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Special Issue "Dietary Iron and Human Health"

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A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (31 March 2013)

Special Issue Editor

Guest Editor
Dr. Mitchell D. Knutson

359 Food Science and Human Nutrition Building, PO Box 110370, Newell Drive, University of Florida, Gainesville, FL 32611-0370, USA
Website | E-Mail
Phone: 352.392.1991
Fax: +352 392 9467
Interests: molecular, cellular, and physiological aspects of iron transport and homeostasis; roles of iron in health and disease

Special Issue Information

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Keywords

  • iron and pregnancy
  • iron and cardiovascular events
  • iron and cancer
  • iron and neurodegeneration
  • iron and diabetes
  • iron and aging
  • iron deficiency
  • iron overload
  • iron transport and homeostasis

Published Papers (14 papers)

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Research

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Open AccessArticle Iron in Child Obesity. Relationships with Inflammation and Metabolic Risk Factors
Nutrients 2013, 5(6), 2222-2230; doi:10.3390/nu5062222
Received: 21 March 2013 / Revised: 27 May 2013 / Accepted: 2 June 2013 / Published: 19 June 2013
Cited by 5 | PDF Full-text (355 KB) | HTML Full-text | XML Full-text
Abstract
Iron (Fe) sequestration is described in overweight and in its associated metabolic complications, i.e., metabolic syndrome (MetS) and non-alcoholic liver fatty disease (NAFLD); however, the interactions between Fe, obesity and inflammation make it difficult to recognize the specific role of each of
[...] Read more.
Iron (Fe) sequestration is described in overweight and in its associated metabolic complications, i.e., metabolic syndrome (MetS) and non-alcoholic liver fatty disease (NAFLD); however, the interactions between Fe, obesity and inflammation make it difficult to recognize the specific role of each of them in the risk of obesity-induced metabolic diseases. Even the usual surrogate marker of Fe stores, ferritin, is influenced by inflammation; therefore, in obese subjects inflammation parameters must be measured together with those of Fe metabolism. This cross-sectional study in obese youth (502 patients; 57% girls): 11.4 ± 3.0 years old (x ± SD); BMI z score 5.5 ± 2.3), multivariate regression analysis showed associations between Fe storage assessed by serum ferritin with risk factors for MetS and NAFLD, assessed by transaminase levels, which were independent of overweight and the acute phase protein fibrinogen. Further studies incorporating the measurement of complementary parameters of Fe metabolism could improve the comprehension of mechanisms involved. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)

