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Navidifar T, Meftah E, Baghsheikhi H, Kazemzadeh K, Karimi H, Rezaei N. Dual role of hepcidin in response to pathogens. Microb Pathog 2025; 203:107496. [PMID: 40118299 DOI: 10.1016/j.micpath.2025.107496] [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: 05/26/2024] [Revised: 03/15/2025] [Accepted: 03/19/2025] [Indexed: 03/23/2025]
Abstract
Hepcidin is the primary regulator of vertebrate iron homeostasis. Its production is stimulated by systemic iron levels and inflammatory signals. Although the role of hepcidin in iron homeostasis is well characterized, its response to pathogenic agents is complex and diverse. In this review, we examine studies that investigate the role of hepcidin in response to infectious agents. Interleukin-6 (IL-6) is a key factor responsible for the induction of hepcidin expression. During infection, hepcidin-mediated depletion of extracellular iron serves as a protective mechanism against a variety of pathogens. However, accumulation of iron in macrophages through hepcidin-mediated pathways may increase susceptibility to intracellular pathogens such as Mycobacterium tuberculosis. Prolonged elevation of hepcidin production can lead to anemia due to reduced iron availability for erythropoiesis, a condition referred to as anemia of inflammation. In addition, we highlight the role of hepcidin upregulation in several infectious contexts, including HIV-associated anemia, iron deficiency anemia in Helicobacter pylori infection, and post-malarial anemia in pediatric patients. In addition, we show that certain infectious agents, such as hepatitis C virus (HCV), can suppress hepcidin production during both the acute and chronic phases of infection, while hepatitis B virus (HBV) exhibits similar suppression during the chronic phase.
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Affiliation(s)
- Tahereh Navidifar
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Elahe Meftah
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hediyeh Baghsheikhi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Kazemzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanie Karimi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
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Hayat N, Akram Z, Khalid N, Ullah NR, Mazhar T. Link between iron-mediated lipid peroxidation and polycystic ovary syndrome (PCOS): exploring the genes underlying iron regulatory mechanism. J Ovarian Res 2025; 18:48. [PMID: 40057801 PMCID: PMC11889770 DOI: 10.1186/s13048-024-01562-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/18/2024] [Indexed: 05/13/2025] Open
Abstract
OBJECTIVE Mechanism underlying the etiology of polycystic ovary syndrome (PCOS) is still debatable. Present study explores the link between iron-mediated ferroptosis and PCOS. METHODOLOGY Blood samples were collected from 150 PCOS females along with healthy controls. Expression analysis of FTH1, NCOA4, GPX4, HAMP, A2M and HP genes was estimated by RT-qPCR. Serum was used for estimation of lipid peroxidation, peroxidase enzyme, ferritin and total protein. RESULTS Relative expression of FTH1 (P < 0.05), HAMP (P < 0.01), GPX4, A2M, HP (P < 0.001) was downregulated and NCOA4 (P < 0.001) was upregulated in PCOS group compared to control. A significant difference was observed in mRNA expression of selected genes when ≤ 30year age group PCOS was compared to > 30year age PCOS group and their respective controls. Deregulation of gene expression was prominent in PCOS group with obese and overweight BMI compared to underweight and normal BMI group. Menstrual cycle length and marital status of PCOS females had no significant association with selected gene expression. Expression deregulation in targeted genes was observed in PCOS patients with complaints of either diabetes, high blood pressure or both. Increased level of lipid peroxidation, serum ferritin and total protein, while decreased peroxidase activity was observed in PCOS group (P < 0.001) compared to control. CONCLUSION The present study postulated the role of iron overload in trigger of ferroptosis following elevated lipid peroxidation and low peroxidase activity. Moreover, unveil the association of genes related to iron-regulating metabolism with etiology of underlying PCOS mechanism.
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Affiliation(s)
- Nighat Hayat
- Cancer Genetics and Epigenetics Lab, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Zertashia Akram
- Cancer Genetics and Epigenetics Lab, Department of Biosciences, COMSATS University, Islamabad, Pakistan.
| | - Nayab Khalid
- Cancer Genetics and Epigenetics Lab, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | | | - Tehmina Mazhar
- Cancer Genetics and Epigenetics Lab, Department of Biosciences, COMSATS University, Islamabad, Pakistan
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Edahiro Y, Komatsu N. Iron deficiency and phlebotomy in patients with polycythemia vera. Int J Hematol 2025; 121:39-44. [PMID: 39528901 DOI: 10.1007/s12185-024-03868-z] [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: 06/11/2024] [Revised: 10/24/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Polycythemia vera (PV) is a myeloproliferative neoplasm that is associated with an elevated risk of thrombosis. Treatment strategies are based on thrombosis risk classification. Phlebotomy is a commonly recommended treatment for all patients with PV, regardless of their risk classification, and reduces the incidence of thrombosis by lowering hematocrit levels. However, patients with PV frequently present with iron deficiency at diagnosis due to increased erythropoiesis, which repeated phlebotomy can exacerbate. This can produce symptoms that diminish quality of life, such as fatigue, lethargy, and impaired concentration. Recently, hepcidin mimetics have been developed to suppress iron utilization in erythropoiesis. Among them, rusfertide has been shown to control hematocrit levels without requiring phlebotomy. Further studies are needed to identify new treatment strategies for PV that also consider iron deficiency.
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Affiliation(s)
- Yoko Edahiro
- Department of Hematology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Norio Komatsu
- Department of Hematology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Department of Advanced Hematology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- PharmaEssentia Japan KK, Minato-ku, Tokyo, 107-0051, Japan
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Peng X, Mo X, Li X. Mechanisms and treatment of anemia related to cardiac arrest. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:457-466. [PMID: 38970520 PMCID: PMC11208403 DOI: 10.11817/j.issn.1672-7347.2024.230497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Indexed: 07/08/2024]
Abstract
Cardiac arrest is a common and fatal emergency situation. Recently, an increasing number of studies have shown that anemia in patients with cardiac arrest is closely related to high mortality rates and poor neurological outcomes. Anemia is prevalent among patients with post-cardiac arrest syndrome (PCAS), but its specific pathogenesis remains unclear. The mechanisms may involve various factors, including reduced production of erythropoietin, oxidative stress/inflammatory responses, gastrointestinal ischemic injury, hepcidin abnormalities, iatrogenic blood loss, and malnutrition. Measures to improve anemia related to cardiac arrest may include blood transfusions, administration of erythropoietin, anti-inflammation and antioxidant therapies, supplementation of hematopoietic materials, protection of gastrointestinal mucosa, and use of hepcidin antibodies and antagonists. Therefore, exploring the latest research progress on the mechanisms and treatment of anemia related to cardiac arrest is of significant guiding importance for improving secondary brain injury caused by anemia and the prognosis of patients with cardiac arrest.
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Affiliation(s)
- Xiang Peng
- Department of Emergency, Xiangya Hospital, Central South University, Changsha 410008.
| | - Xiaoye Mo
- Department of Emergency, Xiangya Hospital, Central South University, Changsha 410008
| | - Xiangmin Li
- Department of Emergency, Xiangya Hospital, Central South University, Changsha 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha 410008, China.
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Randrianarisoa RMF, Ramanandafy H, Mania A, Monjanel H, Trouillier S. Prevalence and diagnostic performance of iron deficiency in polycythemia. Hematology 2023; 28:2204621. [PMID: 37115586 DOI: 10.1080/16078454.2023.2204621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023] Open
Abstract
INTRODUCTION Several observations have shown that patients with polycythemia have iron deficiency. Our objectives were to report the prevalence of iron deficiency and to evaluate the diagnostic performance of serum ferritin in polycythemia vera. PATIENTS AND METHOD This is a retrospective descriptive and analytical study carried out in the internal medicine department of the Henri Mondor Hospital, Aurillac, France. The study involved 114 patients with polycythemia, followed in the department from January 1, 2010 to December 31, 2021. To evaluate the diagnostic performance, the JAK2 mutation was considered as the gold standard of diagnosis. RESULTS Thirty-three patients had polycythemia vera and 76 patients had secondary polycythemia. The mean age of the patients was 61.79 years (±15.44) with a sex ratio of 4.43. The overall prevalence of iron deficiency was 21.05%. The prevalence was 53% in polycythemia vera group and 1.32% in secondary polycythemia group. The risk of iron deficiency was high in polycythemia vera (OR = 115; 95% CI [14.4-918.2], p < 0.0001) and the sensitivity and specificity of serum ferritin were 52.63% and 100% respectively. CONCLUSION Assessment of iron deficiency should be part of the initial evaluation of polycythemia. Iron deficiency had a high specificity during polycythemia vera.
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Affiliation(s)
| | - Herveat Ramanandafy
- Department of Internal Medicine, Joseph Raseta Befelatanana Hospital, Antananarivo, Madagascar
| | - Alexandre Mania
- Department of Internal Medicine, Henri Mondor Hospital, Aurillac, France
| | - Hélène Monjanel
- Department of Internal Medicine, Henri Mondor Hospital, Aurillac, France
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Kaushik SR, Sahu S, Guha H, Saha S, Das R, Kupa RU, Kapfo W, Deka T, Basumatary R, Thong A, Dasgupta A, Goswami B, Pandey AK, Saikia L, Khamo V, Das A, Nanda RK. Low circulatory Fe and Se levels with a higher IL-6/IL-10 ratio provide nutritional immunity in tuberculosis. Front Immunol 2023; 13:985538. [PMID: 36713405 PMCID: PMC9878310 DOI: 10.3389/fimmu.2022.985538] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 11/28/2022] [Indexed: 01/15/2023] Open
Abstract
Tuberculosis (TB) patients show dysregulated immunity, iron metabolism, and anemia. In this study, circulatory cytokines, trace metals, and iron-related proteins (hepcidin, ferroportin, transferrin, Dmt1, Nramp1, ferritin, ceruloplasmin, hemojuvelin, aconitase, and transferrin receptor) were monitored in case (active tuberculosis patients: ATB) and control (non-tuberculosis: NTB and healthy) study populations (n = 72, male: 100%, mean age, 42.94 years; range, 17-83 years). Using serum elemental and cytokine levels, a partial least square discriminate analysis model (PLS-DA) was built, which clustered ATB patients away from NTB and healthy controls. Based on the PLS-DA variable importance in projection (VIP) score and analysis of variance (ANOVA), 13 variables were selected as important biosignatures [IL-18, IL-10, IL-13, IFN-γ, TNF-α, IL-5, IL-12 (p70), IL-1β, copper, zinc, selenium, iron, and aluminum]. Interestingly, low iron and selenium levels and high copper and aluminum levels were observed in ATB subjects. Low circulatory levels of transferrin, ferroportin, and hemojuvelin with higher ferritin and ceruloplasmin levels observed in ATB subjects demonstrate an altered iron metabolism, which partially resolved upon 6 months of anti-TB therapy. The identified biosignature in TB patients demonstrated perturbed iron homeostasis with anemia of inflammation, which could be useful targets for the development of host-directed adjunct therapeutics.
