DOCSLIB.ORG

1 Expression of the Iron Exporter Ferroportin In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1 Expression of the Iron Exporter Ferroportin In EXPRESSION OF THE IRON EXPORTER FERROPORTIN IN RESPONSE TO COPPER DEFICIENCY AND IRON LOADING By SUPAK JENKITKASEMWONG A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2009 1 © 2009 Supak Jenkitkasemwong 2 To my wonderful family, with their great love and support, making this milestone possible 3 ACKNOWLEDGMENTS I first would like to acknowledge my major advisor Dr.Mitchell Knutson who gave me this fantastic opportunity to gain research experience in the nutrition field in his laboratory. It is because of his constant support and advice that made this project possible. I will never be able to convey my full gratitude to him for being such a great mentor both academically and socially. I truly thank Dr. Joseph Prohaska for his collaboration through providing tremendous resources for the current research. I thank my committee members (Dr. Jesse Gregory and Dr. Thomas Yang) for their advice and their making this thesis a success. I thank my lab members (Hyeyoung Nam, Ning Ning Zhao, Sukru Gulec, Chia Yu Wang, Joeva Hepburn and others) for their assistance, suggestions, and good times. I would also like to thank all my previous mentors who, I believe, contribute to my accomplishment one way or another. I thank Adulphan Youngmod and Siraporn Treerattanaphan who are always there supporting me throughout the good and bad times. Last but not least, I gratefully thank my parents, my brother, and my lovely aunt for their love and being my constant source of inspirations. 4 TABLE OF CONTENTS page ACKNOWLEDGEMENTS .............................................................................................................4 LIST OF TABLES ...........................................................................................................................7 LIST OF FIGURES .........................................................................................................................8 ABSTRACT .....................................................................................................................................9 CHAPTER 1 INTRODUCTION ..................................................................................................................11 2 LITERATURE REVIEW .......................................................................................................13 Introduction to Copper ............................................................................................................13 Copper Homeostasis ...............................................................................................................13 Copper Absorption ..........................................................................................................13 Copper Transport and Cellular Uptake ............................................................................16 Copper Excretion .............................................................................................................18 Copper Intake and Requirement.......................................................................................19 Copper Imbalance: Deficiency and Overload ..................................................................19 Effect of Copper Deficiency on Iron Metabolism ..................................................................20 Ferroportin: the only Known Iron Transporter in Mammals ..................................................23 Discovery and Proposed Funtion .....................................................................................23 Ferroportin Regulation ....................................................................................................24 Hormonal regulation of ferroportin by hepcidin ......................................................24 Regulation of ferroportin by IRE/IRP system and cellular iron status ....................26 Mechanism of Cellular Iron Export .................................................................................27 Current Biomarkers for Copper Status ...................................................................................28 Specific Aims ..........................................................................................................................30 3 MATERIALS AND METHODS ...........................................................................................36 Study Designs for Specific Aims I and II ...............................................................................36 Cell Culture and Treatments ...................................................................................................37 Ferroportin Gene and Promoter Analysis ...............................................................................37 Suppression of MRE-binding Transcription Factor (Mtf-1) Expression ................................37 Gene Expression by Quantitative RT-PCR Analysis .............................................................38 Sample Preparation for Western Blot Analysis ......................................................................38 Western Blotting .....................................................................................................................39 Non-heme Iron Assay .............................................................................................................39 5 Statistical Analysis ..................................................................................................................40 4 RESULTS ...............................................................................................................................42 Copper Deficiency Increases Ferroportin Expression in Rat Liver ........................................42 Copper Deficiency Increases Ferroportin Expression in Rat Spleen ......................................43 Ferroportin Expression is not Affected by Copper Deficiency in Mice ................................44 Ferroportin Promoter Analysis ..............................................................................................44 Suppression of MTF-1 Expression Increases Ferroportin mRNA Levels .............................45 5 DISCUSSION .........................................................................................................................60 Specific Aim I ........................................................................................................................60 Specific Aim II ......................................................................................................................63 LIST OF REFERENCES ...............................................................................................................66 BIOGRAPHICAL SKETCH .........................................................................................................73 6 LIST OF TABLES Table page 2-1 Examples of copper (Cu)-related proteins/enzymes and their functions ...........................31 2-2 Recommended Dietary Allowances for copper .................................................................32 3-1 Characteristics of various rodent copper deficiency studies analyzed in the current project ................................................................................................................................41 3-2 Primers sequences chosen for the quantification of gene transcripts of interest ...............41 4-1 Analysis of the mouse ferroportin promoter region within 500 bp upstream of the annotated transcription start site ........................................................................................57 7 LIST OF FIGURES Figure page 2-1 An overview of cellular and systemic copper metabolism ................................................33 2-2 Ferroportin regulation by IRE/IRP system. .......................................................................34 2-3 Mechanism of iron export by ferroportin...........................................................................35 4-1 Copper deficiency after weaning increases ferroportin expression in liver. ......................46 4-2 Postweaning copper deficiency (Rat60) increases hepatic ferroportin expression . ..........47 4-3 Perinatal copper deficiency increases ferroportin expression in liver . .............................48 4-4 Copper deficiency after weaning increases ferroportin expression in spleen . ..................49 4-5 Perinatal copper deficiency increases ferroportin expression in spleen . ..........................50 4-6 Copper deficiency does not increase ferroportin expression in mice. ...............................51 4-7 The ferroportin promoter region contains a highly conserved metal response element (MRE) consensus sequence . .............................................................................................52 4-8 Supression of MTF-1 expression increases steady-state ferroportin mRNA levels. .........52 4-9 Sequence alignment of mouse, rat and human ferroportin promoter regions ....................53 8 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science EXPRESSION OF THE IRON EXPORTER FERROPORTIN IN RESPONSE TO COPPER DEFICIENCY AND IRON LOADING By Supak Jenkitkasemwong May 2009 Chair: Mitchell D. Knutson Major: Food Science and Human Nutrition Copper and iron are metabolically interrelated. In mammals, copper deficiency impairs normal iron
Load more

Recommended publications
  • Iron Regulation by Hepcidin
    Iron regulation by hepcidin Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns J Clin Invest. 2013;123(6):2337-2343. https://doi.org/10.1172/JCI67225. Science in Medicine Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β- thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload. Find the latest version: https://jci.me/67225/pdf Science in medicine Iron regulation by hepcidin Ningning Zhao, An-Sheng Zhang, and Caroline A. Enns Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA. Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physi- ologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia.
    [Show full text]
  • Iron Transport Proteins: Gateways of Cellular and Systemic Iron Homeostasis
    Iron transport proteins: Gateways of cellular and systemic iron homeostasis Mitchell D. Knutson, PhD University of Florida Essential Vocabulary Fe Heme Membrane Transport DMT1 FLVCR Ferroportin HRG1 Mitoferrin Nramp1 ZIP14 Serum Transport Transferrin Transferrin receptor 1 Cytosolic Transport PCBP1, PCBP2 Timeline of identification in mammalian iron transport Year Protein Original Publications 1947 Transferrin Laurell and Ingelman, Acta Chem Scand 1959 Transferrin receptor 1 Jandl et al., J Clin Invest 1997 DMT1 Gunshin et al., Nature; Fleming et al. Nature Genet. 1999 Nramp1 Barton et al., J Leukocyt Biol 2000 Ferroportin Donovan et al., Nature; McKie et al., Cell; Abboud et al. J. Biol Chem 2004 FLVCR Quigley et al., Cell 2006 Mitoferrin Shaw et al., Nature 2006 ZIP14 Liuzzi et al., Proc Natl Acad Sci USA 2008 PCBP1, PCBP2 Shi et al., Science 2013 HRG1 White et al., Cell Metab DMT1 (SLC11A2) • Divalent metal-ion transporter-1 • Former names: Nramp2, DCT1 Fleming et al. Nat Genet, 1997; Gunshin et al., Nature 1997 • Mediates uptake of Fe2+, Mn2+, Cd2+ • H+ coupled transporter (cotransporter, symporter) • Main roles: • intestinal iron absorption Illing et al. JBC, 2012 • iron assimilation by erythroid cells DMT1 (SLC11A2) Yanatori et al. BMC Cell Biology 2010 • 4 different isoforms: 557 – 590 a.a. (hDMT1) Hubert & Hentze, PNAS, 2002 • Function similarly in iron transport • Differ in tissue/subcellular distribution and regulation • Regulated by iron: transcriptionally (via HIF2α) post-transcriptionally (via IRE) IRE = Iron-Responsive Element Enterocyte Lumen DMT1 Fe2+ Fe2+ Portal blood Enterocyte Lumen DMT1 Fe2+ Fe2+ Fe2+ Fe2+ Ferroportin Portal blood Ferroportin (SLC40A1) • Only known mammalian iron exporter Donovan et al., Nature 2000; McKie et al., Cell 2000; Abboud et al.
