Special Issue "Iron as Therapeutic Targets in Human Diseases"

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: 31 May 2019

Special Issue Editors

Guest Editor
Prof. Dr. Paolo Arosio

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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Interests: iron metabolism; ferritin; iron storage
Guest Editor
Dr. Maura Poli

Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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Interests: iron metabolism; hepcidin; ferroptosis
Guest Editor
Dr. Raffaella Gozzelino

Chronic Diseases Research Center (CEDOC)/NOVA Medical School, NOVA University of Lisbon, Portugal
Website | E-Mail
Interests: iron metabolism; heme metabolism; inflammation; neurodegeneration; heme/iron toxicity

Special Issue Information

Dear Colleagues,

Iron is an essential element for almost all organisms, a cofactor playing a crucial role in a number of vital functions, including oxygen transport, DNA synthesis and respiration. However, its ability to exchange electrons renders excess iron potentially toxic, since capable to catalyze the formation of highly poisonous free radicals. As a consequence, iron homeostasis is tightly controlled by sophisticated mechanisms that have been partially elucidated. Because of its biological importance, numerous disorders have been recently linked to deregulation of iron homeostasis, which include not only the typical disorders of iron overload and deficiency, but also cancer and neurodegenerative diseases. This leads iron metabolism to become an interesting therapeutic target for novel pharmacological treatments against these diseases. Several therapies are currently under development for hematological disorders, while other are being considered for different pathologies. The therapeutic targeting under study includes the hepcidin/ferroportin axis for the regulation of systemic iron homeostasis, the complex cytosolic machineries for the regulation of intracellular iron status and its association with oxidative damage and reagents exploiting proteins of iron metabolism such as ferritin and transferrin receptor. A promising potential target is a recently described form of programmed cell death named ferroptosis, in which the role of iron is essential but not completely clarified. This Special Issue has the aim to summarize the state-of-the-art, and the latest findings published in the iron field, as well as to elucidate future directions.

Prof. Dr. Paolo Arosio
Dr. Maura Poli
Dr. Raffaella Gozzelino
Guest Editors

Manuscript Submission Information

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Keywords

  • iron homeostasis
  • ferritin
  • ferritinophagy
  • hepcidin
  • ferroptosis
  • iron chelators
  • neurodegeneration
  • inflammation
  • cancer

Published Papers (33 papers)

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Research

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Open AccessArticle L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia—Report of New Cases
Pharmaceuticals 2019, 12(1), 17; https://doi.org/10.3390/ph12010017
Received: 23 December 2018 / Revised: 18 January 2019 / Accepted: 19 January 2019 / Published: 23 January 2019
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Abstract
Ferritin is a multimeric protein composed of light (L-ferritin) and heavy (H-ferritin) subunits that binds and stores iron inside the cell. A variety of mutations have been reported in the L-ferritin subunit gene (FTL gene) that cause the following five diseases: (1) [...] Read more.
Ferritin is a multimeric protein composed of light (L-ferritin) and heavy (H-ferritin) subunits that binds and stores iron inside the cell. A variety of mutations have been reported in the L-ferritin subunit gene (FTL gene) that cause the following five diseases: (1) hereditary hyperferritinemia with cataract syndrome (HHCS), (2) neuroferritinopathy, a subtype of neurodegeneration with brain iron accumulation (NBIA), (3) benign hyperferritinemia, (4) L-ferritin deficiency with autosomal dominant inheritance, and (5) L-ferritin deficiency with autosomal recessive inheritance. Defects in the FTL gene lead to abnormally high levels of serum ferritin (hyperferritinemia) in HHCS and benign hyperferritinemia, while low levels (hypoferritinemia) are present in neuroferritinopathy and in autosomal dominant and recessive L-ferritin deficiency. Iron disturbances as well as neuromuscular and cognitive deficits are present in some, but not all, of these diseases. Here, we identified two novel FTL variants that cause dominant L-ferritin deficiency and HHCS (c.375+2T > A and 36_42delCAACAGT, respectively), and one previously reported variant (Met1Val) that causes dominant L-ferritin deficiency. Globally, genetic changes in the FTL gene are responsible for multiple phenotypes and an accurate diagnosis is useful for appropriate treatment. To help in this goal, we included a diagnostic algorithm for the detection of diseases caused by defects in FTL gene. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessArticle Iron Absorption in Iron-Deficient Women, Who Received 65 mg Fe with an Indonesian Breakfast, Is Much Better from NaFe(III)EDTA than from Fe(II)SO4, with an Acceptable Increase of Plasma NTBI. A Randomized Clinical Trial
Pharmaceuticals 2018, 11(3), 85; https://doi.org/10.3390/ph11030085
Received: 13 August 2018 / Revised: 4 September 2018 / Accepted: 7 September 2018 / Published: 10 September 2018
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Abstract
Plasma non-transferrin-bound iron (NTBI) is potentially harmful due to the generation of free radicals that cause tissue damage in vascular and other diseases. Studies in iron-replete and iron-deficient subjects, receiving a single oral test dose of Fe(II)SO4 or NaFe(III)EDTA with water, revealed [...] Read more.
Plasma non-transferrin-bound iron (NTBI) is potentially harmful due to the generation of free radicals that cause tissue damage in vascular and other diseases. Studies in iron-replete and iron-deficient subjects, receiving a single oral test dose of Fe(II)SO4 or NaFe(III)EDTA with water, revealed that FeSO4 was well absorbed when compared with NaFeEDTA, while only the Fe(II) compound showed a remarkable increase of NTBI. As NaFeEDTA is successfully used for food fortification, a double-blind randomized cross-over trial was conducted in 11 healthy women with uncomplicated iron deficiency. All subjects received a placebo, 6.5 mg FeSO4, 65 mg FeSO4, 6.5 mg NaFeEDTA, and 65 mg NaFeEDTA with a traditional Indonesian breakfast in one-week intervals. Blood tests were carried out every 60 min for five hours. NTBI detection was performed using the fluorescein-labeled apotransferrin method. Plasma iron values were highly increased after 65 mg NaFeEDTA, twice as high as after FeSO4. A similar pattern was seen for NTBI. After 6.5 mg of NaFeEDTA and FeSO4, NTBI was hardly detectable. NaFeEDTA was highly effective for the treatment of iron deficiency if given with a meal, inhibiting the formation of nonabsorbable Fe-complexes, while NTBI did not exceed the range of normal values for iron-replete subjects. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessArticle Iron Release from Soybean Seed Ferritin Induced by Cinnamic Acid Derivatives
Pharmaceuticals 2018, 11(2), 39; https://doi.org/10.3390/ph11020039
Received: 4 March 2018 / Revised: 15 April 2018 / Accepted: 2 May 2018 / Published: 4 May 2018
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Abstract
Plant ferritin represents a novel class of iron supplement, which widely co-exists with phenolic acids in a plant diet. However, there are few reports on the effect of these phenolic acids on function of ferritin. In this study, we demonstrated that cinnamic acid [...] Read more.
Plant ferritin represents a novel class of iron supplement, which widely co-exists with phenolic acids in a plant diet. However, there are few reports on the effect of these phenolic acids on function of ferritin. In this study, we demonstrated that cinnamic acid derivatives, as widely occurring phenolic acids, can induce iron release from holo soybean seed ferritin (SSF) in a structure-dependent manner. The ability of the iron release from SSF by five cinnamic acids follows the sequence of Cinnamic acid > Chlorogenic acid > Ferulic acid > p-Coumaric acid > Trans-Cinnamic acid. Fluorescence titration in conjunction with dialysis results showed that all of these five compounds have a similar, weak ability to bind with protein, suggesting that their protein-binding ability is not related to their iron release activity. In contrast, both Fe2+-chelating activity and reducibility of these cinnamic acid derivatives are in good agreement with their ability to induce iron release from ferritin. These studies indicate that cinnamic acid and its derivatives could have a negative effect on iron stability of holo soybean seed ferritin in diet, and the Fe2+-chelating activity and reducibility of cinnamic acid and its derivatives have strong relations to the iron release of soybean seed ferritin. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Review