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Affiliation(s)
- Sandeep R. Kaushik
- Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Sukanya Sahu
- Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Hritusree Guha
- Department of Respiratory Medicine, Agartala Government Medical College, Agartala, Tripura, India
| | - Sourav Saha
- Department of Respiratory Medicine, Agartala Government Medical College, Agartala, Tripura, India
| | - Ranjit Das
- Department of Respiratory Medicine, Agartala Government Medical College, Agartala, Tripura, India
| | - Rukuwe-u Kupa
- Healthcare Laboratory and Research Centre, Naga Hospital Authority, Kohima, Nagaland, India
| | - Wetetsho Kapfo
- Healthcare Laboratory and Research Centre, Naga Hospital Authority, Kohima, Nagaland, India
| | - Trinayan Deka
- Department of Microbiology, Assam Medical College, Dibrugarh, Assam, India
| | - Rumi Basumatary
- Department of Microbiology, Assam Medical College, Dibrugarh, Assam, India
| | - Asunu Thong
- District Tuberculosis Centre, Kohima, Nagaland, India
| | - Arunabha Dasgupta
- Department of Medicine, Agartala Government Medical College, Agartala, Tripura, India
| | - Bidhan Goswami
- Department of Microbiology, Agartala Government Medical College, Agartala, Tripura, India
| | - Amit Kumar Pandey
- Mycobacterial Pathogenesis Laboratory, Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, India
| | - Lahari Saikia
- Department of Microbiology, Assam Medical College, Dibrugarh, Assam, India,Department of Microbiology, Gauhati Medical College, Guwahati, Assam, India
| | - Vinotsole Khamo
- Healthcare Laboratory and Research Centre, Naga Hospital Authority, Kohima, Nagaland, India
| | - Anjan Das
- Department of Respiratory Medicine, Agartala Government Medical College, Agartala, Tripura, India,*Correspondence: Ranjan Kumar Nanda, ; Anjan Das,
| | - Ranjan Kumar Nanda
- Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India,*Correspondence: Ranjan Kumar Nanda, ; Anjan Das,
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Chaib M, Hafeez BB, Mandil H, Daria D, Pingili AK, Kumari S, Sikander M, Kashyap VK, Chen GY, Anning E, Tripathi MK, Khan S, Behrman S, Yallapu MM, Jaggi M, Makowski L, Chauhan SC. Reprogramming of pancreatic adenocarcinoma immunosurveillance by a microbial probiotic siderophore. Commun Biol 2022; 5:1181. [PMID: 36333531 PMCID: PMC9636404 DOI: 10.1038/s42003-022-04102-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
There is increasing evidence suggesting the role of microbiome alterations in relation to pancreatic adenocarcinoma and tumor immune functionality. However, molecular mechanisms of the interplay between microbiome signatures and/or their metabolites in pancreatic tumor immunosurveillance are not well understood. We have identified that a probiotic strain (Lactobacillus casei) derived siderophore (ferrichrome) efficiently reprograms tumor-associated macrophages (TAMs) and increases CD8 + T cell infiltration into tumors that paralleled a marked reduction in tumor burden in a syngeneic mouse model of pancreatic cancer. Interestingly, this altered immune response improved anti-PD-L1 therapy that suggests promise of a novel combination (ferrichrome and immune checkpoint inhibitors) therapy for pancreatic cancer treatment. Mechanistically, ferrichrome induced TAMs polarization via activation of the TLR4 pathway that represses the expression of iron export protein ferroportin (FPN1) in macrophages. This study describes a novel probiotic based molecular mechanism that can effectively induce anti-tumor immunosurveillance and improve immune checkpoint inhibitors therapy response in pancreatic cancer.
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Affiliation(s)
- Mehdi Chaib
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center (UTHSC), Memphis, TN, 38163, USA
| | - Bilal B Hafeez
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA.
| | - Hassan Mandil
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center (UTHSC), Memphis, TN, 38163, USA
| | - Deidre Daria
- Department of Microbiology, Immunology and Biochemistry, Memphis, TN, 38163, USA
| | - Ajeeth K Pingili
- Division of Hematology Oncology, Department of Medicine, Memphis, TN, 38163, USA
| | - Sonam Kumari
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center (UTHSC), Memphis, TN, 38163, USA
| | - Mohammed Sikander
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
| | - Vivek K Kashyap
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
| | - Guo-Yun Chen
- Children's Foundation Research Institute at Le Bonheur Children's Hospital, Department of Pediatrics, Memphis, TN, 38163, USA
| | - Emmanuel Anning
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
| | - Manish K Tripathi
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
| | - Sheema Khan
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
| | | | - Murali M Yallapu
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
| | - Liza Makowski
- Department of Medicine, Division of Hematology and Oncology and the UTHSC Center for Cancer Research, Memphis, TN, 38103, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA.
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Wang C, Zhang W, Xu W, Liu Z, Huang K. AMP-activated protein kinase α1 phosphorylates PHD2 to maintain systemic iron homeostasis. Clin Transl Med 2022; 12:e854. [PMID: 35538889 PMCID: PMC9091988 DOI: 10.1002/ctm2.854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Iron is essential for all mammalian life, and either a deficiency or excess of iron can cause diseases. AMP-activated protein kinase (AMPK) is a critical regulator of metabolic homeostasis; however, it has not been established whether AMPK regulates iron metabolism. METHODS Iron, hepcidin and ferroportin levels were examined in mice with global and hepatocyte-specific knockout of AMPKα1 and AMPKα2. Primary AMPKα1 or AMPKα2 deleted hepatocytes were isolated and cultured in hypoxia condition to explore PHD2, HIF and hydroxylated HIF1α levels. We performed immunoprecipitation, in vitro AMPK kinase assay and site-direct mutant assay to detect phosphorylation sites of PHD2. We also obtained liver tissues from patients with anaemia of chronic disease undergoing surgery, AMPKα1 and hydroxylated HIF1α levels were measured by immunohistochemical analysis. RESULTS We found that mice with global deficiency of AMPKα1, but not AMPKα2, exhibited hypoferraemia as well as iron sequestration in the spleen and liver. Hepatocyte-specific, but not myeloid-specific, ablation of AMPKα1 also reduced serum iron levels in association with increased hepcidin and decreased ferroportin protein levels. Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling. Inhibition of PHD2 hydroxylation ameliorated abnormal iron metabolism in hepatic AMPKα1-deficient mice. Furthermore, we found hepatic AMPKα/PHD2/HIFα/ hepcidin axes were highly clinically relevant to anaemia of chronic disease. CONCLUSION In conclusion, these observations suggest that hepatic AMPKα1 has an essential role in maintaining iron homeostasis by PHD2-dependent regulation of hepcidin, thus providing a potentially promising approach for the treatment of iron disturbances in chronic diseases.
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Affiliation(s)
- Cheng Wang
- Clinic Center of Human Gene ResearchUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular AgingTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Department of RheumatologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Wencheng Zhang
- Department of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Wenjing Xu
- Clinic Center of Human Gene ResearchUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Zhaoyu Liu
- Department of CardiologySun Yat‐sen Memorial HospitalSun Yat‐sen University, GuangzhouChina
| | - Kai Huang
- Clinic Center of Human Gene ResearchUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular AgingTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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How J, Hobbs G. Management Issues and Controversies in Low-Risk Patients with Essential Thrombocythemia and Polycythemia Vera. Curr Hematol Malig Rep 2021; 16:473-482. [PMID: 34478054 DOI: 10.1007/s11899-021-00649-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Essential thrombocythemia (ET) and polycythemia vera (PV) are the most common myeloproliferative neoplasms (MPNs). Treatment of ET and PV is based on the risk for subsequent thrombosis. High-risk patients, defined as older than 60, JAK2 V617F-positive patients, or patients with a history of prior thrombosis, merit cytoreduction to control blood counts, whereas a watchful waiting paradigm is utilized in low-risk patients. However, low-risk patients have a host of other specific management issues that arise during their disease course. This review will discuss the most common management issues specific to the care of low-risk patients, including anti-platelet therapy dosing, pregnancy, and indications for early cytoreduction. RECENT FINDINGS Although low-dose aspirin is well established in PV, its indications and dosing regimens are less clear in ET. Recent evidence has supported twice daily low-dose aspirin in ET and observation alone in very low-risk ET patients. Pregnancy is not contraindicated in MPNs, and we recommend aspirin throughout pregnancy with consideration for prophylactic postpartum anticoagulation. High phlebotomy needs, symptom burden, and extreme thrombocytosis are common reasons for initiation of cytoreduction in low-risk patients, although we typically do not start cytoreduction for an isolated high platelet count alone. Recent data has also demonstrated a potential disease-modifying effect of interferons in MPNs, with some experts now advocating the early use of interferon in low-risk patients, although more mature data is needed before practice guidelines change. We evaluate the literature to inform clinical decision-making regarding these controversies, including most recent data that has challenged the "watchful waiting" paradigm. Our discussion provides guidance on common clinical scenarios seen in low-risk ET and PV patients, who face a myriad of complex management decisions in their care.