    [Show full text]
  • Hepcidin Is Not a Marker of Chronic Inflammation in Atherosclerosis Hepcidin Aterosklerozda Kronik Inflamasyonun Bir Göstergesi De¤Ildir
    Original Investigation Orijinal Araflt›rma 239 Hepcidin is not a marker of chronic inflammation in atherosclerosis Hepcidin aterosklerozda kronik inflamasyonun bir göstergesi de¤ildir Aytekin O¤uz, Mehmet Uzunlulu, Nezih Hekim* Department of Internal Medicine, Göztepe Training and Research Hospital, ‹stanbul, Turkey *Pakize Tarz› Laboratory, ‹stanbul, Turkey ABSTRACT Objective: To investigate the relationship between atherosclerosis, an inflammatory disease and hepcidin which is reported as an indi- cator of inflammation Methods: A total of 75 subjects between 40 and 70 years of age were included in the study. The patient group consisted of 40 stable pa- tients who had previously experienced an atherosclerotic event (18 women, 22 men; mean age 56.4±7.1 years). There were two control groups. The first control group consisted of 19 healthy subjects (11 women, 8 men; mean age 52.6± 7.4 years), while the second group inc- luded 16 patients (11 women, 5 men; mean age 56.5±9.3 years) with rheumatoid arthritis and anemia (diseased control group). Hepcidin measurement was performed using Hepcidin Prohormone ELISA (Solid Phase Enzyme-Linked Immunosorbent Assay) test kit. Results: Mean serum hepcidin levels were 243.2±48.8 ng/ml, 374.5±86.4 ng/ml, and 234±59.9 ng/ml in the patient group, in diseased cont- rols, and in healthy controls, respectively. Hepcidin levels were higher in diseased controls compared to the patient group and healthy controls (p=0.001). There were no significant differences between the patient group and healthy controls. Conclusion: These findings did not support the hypothesis that hepcidin levels could be increased in atherosclerotic cardiovascular di- seases as a marker of chronic inflammation.
    [Show full text]
  • Hepcidin Therapeutics
    pharmaceuticals Review Hepcidin Therapeutics Angeliki Katsarou and Kostas Pantopoulos * Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(514)-340-8260 (ext. 25293) Received: 3 November 2018; Accepted: 19 November 2018; Published: 21 November 2018 Abstract: Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art. Keywords: iron metabolism; hepcidin; ferroportin; hemochromatosis; anemia 1. Systemic Iron Homeostasis Iron is an essential constituent of cells and organisms and participates in vital biochemical activities, such as DNA synthesis, oxygen transfer, and energy metabolism. The biological functions of iron are based on its capacity to interact with proteins and on its propensity to switch between the ferrous (Fe2+) and ferric (Fe3+) oxidation states.