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Open AccessReview The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review
Pharmaceuticals 2019, 12(2), 59; https://doi.org/10.3390/ph12020059
Received: 6 March 2019 / Revised: 9 April 2019 / Accepted: 12 April 2019 / Published: 16 April 2019
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Abstract
Early childhood is characterised by high physiological iron demand to support processes including blood volume expansion, brain development and tissue growth. Iron is also required for other essential functions including the generation of effective immune responses. Adequate iron status is therefore a prerequisite [...] Read more.
Early childhood is characterised by high physiological iron demand to support processes including blood volume expansion, brain development and tissue growth. Iron is also required for other essential functions including the generation of effective immune responses. Adequate iron status is therefore a prerequisite for optimal child development, yet nutritional iron deficiency and inflammation-related iron restriction are widespread amongst young children in low- and middle-income countries (LMICs), meaning iron demands are frequently not met. Consequently, therapeutic iron interventions are commonly recommended. However, iron also influences infection pathogenesis: iron deficiency reduces the risk of malaria, while therapeutic iron may increase susceptibility to malaria, respiratory and gastrointestinal infections, besides reshaping the intestinal microbiome. This means caution should be employed in administering iron interventions to young children in LMIC settings with high infection burdens. In this narrative review, we first examine demand and supply of iron during early childhood, in relation to the molecular understanding of systemic iron control. We then evaluate the importance of iron for distinct aspects of physiology and development, particularly focusing on young LMIC children. We finally discuss the implications and potential for interventions aimed at improving iron status whilst minimising infection-related risks in such settings. Optimal iron intervention strategies will likely need to be individually or setting-specifically adapted according to iron deficiency, inflammation status and infection risk, while maximising iron bioavailability and considering the trade-offs between benefits and risks for different aspects of physiology. The effectiveness of alternative approaches not centred around nutritional iron interventions for children should also be thoroughly evaluated: these include direct targeting of common causes of infection/inflammation, and maternal iron administration during pregnancy. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
Open AccessReview Iron in Lung Pathology
Pharmaceuticals 2019, 12(1), 30; https://doi.org/10.3390/ph12010030
Received: 14 December 2018 / Revised: 30 January 2019 / Accepted: 10 February 2019 / Published: 15 February 2019
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Abstract
The lung presents a unique challenge for iron homeostasis. The entire airway is in direct contact with the environment and its iron particulate matter and iron-utilizing microbes. However, the homeostatic and adaptive mechanisms of pulmonary iron regulation are poorly understood. This review provides [...] Read more.
The lung presents a unique challenge for iron homeostasis. The entire airway is in direct contact with the environment and its iron particulate matter and iron-utilizing microbes. However, the homeostatic and adaptive mechanisms of pulmonary iron regulation are poorly understood. This review provides an overview of systemic and local lung iron regulation, as well as the roles of iron in the development of lung infections, airway disease, and lung injury. These mechanisms provide an important foundation for the ongoing development of therapeutic applications. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Neurodegeneration with Brain Iron Accumulation Disorders: Valuable Models Aimed at Understanding the Pathogenesis of Iron Deposition
Pharmaceuticals 2019, 12(1), 27; https://doi.org/10.3390/ph12010027
Received: 19 December 2018 / Revised: 25 January 2019 / Accepted: 29 January 2019 / Published: 9 February 2019
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Abstract
Neurodegeneration with brain iron accumulation (NBIA) is a set of neurodegenerative disorders, which includes very rare monogenetic diseases. They are heterogeneous in regard to the onset and the clinical symptoms, while the have in common a specific brain iron deposition in the region [...] Read more.
Neurodegeneration with brain iron accumulation (NBIA) is a set of neurodegenerative disorders, which includes very rare monogenetic diseases. They are heterogeneous in regard to the onset and the clinical symptoms, while the have in common a specific brain iron deposition in the region of the basal ganglia that can be visualized by radiological and histopathological examinations. Nowadays, 15 genes have been identified as causative for NBIA, of which only two code for iron-proteins, while all the other causative genes codify for proteins not involved in iron management. Thus, how iron participates to the pathogenetic mechanism of most NBIA remains unclear, essentially for the lack of experimental models that fully recapitulate the human phenotype. In this review we reported the recent data on new models of these disorders aimed at highlight the still scarce knowledge of the pathogenesis of iron deposition. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Iron Homeostasis in the Lungs—A Balance between Health and Disease
Pharmaceuticals 2019, 12(1), 5; https://doi.org/10.3390/ph12010005
Received: 20 November 2018 / Revised: 23 December 2018 / Accepted: 25 December 2018 / Published: 1 January 2019
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Abstract
A strong mechanistic link between the regulation of iron homeostasis and oxygen sensing is evident in the lung, where both systems must be properly controlled to maintain lung function. Imbalances in pulmonary iron homeostasis are frequently associated with respiratory diseases, such as chronic [...] Read more.
A strong mechanistic link between the regulation of iron homeostasis and oxygen sensing is evident in the lung, where both systems must be properly controlled to maintain lung function. Imbalances in pulmonary iron homeostasis are frequently associated with respiratory diseases, such as chronic obstructive pulmonary disease and with lung cancer. However, the underlying mechanisms causing alterations in iron levels and the involvement of iron in the development of lung disorders are incompletely understood. Here, we review current knowledge about the regulation of pulmonary iron homeostasis, its functional importance, and the link between dysregulated iron levels and lung diseases. Gaining greater knowledge on how iron contributes to the pathogenesis of these diseases holds promise for future iron-related therapeutic strategies. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Iron Regulation: Macrophages in Control