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Affiliation(s)
- Joan How
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Zero Emerson, Office 138, Boston, MA, 02114, USA.,Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Gabriela Hobbs
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Zero Emerson, Office 138, Boston, MA, 02114, USA.
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Effect of hepcidin antagonists on anemia during inflammatory disorders. Pharmacol Ther 2021; 226:107877. [PMID: 33895185 DOI: 10.1016/j.pharmthera.2021.107877] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 04/20/2021] [Indexed: 12/11/2022]
Abstract
Iron is an essential element for the mammalian body however, its homeostasis must be regulated accurately for appropriate physiological functioning. Alterations in physiological iron levels can lead to moderate to severe iron disorders like chronic and acute iron deficiency (anemia) or iron overload. Hepcidin plays an important role in regulating homeostasis between circulating iron and stored iron in the cells as well as the absorption of dietary iron in the intestine. Inflammatory disorders restrict iron absorption from food due to increased circulating levels of hepcidin. Increased production of hepcidin causes ubiquitination of ferroportin (FPN) leading to its degradation, thereby retaining iron in the spleen, duodenal enterocytes, macrophages, and hepatocytes. Hepcidin inhibitors and antagonists play a consequential role to ameliorate inflammation-associated anemia. Many natural and synthesized compounds, able to reduce hepcidin expression during inflammation have been identified in recent years. Few of which are currently at various phases of clinical trial. This article comprises a comprehensive review of therapeutic approaches for the efficient treatment of anemia associated with inflammation. Many strategies have been developed targeting the hepcidin-FPN axis to rectify iron disorders. Hepcidin modulation with siRNAs, antibodies, chemical compounds, and plant extracts provides new insights for developing advanced therapeutics for iron-related disorders. Hepcidin antagonist's treatment has a high potential to improve iron status in patients with iron disorders, but their clinical success needs further recognition along with the identification and application of new therapeutic approaches.
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Zhao T, Guo X, Sun Y. Iron Accumulation and Lipid Peroxidation in the Aging Retina: Implication of Ferroptosis in Age-Related Macular Degeneration. Aging Dis 2021; 12:529-551. [PMID: 33815881 PMCID: PMC7990372 DOI: 10.14336/ad.2020.0912] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 09/12/2020] [Indexed: 01/19/2023] Open
Abstract
Iron is an essential component in many biological processes in the human body. It is critical for the visual phototransduction cascade in the retina. However, excess iron can be toxic. Iron accumulation and reduced efficiency of intracellular antioxidative defense systems predispose the aging retina to oxidative stress-induced cell death. Age-related macular degeneration (AMD) is characterized by retinal iron accumulation and lipid peroxidation. The mechanisms underlying AMD include oxidative stress-mediated death of retinal pigment epithelium (RPE) cells and subsequent death of retinal photoreceptors. Understanding the mechanism of the disruption of iron and redox homeostasis in the aging retina and AMD is crucial to decipher these mechanisms of cell death and AMD pathogenesis. The mechanisms of retinal cell death in AMD are an area of active investigation; previous studies have proposed several types of cell death as major mechanisms. Ferroptosis, a newly discovered programmed cell death pathway, has been associated with the pathogenesis of several neurodegenerative diseases. Ferroptosis is initiated by lipid peroxidation and is characterized by iron-dependent accumulation. In this review, we provide an overview of the mechanisms of iron accumulation and lipid peroxidation in the aging retina and AMD, with an emphasis on ferroptosis.
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Affiliation(s)
- Tantai Zhao
- 1Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,2Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Xiaojian Guo
- 1Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,2Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
| | - Yun Sun
- 1Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,2Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China
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12
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Distinct Effects of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells. Int J Mol Sci 2021; 22:ijms22031497. [PMID: 33540888 PMCID: PMC7867333 DOI: 10.3390/ijms22031497] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/13/2021] [Accepted: 01/29/2021] [Indexed: 01/03/2023] Open
Abstract
Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by secreting pro-inflammatory cytokines. In bacterial infection, macrophages decrease the serum iron concentration by removing iron from the blood, acting as one of the most important regulatory cells of iron homeostasis. We examined whether the Gram-positive and Gram-negative cell wall components from various bacterial strains affect the cytokine production and iron transport, storage and utilization of THP-1 monocytes in different ways. We found that S. aureus lipoteichoic acid (LTA) was less effective in activating pro-inflammatory cytokine expression that may related to its effect on fractalkine production. LTA-treated cells increased iron uptake through divalent metal transporter-1, but did not elevate the expression of cytosolic and mitochondrial iron storage proteins, suggesting that the cells maintained iron efflux via the ferroportin iron exporter. E. coli and P. aeruginosa lipopolysaccharides (LPSs) acted similarly on THP-1 cells, but the rates of the alterations of the examined proteins were different. E. coli LPS was more effective in increasing the pro-inflammatory cytokine production, meanwhile it caused less dramatic alterations in iron metabolism. P. aeruginosa LPS-treated cells produced a smaller amount of pro-inflammatory cytokines, but caused remarkable elevation of both cytosolic and mitochondrial iron storage proteins and intracellular iron content compared to E. coli LPS. These results prove that LPS molecules from different bacterial sources alter diverse molecular mechanisms in macrophages that prepossess the outcome of the bacterial infection.
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13
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A disease-causing mutation K240E disrupts ferroportin trafficking by SUMO (ferroportin SUMOylation). Biochem Biophys Rep 2021; 25:100873. [PMID: 33490642 PMCID: PMC7809393 DOI: 10.1016/j.bbrep.2020.100873] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 10/20/2020] [Accepted: 12/10/2020] [Indexed: 01/01/2023] Open
Abstract
Ferroportin (Fpn/IREG1/MTP1) is the only known transporter mediating iron efflux from epithelial cells and macrophages, and thus regulates how much iron is released into the circulation. Consequently, Fpn mutations are associated with haemochromatosis. Fpn itself is post-translationally regulated by hepcidin (Hepc) which induces its redistribution and degradation in a ubiquitin-dependent process. Together, the two proteins appear to be the nexus for iron homeostasis. Here we show that a rare gain-of-function mutation (K240E) that is associated with iron overload, impedes Fpn binding and subcellular trafficking by the small ubiquitin-like modifier (SUMO). Whereas wild-type Fpn is ensconced within vesicular bodies, the FpnK240E mutant appeared diffused within the cell when co-expressed with SUMO. Furthermore, compared with wild type Fpn, the sumoylation-defective mutant was constitutively-active, resulting in a lower intracellular labile iron pool than the former. These findings suggest that SUMO may regulate iron homeostasis by controlling Fpn trafficking.
Ferroportin (Fpn) regulates iron efflux. A disease causing mutation (K240E) in a patient causes iron-overload. Fpn K240 is a SUMO conjugation site important for Fpn trafficking to endosomes by SUMO. The Fpn mutant K240E cannot be trafficked properly by SUMO and is a gain-of-function mutant that is constitutively active. FpnK240E effluxes more iron from intracellular stores than wild type Fpn.
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14
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Alizadeh K, Sun Q, McGuire T, Thompson T, Prato FS, Koropatnick J, Gelman N, Goldhawk DE. Hepcidin-mediated Iron Regulation in P19 Cells is Detectable by Magnetic Resonance Imaging. Sci Rep 2020; 10:3163. [PMID: 32081948 PMCID: PMC7035373 DOI: 10.1038/s41598-020-59991-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 02/04/2020] [Indexed: 01/25/2023] Open
Abstract
Magnetic resonance imaging can be used to track cellular activities in the body using iron-based contrast agents. However, multiple intrinsic cellular iron handling mechanisms may also influence the detection of magnetic resonance (MR) contrast: a need to differentiate among those mechanisms exists. In hepcidin-mediated inflammation, for example, downregulation of iron export in monocytes and macrophages involves post-translational degradation of ferroportin. We examined the influence of hepcidin endocrine activity on iron regulation and MR transverse relaxation rates in multi-potent P19 cells, which display high iron import and export activities, similar to alternatively-activated macrophages. Iron import and export were examined in cultured P19 cells in the presence and absence of iron-supplemented medium, respectively. Western blots indicated the levels of transferrin receptor, ferroportin and ubiquitin in the presence and absence of extracellular hepcidin. Total cellular iron was measured by inductively-coupled plasma mass spectrometry and correlated to transverse relaxation rates at 3 Tesla using a gelatin phantom. Under varying conditions of iron supplementation, the level of ferroportin in P19 cells responds to hepcidin regulation, consistent with degradation through a ubiquitin-mediated pathway. This response of P19 cells to hepcidin is similar to that of classically-activated macrophages. The correlation between total cellular iron content and MR transverse relaxation rates was different in hepcidin-treated and untreated P19 cells: slope, Pearson correlation coefficient and relaxation rate were all affected. These findings may provide a tool to non-invasively distinguish changes in endogenous iron contrast arising from hepcidin-ferroportin interactions, with potential utility in monitoring of different macrophage phenotypes involved in pro- and anti-inflammatory signaling. In addition, this work demonstrates that transverse relaxivity is not only influenced by the amount of cellular iron but also by its metabolism.
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Affiliation(s)
- Kobra Alizadeh
- Imaging, Lawson Health Research Institute, London, Ontario, Canada
- Medical Biophysics, Western University, London, Ontario, Canada
- Collaborative Graduate Program in Molecular Imaging, Western University, London, Ontario, Canada
| | - Qin Sun
- Imaging, Lawson Health Research Institute, London, Ontario, Canada
- Medical Biophysics, Western University, London, Ontario, Canada
- Collaborative Graduate Program in Molecular Imaging, Western University, London, Ontario, Canada
| | - Tabitha McGuire
- Imaging, Lawson Health Research Institute, London, Ontario, Canada
| | - Terry Thompson
- Imaging, Lawson Health Research Institute, London, Ontario, Canada
- Medical Biophysics, Western University, London, Ontario, Canada
- Medical Imaging, Western University, London, Ontario, Canada
- Physics and Astronomy, Western University, London, Ontario, Canada
| | - Frank S Prato
- Imaging, Lawson Health Research Institute, London, Ontario, Canada
- Medical Biophysics, Western University, London, Ontario, Canada
- Collaborative Graduate Program in Molecular Imaging, Western University, London, Ontario, Canada
- Medical Imaging, Western University, London, Ontario, Canada
- Physics and Astronomy, Western University, London, Ontario, Canada
| | - Jim Koropatnick
- London Regional Cancer Program, London, Ontario, Canada
- Oncology, Western University, London, Ontario, Canada
| | - Neil Gelman
- Imaging, Lawson Health Research Institute, London, Ontario, Canada
- Medical Biophysics, Western University, London, Ontario, Canada
- Medical Imaging, Western University, London, Ontario, Canada
| | - Donna E Goldhawk
- Imaging, Lawson Health Research Institute, London, Ontario, Canada.