    [Show full text]
  • Hepcidin the Key Regulator of Iron in the Blood St
    Hepcidin The Key Regulator of Iron in the Blood St. Dominic Middle School SMART Team Eclaire Jessup, Dominic Kowalik, Allyssa Larcheid, Samuel Larcheid, Claire Lois, Sara Maslowski, I. Introduction to Hepcidin and Iron Homeostasis Emma Pittman, Joseph Platz, Marissa Puccetti, Tyler Shecterle, Nicole Simson, Emma Wenger Abstract Hepcidin, a peptide hormone, is the key regulator of plasma iron levels in humans, and is known to play an important role in Iron is found everywhere on Earth and is essential to life. The human body contains 3-4 grams of iron Teacher: Ms. LaFlamme Mentor: Dr. Matthew S. Karafin, various human diseases, such as hemochromatosis. Hepcidin inhibits the entry of iron into circulation by binding to and over fifty percent is found in red blood cells (RBCs). Without iron, the oxygen carrying protein ferroportin, a trans-membrane iron export channel found primarily on enterocytes, hepatocytes and macrophages where iron Medical College of Wisconsin, The Blood Center of Wisconsin hemoglobin that fills RBCs cannot be made and the bone marrow cannot carry out erythropoiesis is sequestered. When hepcidin binds to ferroportin, both are drawn into the cell by endocytosis and degraded in a lysosome. When hepcidin levels increase, ferroportin levels on cells decrease and iron cannot be released from cells into the blood. (RBC production). All iron in the body is absorbed from the diet in the duodenum. Hepcidin production by the liver is affected by erythropoiesis in bone marrow, blood oxygenation, certain inflammatory The peptide hormone, hepcidin, controls the release of the dietary iron from duodenal enterocytes III. Hepcidin Structure & Function cytokines, intracellular iron storage, and plasma transferrin.
    [Show full text]
  • The Correlation of the Hepcidin Ferritin Ratio and the Severity of Liver Cirrhosis
    The Correlation of the Hepcidin Ferritin Ratio and the Severity of Liver Cirrhosis Imelda Rey1,2 *, Rustam Effendi-Ys1,3 and Khairani Sukatendel 4 1 Division of Gastroenterohepatology, Internal Medicine Department, Universitas Sumatera Utara , Medan, Indonesia 2 Adam Malik General Hospital, Medan, Indonesia 3 Pirngadi General Hospital, Medan, Indonesia 4 Department of Obstetric and Gynecology, Universitas Sumatera Utara, Medan, Indonesia Keywords: Hepcidin, Liver Cirrhosis, Severity. Abstract: Background. Hepcidin serum level was influenced by the inflammation and iron deposit in chronic liver disease / CLD), but the correlation between the hepcidin ferritin ratio and the severity of liver cirrhosis was still not clear. The aim of this study was to found correlation between the hepcidin ferritin ratio and the severity of liver cirrhosis. Methods. The study was conducted in Gastroenterohepatology Division, Internal Medicine Department, Faculty of Medicine, University of Sumatera Utara. The study was an analytic comparative, cross sectional study. The subject were liver cirrhosis patients that fulllfiled inclusion criteria and informed consent. Results. From 78 liver cirrhosis patients, mean age was 51.36 ± 12.6 years old. Male was more than female ( 44 (56%), 34 (43.6%), respectively. We found that there was no significant difference of the hepcidin ferritin ratio among Child pugh A , Child pugh B and Child pugh C patients (0.17 ; 0.11 and 0.28, respectively, with p = 0.161). Conclusion. There was no significant difference of the hepcidin ferritin ratio among severity of liver cirrhosis. 1 INTRODUCTION chronic liver disease (CLD), but less is known about the correlation between the ratio of hepcidin : Hepcidin is the hormone of iron which produced in ferritin and the severity of liver cirrhosis.
    [Show full text]
  • Ferredoxin Reductase Is Critical for P53-Dependent Tumor Suppression Via Iron Regulatory Protein 2
    Downloaded from genesdev.cshlp.org on October 11, 2021 - Published by Cold Spring Harbor Laboratory Press Ferredoxin reductase is critical for p53- dependent tumor suppression via iron regulatory protein 2 Yanhong Zhang,1,9 Yingjuan Qian,1,2,9 Jin Zhang,1 Wensheng Yan,1 Yong-Sam Jung,1,2 Mingyi Chen,3 Eric Huang,4 Kent Lloyd,5 Yuyou Duan,6 Jian Wang,7 Gang Liu,8 and Xinbin Chen1 1Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California 95616, USA; 2College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210014, China; 3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 4Department of Pathology, School of Medicine, University of California at Davis Health, Sacramento, California 95817, USA; 5Department of Surgery, School of Medicine, University of California at Davis Health, Sacramento, California 95817, USA; 6Department of Dermatology and Internal Medicine, University of California at Davis Health, Sacramento, California 95616, USA; 7Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201 USA; 8Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA Ferredoxin reductase (FDXR), a target of p53, modulates p53-dependent apoptosis and is necessary for steroido- genesis and biogenesis of iron–sulfur clusters. To determine the biological function of FDXR, we generated a Fdxr- deficient mouse model and found that loss of Fdxr led to embryonic lethality potentially due to iron overload in developing embryos. Interestingly, mice heterozygous in Fdxr had a short life span and were prone to spontaneous tumors and liver abnormalities, including steatosis, hepatitis, and hepatocellular carcinoma.