Review

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Open AccessReview Iron, Human Growth, and the Global Epidemic of Obesity
Nutrients 2013, 5(10), 4231-4249; doi:10.3390/nu5104231
Received: 30 August 2013 / Revised: 27 September 2013 / Accepted: 12 October 2013 / Published: 22 October 2013
Cited by 2 | PDF Full-text (246 KB) | HTML Full-text | XML Full-text
Abstract
Iron is an essential nutrient utilized in almost every aspect of cell function and its availability has previously limited life. Those same properties which allow iron to function as a catalyst in the reactions of life also present a threat via generation of
[...] Read more.
Iron is an essential nutrient utilized in almost every aspect of cell function and its availability has previously limited life. Those same properties which allow iron to function as a catalyst in the reactions of life also present a threat via generation of oxygen-based free radicals. Accordingly; life exists at the interface of iron-deficiency and iron-sufficiency. We propose that: (1) human life is no longer positioned at the limits of iron availability following several decades of fortification and supplementation and there is now an overabundance of the metal among individuals of many societies; (2) this increased iron availability exerts a positive effect on growth by targeting molecules critical in regulating the progression of the cell cycle; there is increased growth in humans provided greater amounts of this metal; and indices of obesity can positively correlate with body stores of iron; and (3) diseases of obesity reflect this over-abundance of iron. Testing potential associations between iron availability and both obesity and obesity-related diseases in populations will be difficult since fortification and supplementation is so extensively practiced. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Open AccessReview Mobilization of Stored Iron in Mammals: A Review
Nutrients 2013, 5(10), 4022-4050; doi:10.3390/nu5104022
Received: 1 August 2013 / Revised: 4 September 2013 / Accepted: 12 September 2013 / Published: 10 October 2013
Cited by 31 | PDF Full-text (434 KB) | HTML Full-text | XML Full-text
Abstract
From the nutritional standpoint, several aspects of the biochemistry and physiology of iron are unique. In stark contrast to most other elements, most of the iron in mammals is in the blood attached to red blood cell hemoglobin and transporting oxygen to cells
[...] Read more.
From the nutritional standpoint, several aspects of the biochemistry and physiology of iron are unique. In stark contrast to most other elements, most of the iron in mammals is in the blood attached to red blood cell hemoglobin and transporting oxygen to cells for oxidative phosphorylation and other purposes. Controlled and uncontrolled blood loss thus has a major impact on iron availability. Also, in contrast to most other nutrients, iron is poorly absorbed and poorly excreted. Moreover, amounts absorbed (~1 mg/day in adults) are much less than the total iron (~20 mg/day) cycling into and out of hemoglobin, involving bone marrow erythropoiesis and reticuloendothelial cell degradation of aged red cells. In the face of uncertainties in iron bioavailability, the mammalian organism has evolved a complex system to retain and store iron not immediately in use, and to make that iron available when and where it is needed. Iron is stored innocuously in the large hollow protein, ferritin, particularly in cells of the liver, spleen and bone marrow. Our current understanding of the molecular, cellular and physiological mechanisms by which this stored iron in ferritin is mobilized and distributed—within the cell or to other organs—is the subject of this review. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Figures

Open AccessReview Iron Deficiency in Heart Failure: A Practical Guide
Nutrients 2013, 5(9), 3730-3739; doi:10.3390/nu5093730
Received: 4 July 2013 / Revised: 27 August 2013 / Accepted: 4 September 2013 / Published: 23 September 2013
Cited by 14 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
Iron is an element necessary for cells due to its capacity of transporting oxygen and electrons. One of the important co-morbidities in heart failure is iron deficiency. Iron has relevant biological functions, for example, the formation of haemoglobin, myoglobin and numerous enzymatic groups.
[...] Read more.
Iron is an element necessary for cells due to its capacity of transporting oxygen and electrons. One of the important co-morbidities in heart failure is iron deficiency. Iron has relevant biological functions, for example, the formation of haemoglobin, myoglobin and numerous enzymatic groups. The prevalence of iron deficiency increases with the severity of heart failure. For a long time, the influence of iron deficiency was underestimated especially in terms of worsening of cardiovascular diseases and of developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and cardiovascular diseases indicated new insights in the improvement of therapy. Experimental studies support the understanding of iron metabolism. Many physicians remain doubtful of the use of intravenous iron due to reports of side effects. The aim of this review is to describe iron metabolism in humans, to highlight the influence of iron deficiency on the course and symptoms of heart failure, discuss diagnostic tools of iron deficiency and provide guidance on the use of intravenous iron. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Open AccessReview Iron and Zinc Nutrition in the Economically-Developed World: A Review
Nutrients 2013, 5(8), 3184-3211; doi:10.3390/nu5083184
Received: 3 June 2013 / Revised: 19 July 2013 / Accepted: 26 July 2013 / Published: 13 August 2013
Cited by 18 | PDF Full-text (621 KB) | HTML Full-text | XML Full-text
Abstract
This review compares iron and zinc food sources, dietary intakes, dietary recommendations, nutritional status, bioavailability and interactions, with a focus on adults in economically-developed countries. The main sources of iron and zinc are cereals and meat, with fortificant iron and zinc potentially making
[...] Read more.
This review compares iron and zinc food sources, dietary intakes, dietary recommendations, nutritional status, bioavailability and interactions, with a focus on adults in economically-developed countries. The main sources of iron and zinc are cereals and meat, with fortificant iron and zinc potentially making an important contribution. Current fortification practices are concerning as there is little regulation or monitoring of intakes. In the countries included in this review, the proportion of individuals with iron intakes below recommendations was similar to the proportion of individuals with suboptimal iron status. Due to a lack of population zinc status information, similar comparisons cannot be made for zinc intakes and status. Significant data indicate that inhibitors of iron absorption include phytate, polyphenols, soy protein and calcium, and enhancers include animal tissue and ascorbic acid. It appears that of these, only phytate and soy protein also inhibit zinc absorption. Most data are derived from single-meal studies, which tend to amplify impacts on iron absorption in contrast to studies that utilize a realistic food matrix. These interactions need to be substantiated by studies that account for whole diets, however in the interim, it may be prudent for those at risk of iron deficiency to maximize absorption by reducing consumption of inhibitors and including enhancers at mealtimes. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Open AccessReview Out of Balance—Systemic Iron Homeostasis in Iron-Related Disorders
Nutrients 2013, 5(8), 3034-3061; doi:10.3390/nu5083034
Received: 18 June 2013 / Revised: 16 July 2013 / Accepted: 19 July 2013 / Published: 2 August 2013
Cited by 31 | PDF Full-text (973 KB) | HTML Full-text | XML Full-text
Abstract
Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden
[...] Read more.
Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden worldwide. On the other extreme, iron accumulation in critical organs such as liver, heart, and pancreas causes organ dysfunction due to the generation of oxidative stress. Therefore, systemic iron levels must be tightly balanced. Here we focus on the regulatory role of the hepcidin/ferroportin circuitry as the major regulator of systemic iron homeostasis. We discuss how regulatory cues (e.g., iron, inflammation, or hypoxia) affect the hepcidin response and how impairment of the hepcidin/ferroportin regulatory system causes disorders of iron metabolism. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Figures