- Medical Biophysics, Western University, London, Ontario, Canada.
- Collaborative Graduate Program in Molecular Imaging, Western University, London, Ontario, Canada.
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15
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Vlasveld LT, Janssen R, Bardou-Jacquet E, Venselaar H, Hamdi-Roze H, Drakesmith H, Swinkels DW. Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features. Pharmaceuticals (Basel) 2019; 12:ph12030132. [PMID: 31505869 PMCID: PMC6789780 DOI: 10.3390/ph12030132] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/14/2019] [Accepted: 08/20/2019] [Indexed: 12/14/2022] Open
Abstract
Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality.
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Affiliation(s)
- L Tom Vlasveld
- Department of Internal Medicine, Haaglanden MC-Bronovo, 2597AX The Hague, The Netherlands
| | - Roel Janssen
- Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Edouard Bardou-Jacquet
- Liver Diseases Department, French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, University Hospital Pontchaillou, 35033 Rennes, France
| | - Hanka Venselaar
- Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud, University Medical Center, P.O. Box 9191, 6500 HB Nijmegen, The Netherlands
| | - Houda Hamdi-Roze
- Molecular Genetics Department, French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, University Hospital Pontchaillou, 35033 Rennes, France
| | - Hal Drakesmith
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX39DS, UK
| | - Dorine W Swinkels
- Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
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16
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ALBAYRAK C, TARKUN P, BİRTAŞ ATEŞOĞLU E, ERALDEMİR C, ÖZSOY ÖD, TERZİ DEMİRSOY E, MEHTAP Ö, GEDÜK A, HACIHANEFİOĞLU A. The role of hepcidin, GDF15, and mitoferrin-1 in iron metabolism of polycythemia vera and essential thrombocytosis patients. Turk J Med Sci 2019; 49:74-80. [PMID: 30761871 PMCID: PMC7350842 DOI: 10.3906/sag-1803-13] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background/aim GDF15, hepcidin and mitoferrin-1 (mfrn-1) are proteins involved in systemic iron regulation. There are no studies in the literature demonstrating the serum mfrn-1 levels in polycythemia vera (PV) and essential thrombocythemia (ET) patients. The aim of this study was to investigate GDF15, hepcidin and mfrn-1 levels in PV and ET patients. Materials and methods Ten PV, 17 ET patients, and 27 healthy controls (HCs) were enrolled. GDF15, hepcidin and mfrn-1 values were measured with enzyme-linked immunosorbent assay (ELISA). Results GDF15 levels were higher in the myeloproliferative neoplasm (MPN) group (P = 0.002). Hepcidin levels were not different between MPN patients and HCs. The mfrn-1 levels were lower in MPN patients (P = 0.039). Hepcidin, GDF15, and mfrn-1 levels were not different between PV and ET patients. mfrn-1 levels were lower in ET patients than HCs (P = 0.038). Conclusion Increased erythropoiesis in MPNs may lead to high GDF15 levels in these patients. However, hepcidin was not suppressed despite the increased GDF15 levels and erythropoiesis in these patients. Decrease in mfrn-1 in MPNs can be the result of its increased turnover due to increased myelopoiesis. It can be hypothesized that similar hepcidin levels in patients and controls and low mfrn-1 levels in patients may be a defense mechanism against erythroid activity and thromboembolic complications.
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Affiliation(s)
- Canan ALBAYRAK
- Department of Internal Medicine, School of Medicine, Kocaeli University, KocaeliTurkey
| | - Pınar TARKUN
- Department of Hematology, School of Medicine, Kocaeli University, KocaeliTurkey
- * To whom correspondence should be addressed. E-mail:
| | | | - Ceyla ERALDEMİR
- Department of Biochemistry, School of Medicine, Kocaeli University, KocaeliTurkey
| | - Özgür Doğa ÖZSOY
- Department of Biochemistry, School of Medicine, Kocaeli University, KocaeliTurkey
| | - Esra TERZİ DEMİRSOY
- Department of Hematology, School of Medicine, Kocaeli University, KocaeliTurkey
| | - Özgür MEHTAP
- Department of Hematology, School of Medicine, Kocaeli University, KocaeliTurkey
| | - Ayfer GEDÜK
- Department of Hematology, School of Medicine, Kocaeli University, KocaeliTurkey
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17
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Affiliation(s)
- Jin Kyung Suh
- Department of Pediatrics, College of Medicine, Gachon University, Incheon, Korea
| | - In-sang Jeon
- Department of Pediatrics, College of Medicine, Gachon University, Incheon, Korea
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18
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Oikonomidou PR, Rivella S. What can we learn from ineffective erythropoiesis in thalassemia? Blood Rev 2018; 32:130-143. [PMID: 29054350 PMCID: PMC5882559 DOI: 10.1016/j.blre.2017.10.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 09/30/2017] [Accepted: 10/02/2017] [Indexed: 02/07/2023]
Abstract
Erythropoiesis is a dynamic process regulated at multiple levels to balance proliferation, differentiation and survival of erythroid progenitors. Ineffective erythropoiesis is a key feature of various diseases, including β-thalassemia. The pathogenic mechanisms leading to ineffective erythropoiesis are complex and still not fully understood. Altered survival and decreased differentiation of erythroid progenitors are both critical processes contributing to reduced production of mature red blood cells. Recent studies have identified novel important players and provided major advances in the development of targeted therapeutic approaches. In this review, β-thalassemia is used as a paradigmatic example to describe our current knowledge on the mechanisms leading to ineffective erythropoiesis and novel treatments that may have the potential to improve the clinical phenotype of associated diseases in the future.
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Affiliation(s)
- Paraskevi Rea Oikonomidou
- Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA.
| | - Stefano Rivella
- Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA; Cell and Molecular Biology Graduate Group (CAMB), University of Pennsylvania, Philadelphia, PA, USA.
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19
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Collins JF, Flores SR, Wang X, Anderson GJ. Mechanisms and Regulation of Intestinal Iron Transport. PHYSIOLOGY OF THE GASTROINTESTINAL TRACT 2018:1451-1483. [DOI: 10.1016/b978-0-12-809954-4.00060-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Friedrisch JR, Friedrisch BK. Prophylactic Iron Supplementation in Pregnancy: A Controversial Issue. BIOCHEMISTRY INSIGHTS 2017; 10:1178626417737738. [PMID: 29123406 PMCID: PMC5661664 DOI: 10.1177/1178626417737738] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 09/25/2017] [Indexed: 12/12/2022]
Abstract
In our world today, iron deficiency (ID) is the most frequent nutritional deficiency and it is being considered as an epidemic public health crisis. Women of reproductive age and infants are at particular risk of ID, especially in underdeveloped countries. During pregnancy, iron deficiency anemia is a specific risk factor associated with negative maternal and perinatal outcomes. Many countries have iron supplementation (IS) programs-as recommended by the World Health Organization-during pregnancy; however, IS clinical benefits and risks are unclear. This review aims to discuss the threats and benefits of routine IS on maternal and infant outcomes.
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Affiliation(s)
- João Ricardo Friedrisch
- Hematology and Bone Marrow Transplantation Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | - Bruno Kras Friedrisch
- Departamento de Biologia e Farmácia, Universidade de Santa Cruz do Sul (UNISC), Santa Cruz do Sul, Brazil
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21
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Reichert CO, da Cunha J, Levy D, Maselli LMF, Bydlowski SP, Spada C. Hepcidin: Homeostasis and Diseases Related to Iron Metabolism. Acta Haematol 2017; 137:220-236. [PMID: 28514781 DOI: 10.1159/000471838] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 03/20/2017] [Indexed: 12/14/2022]
Abstract
Iron is an essential metal for cell survival that is regulated by the peptide hormone hepcidin. However, its influence on certain diseases is directly related to iron metabolism or secondary to underlying diseases. Genetic alterations influence the serum hepcidin concentration, which can lead to an iron overload in tissues, as observed in haemochromatosis, in which serum hepcidin or defective hepcidin synthesis is observed. Another genetic imbalance of iron is iron-refractory anaemia, in which serum concentrations of hepcidin are increased, precluding the flow and efflux of extra- and intracellular iron. During the pathogenesis of certain diseases, the resulting oxidative stress, as well as the increase in inflammatory cytokines, influences the transcription of the HAMP gene to generate a secondary anaemia due to the increase in the serum concentration of hepcidin. To date, there is no available drug to inhibit or enhance hepcidin transcription, mostly due to the cytotoxicity described in the in vitro models. The proposed therapeutic targets are still in the early stages of clinical trials. Some candidates are promising, such as heparin derivatives and minihepcidins. This review describes the main pathways of systemic and genetic regulation of hepcidin, as well as its influence on the disorders related to iron metabolism.
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Affiliation(s)
- Cadiele Oliana Reichert
- Clinical Analysis Department, Health Sciences Center, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil
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22
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Abstract
There are numerous blood-based biomarkers for assessing iron stores, but all come with certain limitations. Hepcidin is a hormone primarily produced in the liver that has been proposed as the 'master regulator' of dietary uptake and iron metabolism, and has enormous potential to provide a 'real time' indicator of body iron levels. In this Minireview, the biochemical function of hepcidin in regulating iron levels will be discussed, with a specific focus on how hepcidin can aid in the assessment of iron stores and clinical diagnosis of iron deficiency, iron deficiency anaemia and other iron-related disorders. The role hepcidin itself plays in diseases of iron metabolism will be examined, and current efforts to translate hepcidin assays into the clinic will be critically appraised. Potential limitations of hepcidin as a marker of iron need will also be addressed, as well as the development of new therapies that directly target the hormone that sits atop the hierarchy of systemic iron metabolism.