    [Show full text]
  • Curriculum Vitae
    CURRICULUM VITAE PART I: General Information DATE PREPARED: 1/2018 Name: KARL TIMOTHY KELSEY 70 Ship Street, G-E3, Department of Epidemiology and Pathology and Lab. Office Address: Medicine, Providence, RI 02912 Home Address: 57 Toxteth Street, Brookline, MA 02446 Work E-mail: [email protected] Work FAX: (401) 863-5132 Place of Birth: Minneapolis, Minnesota Education: 1976 B.A., Physics University of Minnesota, Minneapolis, MN 1981 M.D., Medicine University of Minnesota, Minneapolis, MN 1984 M.O.H, Occupational Health Harvard University, Boston, MA Postdoctoral Training: 1981–1982 Resident Diagnostic Radiology Mt. Zion Hospital and Medical Center, San Francisco, CA 1982–1983 Postdoctoral Fellow Environmental Pathology Laboratory of Environmental Pathology University of Minnesota Medical School Minneapolis, Minnesota 1983–1985 Resident Occupational Medicine Harvard School of Public Health, Boston, MA 1985–1987 Postdoctoral Fellow Environmental Carcinogenesis Laboratory of Radiobiology Harvard School of Public Health Boston, Massachusetts Licensure and Certification: 1982 Minnesota Medical License (inactive by choice) 1984 Massachusetts Medical License (inactive by choice) 1986 Board Certification, American Board of Preventive Medicine – Occupational Medicine Academic Appointments: 1986–1987 Lecturer of Community Medicine Tufts University School of Medicine 1987–1991 Assistant Professor of Occupational Medicine Harvard School of Public Health 1988–1991 Assistant Professor of Radiobiology Harvard School of Public Health 1991–1998 Associate Professor of Occupational Medicine Harvard School of Public Health 1991–1998 Associate Professor of Radiobiology Harvard School of Public Health 1995–2007 Associate Physician of Channing Laboratory Brigham and Women’s Hospital 1995–2007 Associate Professor of Medicine Harvard Medical School 1998–2007 Professor of Cancer Biology & Environmental Health Harvard School of Public Health 2007-pres.
    [Show full text]
  • Duodenal Mrna Expression of Iron Related Genes in Response To
    648 SMALL INTESTINE Duodenal mRNA expression of iron related genes in Gut: first published as 10.1136/gut.51.5.648 on 1 November 2002. Downloaded from response to iron loading and iron deficiency in four strains of mice F Dupic, S Fruchon, M Bensaid, O Loreal, P Brissot, N Borot, M P Roth, H Coppin ............................................................................................................................. Gut 2002;51:648–653 Background: Although much progress has been made recently in characterising the proteins involved in duodenal iron trafficking, regulation of intestinal iron transport remains poorly understood. It is not known whether the level of mRNA expression of these recently described molecules is genetically regu- lated. This is of particular interest however as genetic factors are likely to determine differences in iron status among mouse strains and probably also contribute to the phenotypic variability seen with disrup- tion of the haemochromatosis gene. Aims: To investigate this issue, we examined concomitant variations in duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), hephaestin, stimulator of Fe trans- port (SFT), HFE, and transferrin receptor 1 (TfR1) transcripts in response to different dietary iron contents in the four mouse strains C57BL/6, DBA/2, CBA, and 129/Sv. See end of article for authors’ affiliations Subjects: Six mice of each strain were fed normal levels of dietary iron, six were subjected to the same ....................... diet supplemented with
    [Show full text]
  • Ncomms4301.Pdf
    ARTICLE Received 8 Jul 2013 | Accepted 23 Jan 2014 | Published 13 Feb 2014 DOI: 10.1038/ncomms4301 Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism Mikalai Malinouski1,2, Nesrin M. Hasan3, Yan Zhang1,4, Javier Seravalli2, Jie Lin4,5, Andrei Avanesov1, Svetlana Lutsenko3 & Vadim N. Gladyshev1 Trace elements are essential for human metabolism and dysregulation of their homoeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundamental differences in the regulation of different trace elements. Specifically, selenium levels are controlled through the selenocysteine machinery and expression of abundant selenoproteins; copper balance is affected by lipid metabolism and requires machinery involved in protein trafficking and post-translational modifications; and the iron levels are influenced by iron import and expression of the iron/haeme-containing enzymes. Our approach can be applied to a variety of disease models and/or nutritional conditions, and the generated data set opens new directions for studies of human trace element metabolism. 1 Genetics Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 2 Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA. 3 Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA. 4 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
