 04/03/2012] [Accepted: 04/06/2012] [Indexed: 05/25/2023]
Abstract
Changes in some blood parameters after 12-week administration of sodium metavanadate (SMV; 0.125mgV/ml) or/and magnesium sulphate (MS; 0.06mgMg/ml) in drinking water were studied in outbred male Wistar rats (16 rats/each group) to explore the probable mechanism(s) underlying SMV toxicity and check whether Mg at the level selected during SMV co-administration can protect, at least in part, from a possible deleterious action of SMV. Exposure to SMV alone and in combination with MS (a) led to a decrease in fluid and food intake and body weight gain; (b) predisposed the animals to the development of microcytic-hypochromic anaemia (with excessive liver and spleen Fe deposition, unaltered plasma Fe level and enhanced Zn concentration in the erythrocytes (RBCs) characterized by a reduced haematocrit (Ht) index and haemoglobin (Hb) level, unchanged erythrocyte and reticulocyte count, anisocytosis, lowered total iron binding capacity (TIBC) and elevated transferrin saturation (TS); (c) disturbed Cu homeostasis, but (d) did not influence the leukocyte count and the plasma total antioxidant status (TAS). We suggest that abnormal metabolism and accumulation of Fe as well as an altered Cu status and the RBC Zn level might lead to defective Fe utilization and be a factor promoting the development of Fe-utilization anaemia. The disturbances in the antioxidative capacity reported previously in rats' RBCs after SMV intoxication (Ścibior, Zaporowska, Environ. Toxicol. Pharmacol. 30 (2010) 153-161) may suggest that oxidative stress (OS) could also be, in part, involved in the mechanism responsible for the development of anaemia. The Mg dose ingested in combination with V under SMV-MS co-administration (a) was able to decrease, to some extent, the V concentration in the blood, (b) normalized the RBC Mg and Fe levels and (c) restored the values of some parameters of the Fe status near the control values. These results allow a supposition that a higher Mg dose consumed during SMV exposure could have better protective potential and be more effective in limiting the SMV toxicity observed.
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Affiliation(s)
- Agnieszka Ścibior
- The John Paul II Catholic University of Lublin, Institute of Environmental Protection, Department of Zoology and Invertebrate Ecology, Laboratory of Physiology and Animal Biochemistry, Kraśnicka Ave 102, 20-718 Lublin, Poland; Centre of Interdisciplinary Research, The John Paul II Catholic University of Lublin, Kraśnicka Ave 102, 20-718 Lublin, Poland.
| | - Agnieszka Adamczyk
- The John Paul II Catholic University of Lublin, Institute of Environmental Protection, Department of Zoology and Invertebrate Ecology, Laboratory of Physiology and Animal Biochemistry, Kraśnicka Ave 102, 20-718 Lublin, Poland
| | - Dorota Gołębiowska
- The John Paul II Catholic University of Lublin, Institute of Environmental Protection, Department of Zoology and Invertebrate Ecology, Laboratory of Physiology and Animal Biochemistry, Kraśnicka Ave 102, 20-718 Lublin, Poland
| | - Irmina Niedźwiecka
- The John Paul II Catholic University of Lublin, Institute of Environmental Protection, Department of Zoology and Invertebrate Ecology, Laboratory of Physiology and Animal Biochemistry, Kraśnicka Ave 102, 20-718 Lublin, Poland
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Patel M, Ramavataram DVSS. Non transferrin bound iron: nature, manifestations and analytical approaches for estimation. Indian J Clin Biochem 2012; 27:322-32. [PMID: 24082455 DOI: 10.1007/s12291-012-0250-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Accepted: 08/12/2012] [Indexed: 12/20/2022]
Abstract
Iron is an essential trace element and plays a number of vital roles in biological system. It also leads the chains of pathological actions if present in excess and/or present in free form. Major portion of iron in circulation is associated with transferrin, a classical iron transporter, which prevent the existence of free iron. The fraction of iron which is free of transferrin is known as "non transferrin bound iron". Along with the incidence in iron over loaded patient non transferrin bound iron has been indicated in patients without iron overload. It has been suggested as cause as well as consequence in a number of pathological conditions. The major organs influenced by iron toxicity are heart, pancreas, kidney, organs involved in hematopoiesis etc. The most commonly suggested way for iron mediated pathogenesis is through increased oxidative stress and their secondary effects. Generation of free oxygen radicals by iron has been well documented in Fenton chemistry and Haber-Weiss reaction. Non transferrin bound iron has obvious chance to generate the free reactive radicals as it is not been shielded by the protective carrier protein apo transferrin. The nature of non transferrin bound iron is not clear at present time but it is definitely a group of heterogenous iron forms free from transferrin and ferritin. A variety of analytical approaches like colorimetry, chromatography, fluorimetry etc. have been experimented in different research laboratories for estimation of non transferrin bound iron. However the universally accepted gold standard method which can be operated in pathological laboratories is still to be developed.