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Affiliation(s)
- Dominic J Hare
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, Victoria 3052, Australia.
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23
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Markers of iron deficiency in patients with polycythemia vera receiving ruxolitinib or best available therapy. Leuk Res 2017; 56:52-59. [DOI: 10.1016/j.leukres.2017.01.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 12/27/2016] [Accepted: 01/27/2017] [Indexed: 11/22/2022]
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24
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Urrutia PJ, Hirsch EC, González-Billault C, Núñez MT. Hepcidin attenuates amyloid beta-induced inflammatory and pro-oxidant responses in astrocytes and microglia. J Neurochem 2017; 142:140-152. [PMID: 28266714 DOI: 10.1111/jnc.14005] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/27/2017] [Accepted: 02/06/2017] [Indexed: 12/30/2022]
Abstract
Alzheimer's disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal death. Aggregated amyloid-β (Aβ) induces inflammation and oxidative stress, which have pivotal roles in the pathogenesis of AD. Hepcidin is a key regulator of systemic iron homeostasis. Recently, an anti-inflammatory response to hepcidin was reported in macrophages. Under the hypothesis that hepcidin mediates anti-inflammatory response in the brain, in this study, we evaluated the putative anti-inflammatory role of hepcidin on Aβ-activated astrocytes and microglia. Primary culture of astrocytes and microglia were treated with Aβ, with or without hepcidin, and cytokine levels were then evaluated. In addition, the toxicity of Aβ-treated astrocyte- or microglia-conditioned media was tested on neurons, evaluating cellular death and oxidative stress generation. Finally, mice were injected in the right lateral ventricle with Aβ, with or without hepcidin, and hippocampus glial activation and oxidative stress were evaluated. Pre-treatment with hepcidin reduced the expression and secretion of TNF-α and IL-6 in astrocytes and microglia treated with Aβ. Hepcidin also reduced neurotoxicity and oxidative damage triggered by conditioned media obtained from astrocytes and microglia treated with Aβ. Stereotaxic intracerebral injection of hepcidin reduced glial activation and oxidative damage triggered by Aβ injection in mice. Overall, these results are consistent with the hypothesis that in astrocytes and microglia hepcidin down-regulates the inflammatory and pro-oxidant processes induced by Aβ, thus protecting neighboring neurons. This is a newly described property of hepcidin in the central nervous system, which may be relevant for the development of strategies to prevent the neurodegenerative process associated with AD.
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Affiliation(s)
- Pamela J Urrutia
- Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile
| | - Etienne C Hirsch
- Inserm, U 1127, Paris, France.,CNRS, UMR 7225, Paris, France.,Sorbonne Universités, UPMC Univ. Paris 06, UMR S 1127, Paris, France.,Institut du Cerveau et de la Moelle Epinière, ICM, Paris, France
| | - Christian González-Billault
- Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile.,Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.,The Buck Institute for Research on Aging, Novato, California, USA
| | - Marco T Núñez
- Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile
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25
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Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood 2017; 129:1823-1830. [PMID: 28188131 DOI: 10.1182/blood-2016-09-740092] [Citation(s) in RCA: 182] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 01/27/2017] [Indexed: 02/06/2023] Open
Abstract
Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Results from a phase 2 study for the treatment of MF with the Janus kinase 1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, which was unexpected for a JAK1/2 inhibitor, because erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease, we demonstrated that MMB treatment can normalize hemoglobin and red blood cell numbers. We found that this positive effect is driven by direct inhibition of the bone morphogenic protein receptor kinase activin A receptor, type I (ACVR1), and the subsequent reduction of hepatocyte hepcidin production. Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatment of MF, had no inhibitory activity on this pathway. Further, we demonstrated the effect of MMB is not mediated by direct inhibition of JAK2-mediated ferroportin (FPN1) degradation, because neither MMB treatment nor myeloid-specific deletion of JAK2 affected FPN1 expression. Our data support the hypothesis that the improvement of inflammatory anemia by MMB results from inhibition of ACVR1-mediated hepcidin expression in the liver, which leads to increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis.
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Abstract
Iron is an essential metal involved in several major cellular processes required to maintain life. Because of iron's ability to cause oxidative damage, its transport, metabolism, and storage is strictly controlled in the body, especially in the small intestine, liver, and kidney. Iron plays a major role in acute kidney injury and has been a target for therapeutic intervention. However, the therapies that have been effective in animal models of acute kidney injury have not been successful in human beings. Targeting iron trafficking via ferritin, ferroportin, or hepcidin may offer new insights. This review focuses on the biology of iron, particularly in the kidney, and its implications in acute kidney injury.
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Affiliation(s)
- Vyvyca J Walker
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Anupam Agarwal
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Birmingham Veterans Administration Medical Center, Birmingham, AL.
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Identification of Guanosine 5'-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway. Sci Rep 2017; 7:40097. [PMID: 28054602 PMCID: PMC5214259 DOI: 10.1038/srep40097] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 12/01/2016] [Indexed: 12/16/2022] Open
Abstract
Hepcidin, a peptide hormone, is a key regulator in mammalian iron homeostasis. Increased level of hepcidin due to inflammatory conditions stimulates the ferroportin (FPN) transporter internalization, impairing the iron absorption; clinically manifested as anemia of inflammation (AI). Inhibiting hepcidin-mediated FPN degradation is proposed as an important strategy to combat AI. A systematic approach involving in silico, in vitro, ex vivo and in vivo studies is employed to identify hepcidin-binding agents. The virtual screening of 68,752 natural compounds via molecular docking resulted into identification of guanosine 5′-diphosphate (GDP) as a promising hepcidin-binding agent. The molecular dynamics simulations helped to identify the important hepcidin residues involved in stabilization of hepcidin-GDP complex. The results gave a preliminary indication that GDP may possibly inhibit the hepcidin-FPN interactions. The in vitro studies revealed that GDP caused FPN stabilization (FPN-GFP cell lines) and increased the FPN-mediated cellular iron efflux (HepG2 and Caco-2 cells). Interestingly, the co-administration of GDP and ferrous sulphate (FeSO4) ameliorated the turpentine-induced AI in mice (indicated by increased haemoglobin level, serum iron, FPN expression and decreased ferritin level). These results suggest that GDP a promising natural small-molecule inhibitor that targets Hepcidin-FPN complex may be incorporated with iron supplement regimens to ameliorate AI.
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28
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Winton EF, Kota V. Momelotinib in myelofibrosis: JAK1/2 inhibitor with a role in treating and understanding the anemia. Future Oncol 2016; 13:395-407. [PMID: 27785927 DOI: 10.2217/fon-2016-0417] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Myelofibrosis (MF) is a chronic malignancy of the blood-forming system caused by hyperactivation of JAK2/STAT signaling pathway. Small-molecule inhibitors of JAK2 can variably ameliorate MF-related symptoms caused by chronic inflammation and hepatosplenomegaly. Anemia is a significant problem and adverse prognostic factor in over a third of MF patients and is often worsened by JAK2 inhibitors. The JAK1/2 inhibitor momelotinib unexpectedly resulted in reduction of anemia in MF patients during Phase I/II trials. Current Phase III trials will be the basis for seeking regulatory approval of momelotinib during 2017. Studies to determine how momelotinib improves anemia are underway, potentially leading to expanded momelotinib use and/or development of other targeted therapies for treating anemia in MF and related diseases.
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Affiliation(s)
- Elliott F Winton
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Vamsi Kota
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
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Bergamaschi G, Di Sabatino A, Pasini A, Ubezio C, Costanzo F, Grataroli D, Masotti M, Alvisi C, Corazza GR. Intestinal expression of genes implicated in iron absorption and their regulation by hepcidin. Clin Nutr 2016; 36:1427-1433. [PMID: 27729173 DOI: 10.1016/j.clnu.2016.09.021] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 06/16/2016] [Accepted: 09/23/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Through inhibition of iron absorption and iron mobilization from tissue stores, hepcidin exerts a negative control on iron homeostasis. Hepcidin, in fact, promotes the degradation of ferroportin (Fpn1), the iron exporter molecule expressed on the membrane of hepatocytes and macrophages, thus preventing iron release from cells to plasma. Hepcidin effects on enterocytes, however, are less clear. Aim of the present study was to further investigate the regulation of iron absorption by hepcidin. METHODS The transcriptional response of human duodenal mucosa to hepcidin was investigated using organ cultures of duodenal biopsies perendoscopically collected from healthy controls. Biopsies were cultured for 4 h with or without hepcidin-25 and were then assayed for the expression of iron-related genes. RESULTS In samples that had not been exposed to hepcidin, correlations were found between the expression of genes involved in iron absorption: DMT1, Fpn1, Dcytb and HCP1. In ex vivo experiments hepcidin down-regulated mRNA levels of the iron transporters Fpn1, and DMT1, of the ferric reductase Dcytb, of the ferroxidase hephaestin, and of the putative heme carrier protein HCP1. CONCLUSIONS Through the reported transcriptional changes hepcidin can modulate several steps of the iron absorption process, including the reduction of dietary iron by Dcytb, its uptake by enterocytes through DMT1, the mucosal uptake of heme iron by HCP1, and enterocyte iron release to plasma by Fpn1 in conjunction with hephaestin.