    [Show full text]
  • The Potential for Transition Metal-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis
    REVIEW ARTICLE published: 23 July 2014 AGING NEUROSCIENCE doi: 10.3389/fnagi.2014.00173 The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis David B. Lovejoy* and Gilles J. Guillemin Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia Edited by: Modulations of the potentially toxic transition metals iron (Fe) and copper (Cu) are impli- Roger S. Chung, Macquarie cated in the neurodegenerative process in a variety of human disease states including University, USA amyotrophic lateral sclerosis (ALS). However, the precise role played by these metals is Reviewed by: Junming Wang, University of still very much unclear, despite considerable clinical and experimental data suggestive of Mississippi Medical Center, USA a role for these elements in the neurodegenerative process.The discovery of mutations in Ramon Santos El-Bachá, Universidade the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD-1) in ALS patients established Federal da Bahia, Brazil the first known cause of ALS. Recent data suggest that various mutations in SOD-1 affect *Correspondence: metal-binding of Cu and Zn, in turn promoting toxic protein aggregation. Copper home- David B. Lovejoy, Macquarie University, Australian School of ostasis is also disturbed in ALS, and may be relevant to ALS pathogenesis. Another set Advanced Medicine, Motor Neuron of interesting observations in ALS patients involves the key nutrient Fe. In ALS patients, and Neurodegenerative Diseases Fe loading can be inferred by studies showing increased expression of serum ferritin, an Research Group, Building F10A, 2 Fe-storage protein, with high serum ferritin levels correlating to poor prognosis. Magnetic Technology Place, NSW, 2109, Australia resonance imaging of ALS patients shows a characteristic T2 shortening that is attributed e-mail: [email protected] to the presence of Fe in the motor cortex.
    [Show full text]
  • Essential Trace Elements in Human Health: a Physician's View
    Margarita G. Skalnaya, Anatoly V. Skalny ESSENTIAL TRACE ELEMENTS IN HUMAN HEALTH: A PHYSICIAN'S VIEW Reviewers: Philippe Collery, M.D., Ph.D. Ivan V. Radysh, M.D., Ph.D., D.Sc. Tomsk Publishing House of Tomsk State University 2018 2 Essential trace elements in human health UDK 612:577.1 LBC 52.57 S66 Skalnaya Margarita G., Skalny Anatoly V. S66 Essential trace elements in human health: a physician's view. – Tomsk : Publishing House of Tomsk State University, 2018. – 224 p. ISBN 978-5-94621-683-8 Disturbances in trace element homeostasis may result in the development of pathologic states and diseases. The most characteristic patterns of a modern human being are deficiency of essential and excess of toxic trace elements. Such a deficiency frequently occurs due to insufficient trace element content in diets or increased requirements of an organism. All these changes of trace element homeostasis form an individual trace element portrait of a person. Consequently, impaired balance of every trace element should be analyzed in the view of other patterns of trace element portrait. Only personalized approach to diagnosis can meet these requirements and result in successful treatment. Effective management and timely diagnosis of trace element deficiency and toxicity may occur only in the case of adequate assessment of trace element status of every individual based on recent data on trace element metabolism. Therefore, the most recent basic data on participation of essential trace elements in physiological processes, metabolism, routes and volumes of entering to the body, relation to various diseases, medical applications with a special focus on iron (Fe), copper (Cu), manganese (Mn), zinc (Zn), selenium (Se), iodine (I), cobalt (Co), chromium, and molybdenum (Mo) are reviewed.
    [Show full text]