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Affiliation(s)
- Meghna Patel
- Institute of Medical Technology, 173-B New Industrial Estate, Road No. 6G, Udyognagar, Udhana, Surat, Gujarat India
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Naz N, Malik IA, Sheikh N, Ahmad S, Khan S, Blaschke M, Schultze F, Ramadori G. Ferroportin-1 is a 'nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins. J Transl Med 2012; 92:842-56. [PMID: 22469696 DOI: 10.1038/labinvest.2012.52] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Liver is the central organ of iron metabolism. During acute-phase-response (APR), serum iron concentration rapidly decreases. The current study aimed to compare expression and localization of iron transport protein ferroportin-1 (Fpn-1) and of other iron import proteins after experimental tissue damage induced by injecting turpentine oil in the hind limbs of rats and mice. Serum and spleen iron concentration decreased with an increase in total liver, cytoplasmic and nuclear iron concentration. In liver, mRNA amount of Fpn-1, Fpn-1a, Fpn-1b, HFE, hemojuvelin (HJV) and hephaestin (heph) genes showed a rapid decrease. Hepcidin, divalent metal transporter-1 (DMT-1), transferrin (Tf) and Tf-receptor-1 (TfR1), TfR-2 (TfR2) gene expression was increased. Western blot analysis of liver tissue lysate confirmed the changes observed at mRNA level. In spleen, a rapid decrease in gene expression of Fpn-1, Fpn-1a, Fpn-1b, DMT-1, Tf, TfR1 and TfR2, and an increase in hepcidin was observed. Immunohistochemistry of DMT-1 and TfR2 were mainly detected in the nucleus of rat liver and spleen, whereas TfR1 was clearly localized in the plasma membrane. Fpn-1 was mostly found in the nuclei of liver cells, whereas in spleen, the protein was mainly detected in the cell membrane. Western blot analysis of liver fractions confirmed immunohistochemical results. In livers of wild-type mice, gene expression of Fpn-1, Fpn-1a and Fpn-1b was downregulated, whereas hepcidin gene expression was increased. In contrast, these changes were less pronounced in IL-6ko-mice. Cytokine (IL-6, IL-1b and TNF-a) treatment of rat hepatocytes showed a downregulation of Fpn-1, Fpn-1a and Fpn-1b, and upregulation of hepcidin gene expression. Moreover, western blot analysis of cell lysate of IL-6-treated hepatocytes detected, as expected, an increase of a2-macroglobulin (positive acute-phase protein), whereas albumin (negative acute-phase protein) and Fpn-1 were downregulated. Our results demonstrate that liver behaves as a 'sponge' for iron under acute-phase conditions, and Fpn-1 behaves as a negative acute-phase protein in rat hepatocytes mainly, but not exclusively, because of the effect of IL-6. These changes could explain iron retention in the cytoplasm and in the nucleus of hepatocytes during APR.
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Affiliation(s)
- Naila Naz
- Division of Gastroenterology and Endocrinology, Department of Internal Medicine, University Hospital, Georg-August-University, Göttingen, Germany
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Brissot P, Ropert M, Le Lan C, Loréal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta Gen Subj 2011; 1820:403-10. [PMID: 21855608 DOI: 10.1016/j.bbagen.2011.07.014] [Citation(s) in RCA: 458] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Revised: 07/21/2011] [Accepted: 07/28/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Besides transferrin iron, which represents the normal form of circulating iron, non-transferrin bound iron (NTBI) has been identified in the plasma of patients with various pathological conditions in which transferrin saturation is significantly elevated. SCOPE OF THE REVIEW To show that: i) NTBI is present not only during chronic iron overload disorders (hemochromatosis, transfusional iron overload) but also in miscellaneous diseases which are not primarily iron overloaded conditions; ii) this iron species represents a potentially toxic iron form due to its high propensity to induce reactive oxygen species and is responsible for cellular damage not only at the plasma membrane level but also towards different intracellular organelles; iii) the NTBI concept may be expanded to include intracytosolic iron forms which are not linked to ferritin, the major storage protein which exerts, at the cellular level, the same type of protective effect towards the intracellular environment as transferrin in the plasma. MAJOR CONCLUSIONS Plasma NTBI and especially labile plasma iron determinations represent a new important biological tool since elimination of this toxic iron species is a major therapeutic goal. GENERAL SIGNIFICANCE The NTBI approach represents an important mechanistic concept for explaining cellular iron excess and toxicity and provides new important biochemical diagnostic tools. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.
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Affiliation(s)
- Pierre Brissot
- Inserm, UMR991, Liver Metabolisms and Cancer, F-35033 Rennes, France.
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Ghoti H, Fibach E, Westerman M, Gordana O, Ganz T, Rachmilewitz EA. Increased serum hepcidin levels during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndrome. Br J Haematol 2011; 153:118-20. [PMID: 21332711 DOI: 10.1111/j.1365-2141.2011.08587.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Hepcidin is a major regulator of iron metabolism. We evaluated changes in serum hepcidin during 3 months of therapy with the iron-chelator deferasirox in patients with low-risk myelodysplastic syndrome and iron overload. Serum hepcidin was found to be high in these patients, correlated with their iron and oxidative status, and further increased by treatment with deferasirox. These findings support the concept that the hepcidin level represents a balance between the stimulating effect of iron overload and the inhibitory effects of erythropoietic activity and oxidative stress. These preliminary findings favour the rationale for iron chelation therapy in such patients.
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Affiliation(s)
- Hussam Ghoti
- Department of Haematology, Edith Wolfson Medical Centre, Holon, Israel
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