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Affiliation(s)
- Gaetano Bergamaschi
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Antonio Di Sabatino
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Alessandra Pasini
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Cristina Ubezio
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Filippo Costanzo
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Davide Grataroli
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Michela Masotti
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Costanza Alvisi
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Gino R Corazza
- Department of Internal Medicine, University of Pavia Medical School, and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
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Carreau N, Tremblay D, Savona M, Kremyanskaya M, Mascarenhas J. Ironing out the details of iron overload in myelofibrosis: Lessons from myelodysplastic syndromes. Blood Rev 2016; 30:349-56. [DOI: 10.1016/j.blre.2016.04.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 04/04/2016] [Accepted: 04/12/2016] [Indexed: 12/18/2022]
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Chiang S, Kovacevic Z, Sahni S, Lane DJR, Merlot AM, Kalinowski DS, Huang MLH, Richardson DR. Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia. Clin Sci (Lond) 2016; 130:853-70. [PMID: 27129098 DOI: 10.1042/cs20160072] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 02/16/2016] [Indexed: 12/19/2022]
Abstract
The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron-sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.
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Affiliation(s)
- Shannon Chiang
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Sumit Sahni
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Darius J R Lane
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Angelica M Merlot
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Danuta S Kalinowski
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Michael L-H Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia )
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia )
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Koduru P, Abraham BP. The role of ferric carboxymaltose in the treatment of iron deficiency anemia in patients with gastrointestinal disease. Therap Adv Gastroenterol 2016; 9:76-85. [PMID: 26770269 PMCID: PMC4699280 DOI: 10.1177/1756283x15616577] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Iron deficiency anemia (IDA) is the most common form of nutritional anemia worldwide. Iron plays a pivotal role in vital functioning of almost every organ system. IDA affects both physical and psychological functioning of humans. Oral iron is considered as first-line therapy for the treatment of IDA due to low cost, good safety profile and ease of administration. However, the absorption of oral iron is affected by several factors and incidence of gastrointestinal side effects can lead to lack of adherence to therapy as well as poor efficacy. This has led to the emergence of intravenous iron therapy which is clearly superior to oral iron with higher increment of hemoglobin levels and rapid replenishment of iron stores. Ferric carboxymaltose (FCM) is a novel non-dextran intravenous iron form which has been approved for use in patients with iron deficiency who have had inadequate response to oral iron therapy, intolerance to oral iron, or nondialysis-dependent chronic kidney disease. The safety and efficacy of using FCM for the treatment of IDA has been demonstrated in several clinical trials. One dose can provide a large amount of iron and has a very short infusion time. It should be considered as first-line therapy in patients with active inflammation like inflammatory bowel disease when gastrointestinal absorption of oral iron may be compromised. It should also be given to patients who have inadequate response to oral iron therapy. It has been shown to be noninferior to other intravenous iron formulations with a good safety profile and produced fewer anaphylactic reactions.
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Affiliation(s)
- Pramoda Koduru
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, TX, USA
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Oh S, Shin PK, Chung J. Effects of developmental iron deficiency and post-weaning iron repletion on the levels of iron transporter proteins in rats. Nutr Res Pract 2015; 9:613-8. [PMID: 26634050 PMCID: PMC4667202 DOI: 10.4162/nrp.2015.9.6.613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 08/13/2015] [Accepted: 08/19/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/OBJECTIVES Iron deficiency in early life is associated with developmental problems, which may persist until later in life. The question of whether iron repletion after developmental iron deficiency could restore iron homeostasis is not well characterized. In the present study, we investigated the changes of iron transporters after iron depletion during the gestational-neonatal period and iron repletion during the post-weaning period. MATERIALS/METHODS Pregnant rats were provided iron-deficient (< 6 ppm Fe) or control (36 ppm Fe) diets from gestational day 2. At weaning, pups from iron-deficient dams were fed either iron-deficient (ID group) or control (IDR group) diets for 4 week. Pups from control dams were continued to be fed with the control diet throughout the study period (CON). RESULTS Compared to the CON, ID rats had significantly lower hemoglobin and hematocrits in the blood and significantly lower tissue iron in the liver and spleen. Hepatic hepcidin and BMP6 mRNA levels were also strongly down-regulated in the ID group. Developmental iron deficiency significantly increased iron transporters divalent metal transporter 1 (DMT1) and ferroportin (FPN) in the duodenum, but decreased DMT1 in the liver. Dietary iron repletion restored the levels of hemoglobin and hematocrit to a normal range, but the tissue iron levels and hepatic hepcidin mRNA levels were significantly lower than those in the CON group. Both FPN and DMT1 protein levels in the liver and in the duodenum were not different between the IDR and the CON. By contrast, DMT1 in the spleen was significantly lower in the IDR, compared to the CON. The splenic FPN was also decreased in the IDR more than in the CON, although the difference did not reach statistical significance. CONCLUSIONS Our findings demonstrate that iron transporter proteins in the duodenum, liver and spleen are differentially regulated during developmental iron deficiency. Also, post-weaning iron repletion efficiently restores iron transporters in the duodenum and the liver but not in the spleen, which suggests that early-life iron deficiency may cause long term abnormalities in iron recycling from the spleen.
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Affiliation(s)
- Sugyoung Oh
- Department of Food and Nutrition, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
| | - Pill-Kyung Shin
- Department of Food and Nutrition, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
| | - Jayong Chung
- Department of Food and Nutrition, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
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Abstract
Maintaining physiologic iron concentrations in tissues is critical for metabolism and host defense. Iron absorption in the duodenum, recycling of iron from senescent erythrocytes, and iron mobilization from storage in macrophages and hepatocytes constitute the major iron flows into plasma for distribution to tissues, predominantly for erythropoiesis. All iron transfer to plasma occurs through the iron exporter ferroportin. The concentration of functional membrane-associated ferroportin is controlled by its ligand, the iron-regulatory hormone hepcidin, and fine-tuned by regulatory mechanisms serving iron homeostasis, oxygen utilization, host defense, and erythropoiesis. Fundamental questions about the structure and biology of ferroportin remain to be answered.
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35
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Kaitha S, Bashir M, Ali T. Iron deficiency anemia in inflammatory bowel disease. World J Gastrointest Pathophysiol 2015. [PMID: 26301120 DOI: 10.4291/wjgp.v6.i3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD) and is frequently overlooked as a complication. Patients with IBD are commonly found to have iron deficiency anemia (IDA) secondary to chronic blood loss, and impaired iron absorption due to tissue inflammation. Patients with iron deficiency may not always manifest with signs and symptoms; so, hemoglobin levels in patients with IBD must be regularly monitored for earlier detection of anemia. IDA in IBD is associated with poor quality of life, necessitating prompt diagnosis and appropriate treatment. IDA is often associated with inflammation in patients with IBD. Thus, commonly used laboratory parameters are inadequate to diagnose IDA, and newer iron indices, such as reticulocyte hemoglobin content or percentage of hypochromic red cells or zinc protoporphyrin, are required to differentiate IDA from anemia of chronic disease. Oral iron preparations are available and are used in patients with mild disease activity. These preparations are inexpensive and convenient, but can produce gastrointestinal side effects, such as abdominal pain and diarrhea, that limit their use and patient compliance. These preparations are partly absorbed due to inflammation. Non-absorbed iron can be toxic and worsen IBD disease activity. Although cost-effective intravenous iron formulations are widely available and have improved safety profiles, physicians are reluctant to use them. We present a review of the pathophysiologic mechanisms of IDA in IBD, improved diagnostic and therapeutic strategies, efficacy, and safety of iron replacement in IBD.
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Affiliation(s)
- Sindhu Kaitha
- Sindhu Kaitha, Tauseef Ali, Department of Medicine, Section of Gastroenterology, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, United States
| | - Muhammad Bashir
- Sindhu Kaitha, Tauseef Ali, Department of Medicine, Section of Gastroenterology, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, United States
| | - Tauseef Ali
- Sindhu Kaitha, Tauseef Ali, Department of Medicine, Section of Gastroenterology, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, United States
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Kaitha S, Bashir M, Ali T. Iron deficiency anemia in inflammatory bowel disease. World J Gastrointest Pathophysiol 2015; 6:62-72. [PMID: 26301120 PMCID: PMC4540708 DOI: 10.4291/wjgp.v6.i3.62] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 05/09/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD) and is frequently overlooked as a complication. Patients with IBD are commonly found to have iron deficiency anemia (IDA) secondary to chronic blood loss, and impaired iron absorption due to tissue inflammation. Patients with iron deficiency may not always manifest with signs and symptoms; so, hemoglobin levels in patients with IBD must be regularly monitored for earlier detection of anemia. IDA in IBD is associated with poor quality of life, necessitating prompt diagnosis and appropriate treatment. IDA is often associated with inflammation in patients with IBD. Thus, commonly used laboratory parameters are inadequate to diagnose IDA, and newer iron indices, such as reticulocyte hemoglobin content or percentage of hypochromic red cells or zinc protoporphyrin, are required to differentiate IDA from anemia of chronic disease. Oral iron preparations are available and are used in patients with mild disease activity. These preparations are inexpensive and convenient, but can produce gastrointestinal side effects, such as abdominal pain and diarrhea, that limit their use and patient compliance. These preparations are partly absorbed due to inflammation. Non-absorbed iron can be toxic and worsen IBD disease activity. Although cost-effective intravenous iron formulations are widely available and have improved safety profiles, physicians are reluctant to use them. We present a review of the pathophysiologic mechanisms of IDA in IBD, improved diagnostic and therapeutic strategies, efficacy, and safety of iron replacement in IBD.