Pharmaceuticals 2018, 11(4), 137; https://doi.org/10.3390/ph11040137
Received: 15 November 2018 / Revised: 10 December 2018 / Accepted: 12 December 2018 / Published: 14 December 2018
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Abstract
Macrophages are sentinel cells of the innate immune system and have important functions in development, tissue homeostasis, and immunity. These phylogenetically ancient cells also developed a variety of mechanisms to control erythropoiesis and the handling of iron. Red pulp macrophages in the spleen, [...] Read more.
Macrophages are sentinel cells of the innate immune system and have important functions in development, tissue homeostasis, and immunity. These phylogenetically ancient cells also developed a variety of mechanisms to control erythropoiesis and the handling of iron. Red pulp macrophages in the spleen, Kupffer cells in the liver, and central nurse macrophages in the bone marrow ensure a coordinated metabolism of iron to support erythropoiesis. Phagocytosis of senescent red blood cells by macrophages in the spleen and the liver provide a continuous delivery of recycled iron under steady-state conditions and during anemic stress. Central nurse macrophages in the bone marrow utilize this iron and provide a cellular scaffold and niche to promote differentiation of erythroblasts. This review focuses on the role of the distinct macrophage populations that contribute to efficient iron metabolism and highlight important cellular and systemic mechanisms involved in iron-regulating processes. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases
Pharmaceuticals 2018, 11(4), 135; https://doi.org/10.3390/ph11040135
Received: 10 November 2018 / Revised: 5 December 2018 / Accepted: 6 December 2018 / Published: 11 December 2018
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Abstract
Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia [...] Read more.
Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
Open AccessReview Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects
Pharmaceuticals 2018, 11(4), 131; https://doi.org/10.3390/ph11040131
Received: 28 August 2018 / Revised: 16 November 2018 / Accepted: 19 November 2018 / Published: 26 November 2018
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Abstract
Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces [...] Read more.
Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Brain Iron Homeostasis: A Focus on Microglial Iron
Pharmaceuticals 2018, 11(4), 129; https://doi.org/10.3390/ph11040129
Received: 17 October 2018 / Revised: 16 November 2018 / Accepted: 19 November 2018 / Published: 23 November 2018
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Abstract
Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized [...] Read more.
Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized by microglia activation and secretion of proinflammatory cytokines, are hallmarks of neurodegenerative disorders including Alzheimer’ s disease. While substantial efforts have led to an increased understanding of iron metabolism and the role of microglial cells in neuroinflammation, important questions still remain unanswered. Whether or not increased brain iron augments the inflammatory responses of microglial cells, including the molecular cues that guide such responses, is still unclear. How these brain macrophages accumulate, store, and utilize intracellular iron to carry out their various functions under normal and disease conditions is incompletely understood. Here, we describe the known and emerging mechanisms involved in microglial cell iron transport and metabolism as well as inflammatory responses in the brain, with a focus on AD. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia
Pharmaceuticals 2018, 11(4), 128; https://doi.org/10.3390/ph11040128
Received: 9 October 2018 / Revised: 7 November 2018 / Accepted: 19 November 2018 / Published: 22 November 2018
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Abstract
In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both [...] Read more.
In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both human and pig neonates, the initial cause of IDA is low birth iron stores. In piglets this shortage of stored iron results mainly from genetic selection over the past few decades for large litter sizes and high birth weights. As a consequence, pregnant sows cannot provide a sufficient amount of iron to the increasing number of developing fetuses. Supplementation with iron is a common practice for the treatment of IDA in piglets. For decades, the preferred procedure for delivering iron supplements during early life stages has been through the intramuscular injection of a large amount of iron dextran. However, this relatively simple therapy, which in general, efficiently corrects IDA, may generate toxic effects, and by inducing hepcidin expression, may decrease bioavailability of supplemental iron. New iron supplements are considered herein with the aim to combine the improvement of hematological status, blunting of hepcidin expression, and minimizing the toxicity of the administered iron. We propose that iron-deficient piglets constitute a convenient animal model for performing pre-clinical studies with iron supplements. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Hepcidin Therapeutics
Pharmaceuticals 2018, 11(4), 127; https://doi.org/10.3390/ph11040127
Received: 3 November 2018 / Revised: 15 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Emerging and Dynamic Biomedical Uses of Ferritin
Pharmaceuticals 2018, 11(4), 124; https://doi.org/10.3390/ph11040124
Received: 24 October 2018 / Revised: 11 November 2018 / Accepted: 12 November 2018 / Published: 13 November 2018
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Abstract
Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its [...] Read more.
Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its mineral core. However, recent evidence has demonstrated a range of abilities of ferritin that extends well beyond the scope of iron storage. This review aims to discuss novel functions and biomedical uses of ferritin in the processes of iron delivery, delivery of biologics such as chemotherapies and contrast agents, and the utility of ferritin as a biomarker in a number of neurological diseases. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Reductive Mobilization of Iron from Intact Ferritin: Mechanisms and Physiological Implication
Pharmaceuticals 2018, 11(4), 120; https://doi.org/10.3390/ph11040120
Received: 14 October 2018 / Revised: 31 October 2018 / Accepted: 1 November 2018 / Published: 5 November 2018
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Abstract
Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co-assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored [...] Read more.
Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co-assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored as a soluble inorganic ferric iron core. In-vitro (or in cell free systems), the mechanisms of iron(II) oxidation and formation of the mineral core have been extensively investigated, although it is still unclear how iron is loaded into the protein in-vivo. In contrast, there is a wide spread belief that the major pathway of iron mobilization from ferritin involves a lysosomal proteolytic degradation of ferritin, and the dissolution of the iron mineral core. However, it is still unclear whether other auxiliary iron mobilization mechanisms, involving physiological reducing agents and/or cellular reductases, contribute to the release of iron from ferritin. In vitro iron mobilization from ferritin can be achieved using different reducing agents, capable of easily reducing the ferritin iron core, to produce soluble ferrous ions that are subsequently chelated by strong iron(II)-chelating agents. Here, we review our current understanding of iron mobilization from ferritin by various reducing agents, and report on recent results from our laboratory, in support of a mechanism that involves a one-electron transfer through the protein shell to the iron mineral core. The physiological significance of the iron reductive mobilization from ferritin by the non-enzymatic FMN/NAD(P)H system is also discussed. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value
Pharmaceuticals 2018, 11(4), 115; https://doi.org/10.3390/ph11040115
Received: 28 September 2018 / Revised: 19 October 2018 / Accepted: 21 October 2018 / Published: 23 October 2018
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Abstract
Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is [...] Read more.
Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in TFR2 gene are responsible for type 3 hereditary hemochromatosis (HFE3), a genetically heterogeneous disease characterized by systemic iron overload. It has been recently pointed out that Hepc production and iron regulation could be exerted also in tissues other than liver, and that Tfr2 has an extrahepatic role in iron metabolism as well. This review summarizes all the most recent data on Tfr2 extrahepatic role, taking into account the putative distinct roles of the two main Tfr2 isoforms, Tfr2α and Tfr2β. Representing Hepc modulation an effective approach to correct iron balance impairment in common human diseases, and with Tfr2 being one of its regulators, it would be worthwhile to envisage Tfr2 as a therapeutic target. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview The Role of NCOA4-Mediated Ferritinophagy in Health and Disease
Pharmaceuticals 2018, 11(4), 114; https://doi.org/10.3390/ph11040114
Received: 8 September 2018 / Revised: 17 October 2018 / Accepted: 19 October 2018 / Published: 23 October 2018
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Abstract
Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in [...] Read more.
Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Links Between Iron and Lipids: Implications in Some Major Human Diseases
Pharmaceuticals 2018, 11(4), 113; https://doi.org/10.3390/ph11040113
Received: 31 August 2018 / Revised: 18 October 2018 / Accepted: 19 October 2018 / Published: 22 October 2018
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Abstract
Maintenance of iron homeostasis is critical to cellular health as both its excess and insufficiency are detrimental. Likewise, lipids, which are essential components of cellular membranes and signaling mediators, must also be tightly regulated to hinder disease progression. Recent research, using a myriad [...] Read more.
Maintenance of iron homeostasis is critical to cellular health as both its excess and insufficiency are detrimental. Likewise, lipids, which are essential components of cellular membranes and signaling mediators, must also be tightly regulated to hinder disease progression. Recent research, using a myriad of model organisms, as well as data from clinical studies, has revealed links between these two metabolic pathways, but the mechanisms behind these interactions and the role these have in the progression of human diseases remains unclear. In this review, we summarize literature describing cross-talk between iron and lipid pathways, including alterations in cholesterol, sphingolipid, and lipid droplet metabolism in response to changes in iron levels. We discuss human diseases correlating with both iron and lipid alterations, including neurodegenerative disorders, and the available evidence regarding the potential mechanisms underlying how iron may promote disease pathogenesis. Finally, we review research regarding iron reduction techniques and their therapeutic potential in treating patients with these debilitating conditions. We propose that iron-mediated alterations in lipid metabolic pathways are involved in the progression of these diseases, but further research is direly needed to elucidate the mechanisms involved. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Potential Treatment of Retinal Diseases with Iron Chelators
Pharmaceuticals 2018, 11(4), 112; https://doi.org/10.3390/ph11040112
Received: 1 September 2018 / Revised: 8 October 2018 / Accepted: 10 October 2018 / Published: 22 October 2018
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Abstract
Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in [...] Read more.
Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Protective Role of Histidine Supplementation Against Oxidative Stress Damage in the Management of Anemia of Chronic Kidney Disease
Pharmaceuticals 2018, 11(4), 111; https://doi.org/10.3390/ph11040111
Received: 30 August 2018 / Revised: 16 October 2018 / Accepted: 16 October 2018 / Published: 21 October 2018
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Abstract
Anemia is a major health condition associated with chronic kidney disease (CKD). A key underlying cause of this disorder is iron deficiency. Although intravenous iron treatment can be beneficial in correcting CKD-associated anemia, surplus iron can be detrimental and cause complications. Excessive generation [...] Read more.
Anemia is a major health condition associated with chronic kidney disease (CKD). A key underlying cause of this disorder is iron deficiency. Although intravenous iron treatment can be beneficial in correcting CKD-associated anemia, surplus iron can be detrimental and cause complications. Excessive generation of reactive oxygen species (ROS), particularly by mitochondria, leads to tissue oxidation and damage to DNA, proteins, and lipids. Oxidative stress increase in CKD has been further implicated in the pathogenesis of vascular calcification. Iron supplementation leads to the availability of excess free iron that is toxic and generates ROS that is linked, in turn, to inflammation, endothelial dysfunction, and cardiovascular disease. Histidine is indispensable to uremic patients because of the tendency toward negative plasma histidine levels. Histidine-deficient diets predispose healthy subjects to anemia and accentuate anemia in chronic uremic patients. Histidine is essential in globin synthesis and erythropoiesis and has also been implicated in the enhancement of iron absorption from human diets. Studies have found that L-histidine exhibits antioxidant capabilities, such as scavenging free radicals and chelating divalent metal ions, hence the advocacy for its use in improving oxidative stress in CKD. The current review advances and discusses evidence for iron-induced toxicity in CKD and the mechanisms by which histidine exerts cytoprotective functions. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores
