Pharmaceuticals

Editorial

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9 pages, 212 KiB

Open AccessEditorial

Iron as Therapeutic Target in Human Diseases

by Raffaella Gozzelino, Maura Poli and Paolo Arosio

Pharmaceuticals 2019, 12(4), 178; https://doi.org/10.3390/ph12040178 - 5 Dec 2019

Cited by 4 | Viewed by 3381

Abstract

Iron is essential for almost all organisms, being involved in oxygen transport, DNA synthesis, and respiration; however, it is also potentially toxic via the formation of free radicals [...] Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

Research

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16 pages, 3285 KiB

Open AccessArticle

The Antitumor Didox Acts as an Iron Chelator in Hepatocellular Carcinoma Cells

by Michela Asperti, Luca Cantamessa, Simone Ghidinelli, Magdalena Gryzik, Andrea Denardo, Arianna Giacomini, Giovanna Longhi, Alessandro Fanzani, Paolo Arosio and Maura Poli

Pharmaceuticals 2019, 12(3), 129; https://doi.org/10.3390/ph12030129 - 2 Sep 2019

Cited by 10 | Viewed by 4902

Abstract

Ribonucleotide reductase (RR) is the rate-limiting enzyme that controls the deoxynucleotide triphosphate synthesis and it is an important target of cancer treatment, since it is expressed in tumor cells in proportion to their proliferation rate, their invasiveness and poor prognosis. Didox, a derivative [...] Read more.

Ribonucleotide reductase (RR) is the rate-limiting enzyme that controls the deoxynucleotide triphosphate synthesis and it is an important target of cancer treatment, since it is expressed in tumor cells in proportion to their proliferation rate, their invasiveness and poor prognosis. Didox, a derivative of hydroxyurea (HU), is one of the most potent pharmaceutical inhibitors of this enzyme, with low in vivo side effects. It inhibits the activity of the subunit RRM2 and deoxyribonucleotides (dNTPs) synthesis, and it seems to show iron-chelating activity. In the present work, we mainly investigated the iron-chelating properties of didox using the HA22T/VGH cell line, as a model of hepatocellular carcinoma (HCC). We confirmed that didox induced cell death and that this effect was suppressed by iron supplementation. Interestingly, cell treatments with didox caused changes of cellular iron content, TfR1 and ferritin levels comparable to those caused by the iron chelators, deferoxamine (DFO) and deferiprone (DFP). Chemical studies showed that didox has an affinity binding to Fe³⁺ comparable to that of DFO and DFP, although with slower kinetic. Structural modeling indicated that didox is a bidentated iron chelator with two theoretical possible positions for the binding and among them that with the two hydroxyls of the catechol group acting as ligands is the more likely one. The iron chelating property of didox may contribute to its antitumor activity not only blocking the formation of the tyrosil radical on Tyr122 (such as HU) on RRM2 (essential for its activity) but also sequestering the iron needed by this enzyme and to the cell proliferation. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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12 pages, 2254 KiB

Open AccessArticle

by Graça Porto, Eugénia Cruz, Maria José Teles and Maria de Sousa

Pharmaceuticals 2019, 12(3), 122; https://doi.org/10.3390/ph12030122 - 22 Aug 2019

Cited by 8 | Viewed by 5185

Abstract

The HFE gene (OMIM 235200), most commonly associated with the genetic iron overload disorder Hemochromatosis, was identified by Feder et al. in 1996, as a major histocompatibilty complex (MHC) class I like gene, first designated human leukocyte antigen-H (HLA-H). This discovery was thus [...] Read more.