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37
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Nakanishi T, Hasuike Y, Nanami M, Yahiro M, Kuragano T. Novel iron-containing phosphate binders and anemia treatment in CKD: oral iron intake revisited. Nephrol Dial Transplant 2015; 31:1588-94. [PMID: 26142396 DOI: 10.1093/ndt/gfv268] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 06/05/2015] [Indexed: 01/01/2023] Open
Abstract
Recent reports have shown that novel phosphate binders containing iron are not only efficacious for the treatment of hyperphosphatemia but also may reduce the need for erythropoiesis-stimulating agents and intravenous (IV) iron for anemia management in patients on maintenance hemodialysis (MHD). Possible healthcare cost savings, which have not been demonstrated in a long-term study, may be an additional advantage of using such multi-pronged treatment strategies for the control of both hyperphosphatemia and iron needs. It is currently assumed that oral iron supplementation is less efficient than the IV route in patients with chronic kidney disease (CKD). The unexpected efficacy of novel iron-containing phosphate binders, such as ferric citrate, in repleting insufficient iron stores and improving the anemia of CKD could change this view. Previous assumptions of self-controlled iron uptake by 'mucosal block' or hepcidin, or else by impaired intestinal iron absorption due to CKD-associated inflammation cannot be reconciled with recent observations of the effects of ferric citrate administration. Citrate in the intestinal lumen may partly contribute to the acceleration of iron absorption. Animal experiments and clinical studies have also shown that oral iron overload can cause excessive iron accumulation despite high hepcidin levels, which are not able to block iron absorption completely. However, like with IV iron agents, no long-term safety data exist with respect to the effects of iron-containing phosphate binders on 'hard' patient outcomes. Future randomized prospective studies in patients with CKD are necessary to establish the safety of oral iron-containing phosphate binders for the control of both hyperphosphatemia and renal anemia.
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Affiliation(s)
- Takeshi Nakanishi
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yukiko Hasuike
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masayoshi Nanami
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mana Yahiro
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takahiro Kuragano
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nishinomiya, Japan
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Chen B, Li GF, Shen Y, Huang XI, Xu YJ. Reducing iron accumulation: A potential approach for the prevention and treatment of postmenopausal osteoporosis. Exp Ther Med 2015; 10:7-11. [PMID: 26170904 DOI: 10.3892/etm.2015.2484] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 04/27/2015] [Indexed: 01/21/2023] Open
Abstract
Postmenopausal osteoporosis (PMOP) is a systemic bone metabolism disease, characterized by progressive bone loss following menopause and a subsequent increase in fracture risk. Estrogen deficiency as a result of menopause is known to increase bone resorption and accelerate bone loss. Furthermore, postmenopausal women may exhibit iron accumulation, in addition to estrogen deficiency. Elevated iron levels are a risk factor for PMOP in postmenopausal women, and reducing the iron overload has been demonstrated to benefit bone cell metabolism in vitro and improve the bone in vivo by normalizing osteoclastic bone resorption and formation. The identification of hepcidin was a key development in the field of iron metabolism in the previous decade. We hypothesize that hepcidin may aid in the prevention and treatment of PMOP due to its capacity to control body iron stores and its intrinsic effects on osteoblast function. The aim of the current review was to highlight the role of iron accumulation in the pathogenesis of PMOP and to evaluate the possible use of hepcidin as a potential therapy for this condition.
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Affiliation(s)
- Bin Chen
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Guang-Fei Li
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Ying Shen
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - X I Huang
- Division of Rheumatology, NYU Hospital for Joint Diseases, New York, NY 10003, USA
| | - You-Jia Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
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Kong WN, Wu Q, Shen D, Zhao SE, Guo P, Duan XL, Chang YZ. Age-dependent expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, and hephaestin in the duodenum of rats. J Gastroenterol Hepatol 2015; 30:513-20. [PMID: 25318588 DOI: 10.1111/jgh.12830] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/12/2014] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND AIM The body's requirement for iron is different at different developmental stages. However, the molecular mechanisms of age-dependent iron metabolism are poorly understood. In the present study, we investigated the expression of iron transport proteins in the duodenum of Sprague-Dawley rats at five different age stages. METHODS Male Sprague-Dawley rats at postnatal week (PNW) 1, 3, 12, 44, and 88 were employed in the study. Serum iron status and tissue non-heme iron concentrations in the spleen, liver, bone marrow, heart, kidney, duodenal epithelium, and gastrocnemius were examined at each age stage. The expression of duodenal cytochrome b (DcytB), divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), hephaestin, and hepcidin were measured by real-time polymerase chain reaction or Western blot. RESULTS The levels of serum iron and transferrin saturation were higher in the rats at PNW1 and 3 than in those at PNW12, 44, and 88. Non-heme iron contents decreased from PNW1 to PNW3 and then increased thereafter. Duodenal DcytB, DMT1, and FPN1 increased to the highest level at PNW3 and then decreased from PNW12 to 88. The hepatic hepcidin mRNA level decreased to the lowest level at PNW3 and then increased with age. CONCLUSION Our findings showed that age had a significant effect on body iron status. The increased duodenal DcytB, DMT1, and FPN1 expression can enhance intestinal iron absorption to meet the high iron requirements in infants. Hepcidin or enterocyte iron levels may be involved in the regulation of age-dependent FPN1, DMT1, and DcytB expression in the duodenum.
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Affiliation(s)
- Wei-Na Kong
- Laboratory of Molecular Iron Metabolism, College of Life Science, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Hebei Normal University, Shijiazhuang, Hebei Province, China; Bioreactor and Protein Drug Research and Development Center of Hebei Universities, Hebei Chemical and Pharmaceutical College, Shijiazhuang, Hebei Province, China
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The iron-regulatory hormone hepcidin: A possible therapeutic target? Pharmacol Ther 2015; 146:35-52. [DOI: 10.1016/j.pharmthera.2014.09.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 09/02/2014] [Indexed: 01/19/2023]
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41
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Seo YA, Lee S, Hennigar SR, Kelleher SL. Prolactin (PRL)-stimulated ubiquitination of ZnT2 mediates a transient increase in zinc secretion followed by ZnT2 degradation in mammary epithelial cells. J Biol Chem 2014; 289:23653-61. [PMID: 25016022 DOI: 10.1074/jbc.m113.531145] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The zinc transporter ZnT2 imports zinc into secretory vesicles and regulates zinc export from the mammary epithelial cell. Mutations in ZnT2 substantially impair zinc secretion into milk. The lactogenic hormone prolactin (PRL) transcriptionally increases ZnT2 expression through the Jak2/STAT5 signaling pathway, increasing zinc accumulation in secretory vesicles and zinc secretion. Herein, we report that PRL post-translationally stimulated ZnT2 ubiquitination, which altered ZnT2 trafficking and augmented vesicular zinc accumulation and secretion from mammary epithelial cells in a transient manner. Ubiquitination then down-regulated zinc secretion by stimulating degradation of ZnT2. Mutagenesis of two N-terminal lysine residues (K4R and K6R) inhibited ZnT2 ubiquitination, vesicular zinc accumulation and secretion, and protein degradation. These findings establish that PRL post-translationally regulates ZnT2-mediated zinc secretion in a multifactorial manner, first by enhancing zinc accumulation in vesicles to transiently enhance zinc secretion and then by activating ubiquitin-dependent ZnT2 degradation. This provides insight into novel mechanisms through which ZnT2 and zinc transport is tightly regulated in mammary epithelial cells.
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Affiliation(s)
- Young Ah Seo
- the Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and the Departments of Genetics and Complex Diseases and Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115
| | - Sooyeon Lee
- the Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and From the Departments of Cell and Molecular Physiology
| | - Stephen R Hennigar
- the Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and
| | - Shannon L Kelleher
- the Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and From the Departments of Cell and Molecular Physiology, Pharmacology, and Surgery, Penn State Hershey College of Medicine, Hershey, Pennsylvania 17033,
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42
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Musci G, Polticelli F, Bonaccorsi di Patti MC. Ceruloplasmin-ferroportin system of iron traffic in vertebrates. World J Biol Chem 2014; 5:204-215. [PMID: 24921009 PMCID: PMC4050113 DOI: 10.4331/wjbc.v5.i2.204] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 02/19/2014] [Indexed: 02/05/2023] Open
Abstract
Safe trafficking of iron across the cell membrane is a delicate process that requires specific protein carriers. While many proteins involved in iron uptake by cells are known, only one cellular iron export protein has been identified in mammals: ferroportin (SLC40A1). Ceruloplasmin is a multicopper enzyme endowed with ferroxidase activity that is found as a soluble isoform in plasma or as a membrane-associated isoform in specific cell types. According to the currently accepted view, ferrous iron transported out of the cell by ferroportin would be safely oxidized by ceruloplasmin to facilitate loading on transferrin. Therefore, the ceruloplasmin-ferroportin system represents the main pathway for cellular iron egress and it is responsible for physiological regulation of cellular iron levels. The most recent findings regarding the structural and functional features of ceruloplasmin and ferroportin and their relationship will be described in this review.
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43
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Kong WN, Lei YH, Chang YZ. The regulation of iron metabolism in the mononuclear phagocyte system. Expert Rev Hematol 2014; 6:411-8. [PMID: 23991927 DOI: 10.1586/17474086.2013.814840] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The daily iron absorption and loss are small and iron metabolism in human is characterized by a limited external exchange and by an efficient reutilization of iron from internal sources. The mononuclear phagocyte system (MPS) plays a key role in recycling iron from hemoglobin of senescent or damaged erythrocytes, which is important in maintaining iron homeostasis. Many iron-related proteins are expressed in the MPS, including heme oxygenase (HO) for heme degradation, the iron importer transferrin receptor 1 (TfR1) and divalent metal transport 1 (DMT1), the iron exporter ferroportin 1 (FPN1) and the iron regulatory hormone hepcidin. Insights into the regulatory mechanisms that control the regulation of iron metabolism proteins in the MPS will deepen our understanding about the molecular mechanism of iron homeostasis and iron-related diseases.
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Affiliation(s)
- Wei-Na Kong
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, P. R. China
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44
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Abstract
β-thalassemia is an inherited disorder due to mutations found in the β-globin gene, leading to anemia and requiring sporadic or chronic blood transfusions for survival. Without proper chelation, β-thalassemia results in iron overload. Ineffective erythropoiesis can lead to iron overload even in untransfused patients who are affected by β-thalassemia intermedia. Better understanding of the molecular biologic aspects of this disorder has led to improvements in population screening and prenatal diagnosis, which, in turn, have led to dramatic reductions in the number of children born with β-thalassemia major in the Mediterranean littoral. However, as a consequence of decreases in neonatal and childhood mortality in other geographical areas, β-thalassemia has become a worldwide clinical problem. A number of unsolved pathophysiological issues remain, such as ineffective erythropoieis, abnormal iron absorption, oxidative stress, splenomegaly and thrombosis. In the last few years, novel studies have the potential to introduce new therapeutic approaches that might reduce these problems and limit the need for blood transfusion.