Pharmaceuticals 2018, 11(4), 110; https://doi.org/10.3390/ph11040110
Received: 3 October 2018 / Revised: 17 October 2018 / Accepted: 18 October 2018 / Published: 20 October 2018
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Abstract
Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully used by novel antibacterial drugs. We focused our interest on the design of chelators to address Mycobacterium avium infections. Taking into account the molecular structure [...] Read more.
Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully used by novel antibacterial drugs. We focused our interest on the design of chelators to address Mycobacterium avium infections. Taking into account the molecular structure of mycobacterial siderophores and considering that new chelators must be able to compete for Fe(III), we selected ligands of the 3-hydroxy-4-pyridinone class to achieve our purpose. After choosing the type of chelating unit it was also our objective to design chelators that could be monitored inside the cell and for that reason we designed chelators that could be functionalized with fluorophores. We didn’t realize at the time that the incorporation a fluorophore, to allow spectroscopic detection, would be so relevant for the antimycobacterial effect or to determine the affinity of the chelators towards biological membranes. From a biophysical perspective, this is a fascinating illustration of the fact that functionalization of a molecule with a particular label may lead to a change in its membrane permeation properties and result in a dramatic change in biological activity. For that reason we believe it is interesting to give a critical account of our entire work in this area and justify the statement “to label means to change”. New perspectives regarding combined therapeutic approaches and the use of rhodamine B conjugates to target closely related problems such as bacterial resistance and biofilm production are also discussed. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases
Pharmaceuticals 2018, 11(4), 109; https://doi.org/10.3390/ph11040109
Received: 25 June 2018 / Revised: 31 July 2018 / Accepted: 3 August 2018 / Published: 19 October 2018
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Abstract
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. [...] Read more.
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Influence of Iron on Bone Homeostasis
Pharmaceuticals 2018, 11(4), 107; https://doi.org/10.3390/ph11040107
Received: 1 September 2018 / Revised: 5 October 2018 / Accepted: 12 October 2018 / Published: 18 October 2018
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Abstract
Bone homeostasis is a complex process, wherein osteoclasts resorb bone and osteoblasts produce new bone tissue. For the maintenance of skeletal integrity, this sequence has to be tightly regulated and orchestrated. Iron overload as well as iron deficiency disrupt the delicate balance between [...] Read more.
Bone homeostasis is a complex process, wherein osteoclasts resorb bone and osteoblasts produce new bone tissue. For the maintenance of skeletal integrity, this sequence has to be tightly regulated and orchestrated. Iron overload as well as iron deficiency disrupt the delicate balance between bone destruction and production, via influencing osteoclast and osteoblast differentiation as well as activity. Iron overload as well as iron deficiency are accompanied by weakened bones, suggesting that balanced bone homeostasis requires optimal—not too low, not too high—iron levels. The goal of this review is to summarize our current knowledge about how imbalanced iron influence skeletal health. Better understanding of this complex process may help the development of novel therapeutic approaches to deal with the pathologic effects of altered iron levels on bone. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Oxidative Stress and Cardiovascular Complications in Chronic Kidney Disease, the Impact of Anaemia
Pharmaceuticals 2018, 11(4), 103; https://doi.org/10.3390/ph11040103
Received: 11 September 2018 / Revised: 30 September 2018 / Accepted: 1 October 2018 / Published: 11 October 2018
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Abstract
Patients with chronic kidney disease (CKD) have significant cardiovascular morbidity and mortality as a result of risk factors such as left ventricular hypertrophy (LVH), oxidative stress, and inflammation. The presence of anaemia in CKD further increases the risk of LVH and oxidative stress, [...] Read more.
Patients with chronic kidney disease (CKD) have significant cardiovascular morbidity and mortality as a result of risk factors such as left ventricular hypertrophy (LVH), oxidative stress, and inflammation. The presence of anaemia in CKD further increases the risk of LVH and oxidative stress, thereby magnifying the deleterious consequence in uraemic cardiomyopathy (UCM), and aggravating progression to failure and increasing the risk of sudden cardiac death. This short review highlights the specific cardio-renal oxidative stress in CKD and provides an understanding of the pathophysiology and impact of uraemic toxins, inflammation, and anaemia on oxidative stress. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Gut Microbiota and Iron: The Crucial Actors in Health and Disease
Pharmaceuticals 2018, 11(4), 98; https://doi.org/10.3390/ph11040098
Received: 12 September 2018 / Revised: 30 September 2018 / Accepted: 2 October 2018 / Published: 5 October 2018
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Abstract
Iron (Fe) is a highly ample metal on planet earth (~35% of the Earth’s mass) and is particularly essential for most life forms, including from bacteria to mammals. Nonetheless, iron deficiency is highly prevalent in developing countries, and oral administration of this metal [...] Read more.
Iron (Fe) is a highly ample metal on planet earth (~35% of the Earth’s mass) and is particularly essential for most life forms, including from bacteria to mammals. Nonetheless, iron deficiency is highly prevalent in developing countries, and oral administration of this metal is so far the most effective treatment for human beings. Notably, the excessive amount of unabsorbed iron leave unappreciated side effects at the highly interactive host–microbe interface of the human gastrointestinal tract. Recent advances in elucidating the molecular basis of interactions between iron and gut microbiota shed new light(s) on the health and pathogenesis of intestinal inflammatory diseases. We here aim to present the dynamic modulation of intestinal microbiota by iron availability, and conversely, the influence on dietary iron absorption in the gut. The central part of this review is intended to summarize our current understanding about the effects of luminal iron on host–microbe interactions in the context of human health and disease. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Sucrosomial® Iron: A New Generation Iron for Improving Oral Supplementation