Open AccessReview Potential of Phytase-Mediated Iron Release from Cereal-Based Foods: A Quantitative View
Nutrients 2013, 5(8), 3074-3098; doi:10.3390/nu5083074
Received: 12 April 2013 / Revised: 1 July 2013 / Accepted: 17 July 2013 / Published: 2 August 2013
Cited by 8 | PDF Full-text (534 KB) | HTML Full-text | XML Full-text
Abstract
The major part of iron present in plant foods such as cereals is largely unavailable for direct absorption in humans due to complexation with the negatively charged phosphate groups of phytate (myo-inositol (1,2,3,4,5,6)-hexakisphosphate). Human biology has not evolved an
[...] Read more.
The major part of iron present in plant foods such as cereals is largely unavailable for direct absorption in humans due to complexation with the negatively charged phosphate groups of phytate (myo-inositol (1,2,3,4,5,6)-hexakisphosphate). Human biology has not evolved an efficient mechanism to naturally release iron from iron phytate complexes. This narrative review will evaluate the quantitative significance of phytase-catalysed iron release from cereal foods. In vivo studies have shown how addition of microbially derived phytases to cereal-based foods has produced increased iron absorption via enzyme-catalysed dephosphorylation of phytate, indicating the potential of this strategy for preventing and treating iron deficiency anaemia. Despite the immense promise of this strategy and the prevalence of iron deficiency worldwide, the number of human studies elucidating the significance of phytase-mediated improvements in iron absorption and ultimately in iron status in particularly vulnerable groups is still low. A more detailed understanding of (1) the uptake mechanism for iron released from partially dephosphorylated phytate chelates, (2) the affinity of microbially derived phytases towards insoluble iron phytate complexes, and (3) the extent of phytate dephosphorylation required for iron release from inositol phosphates is warranted. Phytase-mediated iron release can improve iron absorption from plant foods. There is a need for development of innovative strategies to obtain better effects. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Open AccessReview Iron Deprivation in Cancer––Potential Therapeutic Implications
Nutrients 2013, 5(8), 2836-2859; doi:10.3390/nu5082836
Received: 4 June 2013 / Revised: 12 July 2013 / Accepted: 16 July 2013 / Published: 24 July 2013
Cited by 29 | PDF Full-text (683 KB) | HTML Full-text | XML Full-text
Abstract
Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on
[...] Read more.
Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention in a variety of cancers. Here, we will review iron homeostasis in non-malignant and malignant cells, the widespread effects of iron depletion on the cell, the various iron chelators that have been explored in the treatment of cancer, and the tumor types that have been most commonly studied in the context of iron chelation. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Figures