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Affiliation(s)
- Stefano Rivella
- Weill College Medical Center, Department of Pediatrics, Division of Hematology, Oncology, 515 E 71st Street, S702, New York, NY 10021, USA, Tel.: +1 212 746 4941, ,
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45
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A systems biology approach to iron metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 844:201-25. [PMID: 25480643 DOI: 10.1007/978-1-4939-2095-2_10] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Iron is critical to the survival of almost all living organisms. However, inappropriately low or high levels of iron are detrimental and contribute to a wide range of diseases. Recent advances in the study of iron metabolism have revealed multiple intricate pathways that are essential to the maintenance of iron homeostasis. Further, iron regulation involves processes at several scales, ranging from the subcellular to the organismal. This complexity makes a systems biology approach crucial, with its enabling technology of computational models based on a mathematical description of regulatory systems. Systems biology may represent a new strategy for understanding imbalances in iron metabolism and their underlying causes.
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46
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Abstract
Iron is an essential nutrient that is tightly regulated. A principal function of the liver is the regulation of iron homeostasis. The liver senses changes in systemic iron requirements and can regulate iron concentrations in a robust and rapid manner. The last 10 years have led to the discovery of several regulatory mechanisms in the liver that control the production of iron regulatory genes, storage capacity, and iron mobilization. Dysregulation of these functions leads to an imbalance of iron, which is the primary cause of iron-related disorders. Anemia and iron overload are two of the most prevalent disorders worldwide and affect over a billion people. Several mutations in liver-derived genes have been identified, demonstrating the central role of the liver in iron homeostasis. During conditions of excess iron, the liver increases iron storage and protects other tissues, namely, the heart and pancreas from iron-induced cellular damage. However, a chronic increase in liver iron stores results in excess reactive oxygen species production and liver injury. Excess liver iron is one of the major mechanisms leading to increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.
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Affiliation(s)
- Erik R Anderson
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
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47
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Le Gac G, Ka C, Joubrel R, Gourlaouen I, Lehn P, Mornon JP, Férec C, Callebaut I. Structure-function analysis of the human ferroportin iron exporter (SLC40A1): effect of hemochromatosis type 4 disease mutations and identification of critical residues. Hum Mutat 2013; 34:1371-80. [PMID: 23784628 DOI: 10.1002/humu.22369] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 06/06/2013] [Indexed: 11/06/2022]
Abstract
Ferroportin (SLC40A1) is the only known iron exporter in mammals and is considered a key coordinator of the iron balance between intracellular and systemic iron homeostasis. However, the structural organization of ferroportin in the lipid bilayer remains controversial and very little is known about the mechanism underlying iron egress. In the present study, we have developed an approach based on comparative modeling, which has led to the construction of a model of the three-dimensional (3D) structure of ferroportin by homology to the crystal structure of a Major Facilitator Superfamily member (EmrD). This model predicts atomic details for the organization of ferroportin transmembrane helices and is in agreement with our current understanding of the ferroportin function and its interaction with hepcidin. Using in vitro experiments, we demonstrate that this model can be used to identify novel critical amino acids. In particular, we show that the tryptophan residue 42 (p.Trp42), which is localized within the extracellular end of the ferroportin pore, is likely involved in both the iron export function and in the mechanism of inhibition by hepcidin. Thus, our 3D model provides a new perspective for understanding the molecular basis of ferroportin functions and dysfunctions.
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Affiliation(s)
- Gérald Le Gac
- Inserm UMR1078, Université de Brest, SFR SnInBioS, Centre Hospitalier Régional Universitaire - Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Etablissement Français du Sang - Bretagne, Brest, France
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48
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Tarkun P, Mehtap O, Atesoğlu EB, Geduk A, Musul MM, Hacihanefioglu A. Serum hepcidin and growth differentiation factor-15 (GDF-15) levels in polycythemia vera and essential thrombocythemia. Eur J Haematol 2013; 91:228-235. [PMID: 23731455 DOI: 10.1111/ejh.12150] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2013] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Hepcidin plays a regulatory role in systemic iron homeostasis. GDF-15 has been found to be expressed from matured erythroblasts and very high levels of GDF-15 suppresses hepcidin secretion. In this study, we evaluated hepcidin and GDF-15 levels in polycythemia vera (PV) and essential thrombocythemia (ET). METHODS The study included 29 patients and 21 healthy controls. The patient group included 13 patients with ET and 16 patients with PV. Serum hepcidin and GDF-15 levels were measured at the time of diagnosis, before the initiation of any therapy. RESULTS Hepcidin levels did not differ significantly in patients with chronic myeloproliferative disease (CMPD) and healthy controls. However, GDF-15 levels were significantly increased in patients with CMPD (P = 0.038). No difference could be found between patients with PV and ET in terms of hepcidin and GDF-15 levels. Patients with JAK2-V617F mutation had increased GDF-15 levels when compared with patients without this mutation (P: 0.006). CONCLUSIONS The levels of GDF-15 were higher in CMPD, which are characterized by increased erythropoiesis, and this effect was more pronounced particularly in individuals with JAK2-V617F mutation. Hepcidin levels were not suppressed despite the increased erythroid activity and GDF-15 levels may be protective against the clinical complications of the disease such as thrombosis. This study revealed that, hepcidin levels were not suppressed despite increased erythroid activity and high GDF-15 levels in CMPD. We hypothesized that, this may be an attempt to prevent further amplification of erythropoietic activity by reducing iron utilization.
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Affiliation(s)
- Pinar Tarkun
- Department of Hematology, Medical Faculty, Kocaeli University, Kocaeli, Turkey
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49
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Paesano R, Natalizi T, Berlutti F, Valenti P. Body iron delocalization: the serious drawback in iron disorders in both developing and developed countries. Pathog Glob Health 2013; 106:200-16. [PMID: 23265420 DOI: 10.1179/2047773212y.0000000043] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Over 2 billion people in both developing as well as developed countries - over 30% of the world's population - are anaemic. With the classical preconception that oral iron administration or the intake of foods rich in iron increase haemoglobin concentration and reduce the prevalence of anaemia, specific programs have been designed, but iron supplementations have been less effective than expected. Of note, this hazardous simplification on iron status neglects its distribution in the body. The correct balance of iron, defined iron homeostasis, involves a physiological ratio of iron between tissues/secretions and blood, thus avoiding its delocalization as iron accumulation in tissues/secretions and iron deficiency in blood. Changes in iron status can affect the inflammatory response in multiple ways, particularly in the context of infection, an idea that is worth remembering when considering the value of iron supplementation in areas of the world where infections are highly prevalent. The enhanced availability of free iron can increase susceptibility and severity of microbial and parasitic infections. The discovery of the hepcidin-ferroportin (Fpn) complex, which greatly clarified the enigmatic mechanism that supervises the iron homeostasis, should prompt to a critical review on iron supplementation, ineffective on the expression of the most important proteins of iron metabolism. Therefore, it is imperative to consider new safe and efficient therapeutic interventions to cure iron deficiency (ID) and ID anaemia (IDA) associated or not to the inflammation. In this respect, lactoferrin (Lf) is emerging as an important regulator of both iron and inflammatory homeostasis. Oral administration of Lf in subjects suffering of ID and IDA is safe and effective in significantly increasing haematological parameters and contemporary decreasing serum IL-6 levels, thus restoring iron localization through the direct or indirect modulation of hepcidin and ferroportin synthesis. Of note, the nuclear localization of Lf suggests that this molecule may be involved in the transcriptional regulation of some genes of host inflammatory response. We recently also reported that combined administration of oral and intravaginal Lf on ID and IDA pregnant women with preterm delivery threat, significantly increased haematological parameters, reduced IL-6 levels in both serum and cervicovaginal fluid, cervicovaginal prostaglandin PGF2α, and suppressed uterine contractility. Moreover, Lf combined administration blocked further the shortening of cervical length and the increase of foetal fibronectin, thus prolonging the length of pregnancy until the 37th-38th week of gestation. These new Lf functions effective in curing ID and IDA through the restoring of iron and inflammatory homeostasis and in preventing preterm delivery, could have a great relevance in developing countries, where ID and IDA and inflammation-associated anaemia represent the major risk factors of preterm delivery and maternal and neonatal death.
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Affiliation(s)
- R Paesano
- Department of Woman Health and Territorial Medicine, Sapienza University of Rome, Italy
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50
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Treon SP, Tripsas CK, Ciccarelli BT, Manning RJ, Patterson CJ, Sheehy P, Hunter ZR. Patients with Waldenström macroglobulinemia commonly present with iron deficiency and those with severely depressed transferrin saturation levels show response to parenteral iron administration. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2013; 13:241-3. [PMID: 23523274 DOI: 10.1016/j.clml.2013.02.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Anemia often prompts therapy in Waldenström macroglobulinemia (WM), although is not fully explained by bone marrow disease involvement in many patients. Hepcidin regulates gut absorption and distribution of iron and is elevated and associated with anemia in WM. Since hepcidin evaluation remains experimental, we initiated an American Board of Internal Medicine (ABIM) practice improvement project to determine baseline transferrin saturation (TSAT) levels in untreated anemic patients with WM. Among 108 patients with WM evaluated, 56 (52%) had a TSAT level ≤ 20%, which included 25 (23%) patients with severely depressed TSAT levels (≤ 10%). Sixteen patients with TSAT levels ≤ 10% received parenteral iron, and 14 of these patients showed improved hematocrit values (28.75% to 32.75%; P < .0001), mean corpuscular volume (MCV) (84.7 to 89.9; P = .006), and TSAT levels (8.1% to 21.2%; P < .0001). Anemia in 8 of these patients was previously refractory to oral iron therapy. Routine screening of iron saturation levels may therefore identify patients with WM and severe iron deficiency who may be candidates for parenteral iron therapy.
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Affiliation(s)
- Steven P Treon
- Bing Center for Waldenström's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA 02115, USA.
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