Pharmaceuticals 2018, 11(4), 97; https://doi.org/10.3390/ph11040097
Received: 30 August 2018 / Revised: 28 September 2018 / Accepted: 2 October 2018 / Published: 4 October 2018
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Abstract
Iron deficiency (ID) is usually treated with oral iron salts, but up to 50% of patients complain of gastrointestinal side effects, leading to reduced compliance with treatment. Intravenous (IV) iron formulations are increasingly safe, but there is still a risk of infusion, hypersensitivity [...] Read more.
Iron deficiency (ID) is usually treated with oral iron salts, but up to 50% of patients complain of gastrointestinal side effects, leading to reduced compliance with treatment. Intravenous (IV) iron formulations are increasingly safe, but there is still a risk of infusion, hypersensitivity reactions and the need for venous access and infusion monitoring. Sucrosomial® Iron (SI) is an innovative oral iron formulation in which ferric pyrophosphate is protected by a phospholipid bilayer plus a sucrester matrix (sucrosome), which is absorbed through para-cellular and trans-cellular routes (M cells). This confers SI’s unique structural, physicochemical and pharmacokinetic characteristics, together with its high iron bioavailability and excellent gastrointestinal tolerance. The analysis of the available evidence supports oral SI iron as a valid option for ID treatment, which is more efficacious and tolerable than oral iron salts. SI has also demonstrated a similar effectiveness, with lower risks, in patients usually receiving IV iron (e.g., chronic kidney disease, cancer, bariatric surgery). Thus, oral SI emerges as a valuable first option for treating ID, especially for subjects with intolerance to iron salts or those for whom iron salts are inefficacious. Moreover, SI should also be considered as an alternative to IV iron for initial and/or maintenance treatment in different patient populations. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Anemia and Iron Deficiency in Cancer Patients: Role of Iron Replacement Therapy
Pharmaceuticals 2018, 11(4), 94; https://doi.org/10.3390/ph11040094
Received: 31 August 2018 / Revised: 27 September 2018 / Accepted: 28 September 2018 / Published: 30 September 2018
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Abstract
Anemia in cancer patients is quite common, with remarkable negative impacts on quality of life and overall prognosis. The pathogenesis is complex and typically multifactorial, with iron deficiency (ID) often being a major and potentially treatable contributor. In turn, ID in cancer patients [...] Read more.
Anemia in cancer patients is quite common, with remarkable negative impacts on quality of life and overall prognosis. The pathogenesis is complex and typically multifactorial, with iron deficiency (ID) often being a major and potentially treatable contributor. In turn, ID in cancer patients can be due to multiple concurring mechanisms, including bleeding (e.g., in gastrointestinal cancers or after surgery), malnutrition, medications, and hepcidin-driven iron sequestration into macrophages with subsequent iron-restricted erythropoiesis. Indeed, either absolute or functional iron deficiency (AID or FID) can occur. While for absolute ID there is a general consensus regarding the laboratory definition (that is ferritin levels <100 ng/mL ± transferrin saturation (TSAT) <20%), a shared definition of functional ID is still lacking. Current therapeutic options in cancer anemia include iron replacement, erythropoietic stimulating agents (ESAs), and blood transfusions. The latter should be kept to a minimum, because of concerns regarding risks, costs, and limited resources. Iron therapy has proved to be a valid approach to enhance efficacy of ESAs and to reduce transfusion need. Available guidelines focus mainly on patients with chemotherapy-associated anemia, and generally suggest intravenous (IV) iron when AID or FID is present. However, in the case of FID, the upper limit of ferritin in association with TSAT <20% at which iron should be prescribed is a matter of controversy, ranging up to 800 ng/mL. An increasingly recognized indication to IV iron in cancer patients is represented by preoperative anemia in elective oncologic surgery. In this setting, the primary goal of treatment is to decrease the need of blood transfusions in the perioperative period, rather than improving anemia-related symptoms as in chemotherapy-associated anemia. Protocols are mainly based on experiences of Patient Blood Management (PBM) in non-oncologic surgery, but no specific guidelines are available for oncologic surgery. Here we discuss some possible approaches to the management of ID in cancer patients in different clinical settings, based on current guidelines and recommendations, emphasizing the need for further research in the field. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?
Pharmaceuticals 2018, 11(3), 89; https://doi.org/10.3390/ph11030089
Received: 10 August 2018 / Revised: 15 September 2018 / Accepted: 17 September 2018 / Published: 19 September 2018
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Abstract
Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. [...] Read more.
Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. Many evidences indicate that frataxin deficiency causes the deregulation of cellular iron homeostasis. In this review, we will discuss several hypotheses proposed for frataxin function, their caveats, and how they could provide an explanation for the deregulation of iron homeostasis found in frataxin-deficient cells. We will also focus on the potential mechanisms causing cellular dysfunction in Friedreich Ataxia and on the potential use of the iron chelator deferiprone as a therapeutic agent for this disease. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Mitochondrial Targeting in Neurodegeneration: A Heme Perspective
Pharmaceuticals 2018, 11(3), 87; https://doi.org/10.3390/ph11030087
Received: 18 July 2018 / Revised: 7 September 2018 / Accepted: 14 September 2018 / Published: 18 September 2018
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Abstract
Mitochondrial dysfunction has achieved an increasing interest in the field of neurodegeneration as a pathological hallmark for different disorders. The impact of mitochondria is related to a variety of mechanisms and several of them can co-exist in the same disease. The central role [...] Read more.