Open AccessReview Influence of microRNA on the Maintenance of Human Iron Metabolism
Nutrients 2013, 5(7), 2611-2628; doi:10.3390/nu5072611
Received: 2 May 2013 / Revised: 19 June 2013 / Accepted: 24 June 2013 / Published: 10 July 2013
Cited by 9 | PDF Full-text (495 KB) | HTML Full-text | XML Full-text
Abstract
Iron is an essential nutrient critical for many cellular functions including DNA synthesis, ATP generation, and cellular proliferation. Though essential, excessive iron may contribute to the generation of free radicals capable of damaging cellular lipids, proteins, and nucleic acids. As such, the maintenance
[...] Read more.
Iron is an essential nutrient critical for many cellular functions including DNA synthesis, ATP generation, and cellular proliferation. Though essential, excessive iron may contribute to the generation of free radicals capable of damaging cellular lipids, proteins, and nucleic acids. As such, the maintenance and control of cellular iron homeostasis is critical to prevent either iron deficiency or iron toxicity conditions. The maintenance of cellular iron homeostasis is largely coordinated by a family of cytosolic RNA binding proteins known as Iron Regulatory Proteins (IRP) that function to post-transcriptionally control the translation and/or stability of mRNA encoding proteins required for iron uptake, storage, transport, and utilization. More recently, a class of small non-coding RNA known as microRNA (miRNA) has also been implicated in the control of iron metabolism. To date, miRNA have been demonstrated to post-transcriptionally regulate the expression of genes associated with iron acquisition (transferrin receptor and divalent metal transporter), iron export (ferroportin), iron storage (ferritin), iron utilization (ISCU), and coordination of systemic iron homeostasis (HFE and hemojevelin). Given the diversity of miRNA and number of potential mRNA targets, characterizing factors that contribute to alterations in miRNA expression, biogenesis, and processing will enhance our understanding of mechanisms by which cells respond to changes in iron demand and/or iron availability to control cellular iron homeostasis. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Open AccessReview Intestinal Iron Homeostasis and Colon Tumorigenesis
Nutrients 2013, 5(7), 2333-2351; doi:10.3390/nu5072333
Received: 3 May 2013 / Revised: 29 May 2013 / Accepted: 7 June 2013 / Published: 28 June 2013
Cited by 11 | PDF Full-text (551 KB) | HTML Full-text | XML Full-text
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations
[...] Read more.
Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations or excess dietary iron uptake has been identified as a risk factor for CRC. Intestinal iron is tightly controlled by iron transporters that are responsible for iron uptake, distribution, and export. Dysregulation of intestinal iron transporters are observed in CRC and lead to iron accumulation in tumors. Intratumoral iron results in oxidative stress, lipid peroxidation, protein modification and DNA damage with consequent promotion of oncogene activation. In addition, excess iron in intestinal tumors may lead to increase in tumor-elicited inflammation and tumor growth. Limiting intratumoral iron through specifically chelating excess intestinal iron or modulating activities of iron transporter may be an attractive therapeutic target for CRC. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Open AccessReview Multi-Copper Oxidases and Human Iron Metabolism
Nutrients 2013, 5(7), 2289-2313; doi:10.3390/nu5072289
Received: 11 March 2013 / Revised: 29 May 2013 / Accepted: 6 June 2013 / Published: 27 June 2013
Cited by 32 | PDF Full-text (1323 KB) | HTML Full-text | XML Full-text
Abstract
Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different
[...] Read more.
Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. To date, three multi-copper oxidases have been detected in humans—ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Ferroportin exports iron as Fe2+, but transferrin, the major iron transporter protein of blood, can bind only Fe3+ effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. In this manuscript, we review the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Figures