Mitochondrial dysfunction has achieved an increasing interest in the field of neurodegeneration as a pathological hallmark for different disorders. The impact of mitochondria is related to a variety of mechanisms and several of them can co-exist in the same disease. The central role of mitochondria in neurodegenerative disorders has stimulated studies intended to implement therapeutic protocols based on the targeting of the distinct mitochondrial processes. The review summarizes the most relevant mechanisms by which mitochondria contribute to neurodegeneration, encompassing therapeutic approaches. Moreover, a new perspective is proposed based on the heme impact on neurodegeneration. The heme metabolism plays a central role in mitochondrial functions, and several evidences indicate that alterations of the heme metabolism are associated with neurodegenerative disorders. By reporting the body of knowledge on this topic, the review intends to stimulate future studies on the role of heme metabolism in neurodegeneration, envisioning innovative strategies in the struggle against neurodegenerative diseases. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes
Pharmaceuticals 2018, 11(3), 84; https://doi.org/10.3390/ph11030084
Received: 6 August 2018 / Revised: 27 August 2018 / Accepted: 28 August 2018 / Published: 1 September 2018
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Abstract
Iron is an essential nutrient for almost all living organisms, but is not easily made available. Hosts and pathogens engage in a fight for the metal during an infection, leading to major alterations in the host’s iron metabolism. Important pathological consequences can emerge [...] Read more.
Iron is an essential nutrient for almost all living organisms, but is not easily made available. Hosts and pathogens engage in a fight for the metal during an infection, leading to major alterations in the host’s iron metabolism. Important pathological consequences can emerge from the mentioned interaction, including anemia. Several recent reports have highlighted the alterations in iron metabolism caused by different types of infection, and several possible therapeutic strategies emerge, based on the targeting of the host’s iron metabolism. Here, we review the most recent literature on iron metabolism alterations that are induced by infection, the consequent development of anemia, and the potential therapeutic approaches to modulate iron metabolism in order to correct iron-related pathologies and control the ongoing infection. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
Open AccessReview Intravenous Irons: From Basic Science to Clinical Practice
Pharmaceuticals 2018, 11(3), 82; https://doi.org/10.3390/ph11030082
Received: 1 August 2018 / Revised: 22 August 2018 / Accepted: 23 August 2018 / Published: 27 August 2018
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Abstract
Iron is an essential trace mineral necessary for life, and iron deficiency anaemia (IDA) is one of the most common haematological problems worldwide, affecting a sixth of the global population. Principally linked to poverty, malnutrition and infection in developing countries, in Western countries [...] Read more.
Iron is an essential trace mineral necessary for life, and iron deficiency anaemia (IDA) is one of the most common haematological problems worldwide, affecting a sixth of the global population. Principally linked to poverty, malnutrition and infection in developing countries, in Western countries the pathophysiology of IDA is primarily linked to blood loss, malabsorption and chronic disease. Oral iron replacement therapy is a simple, inexpensive treatment, but is limited by gastrointestinal side effects that are not inconsequential to some patients and are of minimal efficacy in others. Third generation intravenous (IV) iron therapies allow rapid and complete replacement dosing without the toxicity issues inherent with older iron preparations. Their characteristic, strongly-bound iron-carbohydrate complexes exist as colloidal suspensions of iron oxide nanoparticles with a polynuclear Fe(III)-oxyhydroxide/oxide core surrounded by a carbohydrate ligand. The physicochemical differences between the IV irons include mineral composition, crystalline structure, conformation, size and molecular weight, but the most important difference is the carbohydrate ligand, which influences complex stability, iron release and immunogenicity, and which is a unique feature of each drug. Recent studies have highlighted different adverse event profiles associated with third-generation IV irons that reflect their different structures. The increasing clinical evidence base has allayed safety concerns linked to older IV irons and widened their clinical use. This review considers the properties of the different IV irons, and how differences might impact current and future clinical practice. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessCorrection Correction: Mateusz, S., et al. Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia. Pharmaceuticals 2018, 11, 128
Pharmaceuticals 2019, 12(1), 22; https://doi.org/10.3390/ph12010022
Received: 9 October 2018 / Accepted: 19 November 2018 / Published: 29 January 2019
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Abstract
The authors wish to make the following corrections to this paper [1]: the term “liposomal” should be replaced with the term “sucrosomial” in the following places [...] Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
Open AccessHypothesis How Eliminating Malaria May Also Prevent Iron Deficiency in African Children
Pharmaceuticals 2018, 11(4), 96; https://doi.org/10.3390/ph11040096
Received: 30 August 2018 / Revised: 21 September 2018 / Accepted: 21 September 2018 / Published: 1 October 2018
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Abstract
Malaria and iron deficiency are common among children living in sub-Saharan Africa. Several studies have linked a child’s iron status to their future risk of malaria infection; however, few have examined whether malaria might be a cause of iron deficiency. Approximately a quarter [...] Read more.
Malaria and iron deficiency are common among children living in sub-Saharan Africa. Several studies have linked a child’s iron status to their future risk of malaria infection; however, few have examined whether malaria might be a cause of iron deficiency. Approximately a quarter of African children at any one time are infected by malaria and malaria increases hepcidin and tumor necrosis factor-α concentrations leading to poor iron absorption and recycling. In support of a hypothetical link between malaria and iron deficiency, studies indicate that the prevalence of iron deficiency in children increases over a malaria season and decreases when malaria transmission is interrupted. The link between malaria and iron deficiency can be tested through the use of observational studies, randomized controlled trials and genetic epidemiology studies, each of which has its own strengths and limitations. Confirming the existence of a causal link between malaria infection and iron deficiency would readjust priorities for programs to prevent and treat iron deficiency and would demonstrate a further benefit of malaria control. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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