Open AccessReview Iron Absorption in Drosophila melanogaster
Nutrients 2013, 5(5), 1622-1647; doi:10.3390/nu5051622
Received: 12 April 2013 / Revised: 3 May 2013 / Accepted: 7 May 2013 / Published: 17 May 2013
Cited by 17 | PDF Full-text (723 KB) | HTML Full-text | XML Full-text
Abstract
The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export
[...] Read more.
The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Figures

Open AccessReview Iron Deficiency and Bariatric Surgery
Nutrients 2013, 5(5), 1595-1608; doi:10.3390/nu5051595
Received: 7 April 2013 / Revised: 15 April 2013 / Accepted: 6 May 2013 / Published: 15 May 2013
Cited by 5 | PDF Full-text (363 KB) | HTML Full-text | XML Full-text
Abstract
It is estimated that the prevalence of anaemia in patients scheduled for bariatric surgery is higher than in the general population and the prevalence of iron deficiencies (with or without anaemia) may be higher as well. After surgery, iron deficiencies and anaemia may
[...] Read more.
It is estimated that the prevalence of anaemia in patients scheduled for bariatric surgery is higher than in the general population and the prevalence of iron deficiencies (with or without anaemia) may be higher as well. After surgery, iron deficiencies and anaemia may occur in a higher percentage of patients, mainly as a consequence of nutrient deficiencies. In addition, perioperative anaemia has been related with increased postoperative morbidity and mortality and poorer quality of life after bariatric surgery. The treatment of perioperative anaemia and nutrient deficiencies has been shown to improve patients’ outcomes and quality of life. All patients should undergo an appropriate nutritional evaluation, including selective micronutrient measurements (e.g., iron), before any bariatric surgical procedure. In comparison with purely restrictive procedures, more extensive perioperative nutritional evaluations are required for malabsorptive procedures due to their nutritional consequences. The aim of this study was to review the current knowledge of nutritional deficits in obese patients and those that commonly appear after bariatric surgery, specifically iron deficiencies and their consequences. As a result, some recommendations for screening and supplementation are presented. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)
Open AccessReview Regulatory Effects of Cu, Zn, and Ca on Fe Absorption: The Intricate Play between Nutrient Transporters
Nutrients 2013, 5(3), 957-970; doi:10.3390/nu5030957
Received: 4 February 2013 / Revised: 8 March 2013 / Accepted: 15 March 2013 / Published: 20 March 2013
Cited by 9 | PDF Full-text (450 KB) | HTML Full-text | XML Full-text
Abstract
Iron is an essential nutrient for almost every living organism because it is required in a number of biological processes that serve to maintain life. In humans, recycling of senescent erythrocytes provides most of the daily requirement of iron. In addition, we need
[...] Read more.
Iron is an essential nutrient for almost every living organism because it is required in a number of biological processes that serve to maintain life. In humans, recycling of senescent erythrocytes provides most of the daily requirement of iron. In addition, we need to absorb another 1–2 mg Fe from the diet each day to compensate for losses due to epithelial sloughing, perspiration, and bleeding. Iron absorption in the intestine is mainly regulated on the enterocyte level by effectors in the diet and systemic regulators accessing the enterocyte through the basal lamina. Recently, a complex meshwork of interactions between several trace metals and regulatory proteins was revealed. This review focuses on advances in our understanding of Cu, Zn, and Ca in the regulation of iron absorption. Ascorbate as an important player is also considered. Full article
(This article belongs to the Special Issue Dietary Iron and Human Health)

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