The HFE gene (OMIM 235200), most commonly associated with the genetic iron overload disorder Hemochromatosis, was identified by Feder et al. in 1996, as a major histocompatibilty complex (MHC) class I like gene, first designated human leukocyte antigen-H (HLA-H). This discovery was thus accomplished 20 years after the realization of the first link between the then “idiopathic” hemochromatosis and the human leukocyte antigens (HLA). The availability of a good genetic marker in subjects homozygous for the C282Y variant in HFE (hereditary Fe), the reliability in serum markers such as transferrin saturation and serum ferritin, plus the establishment of noninvasive methods for the estimation of hepatic iron overload, all transformed hemochromatosis into a unique age related disease where prevention became the major goal. We were challenged by the finding of iron overload in a 9-year-old boy homozygous for the C282Y HFE variant, with two brothers aged 11 and 5 also homozygous for the mutation. We report a 20 year follow-up during which the three boys were seen yearly with serial determinations of iron parameters and lymphocyte counts. This paper is divided in three sections: Learning, applying, and questioning. The result is the illustration of hemochromatosis as an age related disease in the transition from childhood to adult life and the confirmation of the inextricable link between iron overload and the cells of the immune system. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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10 pages, 3309 KiB

Open AccessArticle

Changes in Iron Metabolism Induced by Anti-Interleukin-6 Receptor Monoclonal Antibody are Associated with an Increased Risk of Infection

by Renata Ribeiro, Frederico Batista, Filipe Seguro Paula and José Delgado Alves

Pharmaceuticals 2019, 12(3), 100; https://doi.org/10.3390/ph12030100 - 28 Jun 2019

Cited by 2 | Viewed by 3597

Abstract

(1) Background: Treatment of patients with rheumatoid arthritis (RA) with an anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (tocilizumab) has been found to influence iron metabolism. The objective of the present study was to ascertain whether changes in iron metabolism induced by anti-IL-6R biologic therapy [...] Read more.

(1) Background: Treatment of patients with rheumatoid arthritis (RA) with an anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (tocilizumab) has been found to influence iron metabolism. The objective of the present study was to ascertain whether changes in iron metabolism induced by anti-IL-6R biologic therapy were independently associated with an increased infection risk. (2) Methods: A prospective longitudinal study of patients with RA treated with tocilizumab was conducted. RA patients treated with an antitumor necrosis factor α monoclonal antibody were also included as a control group. The primary outcome was occurrence of infection during the first 24 months of biologic therapy. (3) Results: A total of 15 patients were included, with a mean age of 51.0 ± 4,1 and 73.3% (n = 11) female. A multivariate survival regression model, adjusted for confounding factors, was fitted for each of the iron metabolism variables. Hazard ratios for being above the median of each parameter was considered. Transferrin saturation above the median value (>32.1%) was associated with a higher infection risk (HR 4.3; 95%CI 1.0–19.69; p = 0.05). Similarly, although non-significantly, higher serum iron was strongly associated with infection occurrence. (4) Conclusions: This study identified a probable association between infection risk and higher serum iron and transferrin saturation in patients with RA on anti-IL-6R biologic therapy. We suggest that both these parameters should be considered relevant contributing factors for infection occurrence in patients on anti-IL-6R therapy. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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15 pages, 4360 KiB

Open AccessCommunication

Deregulation of Hepatic Mek1/2–Erk1/2 Signaling Module in Iron Overload Conditions

by Naveen Kumar Tangudu, Nils Buth, Pavel Strnad, Ion C. Cirstea and Maja Vujić Spasić

Pharmaceuticals 2019, 12(2), 70; https://doi.org/10.3390/ph12020070 - 7 May 2019

Cited by 44 | Viewed by 4297

Abstract

The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations [...] Read more.

The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations into the signals that control hepcidin expression, little progress has been made towards investigations into intracellular signaling in the liver under excess of iron. This study examined hepatic signaling pathways underlying acquired and genetic iron overload conditions. Our data demonstrate that hepatic iron overload associates with a decline in the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) kinase (Mek1/2) pathway by selectively affecting the phosphorylation of Erk1/2. We propose that Mek1/2-Erk1/2 signaling is uncoupled from iron-Bmp-Smad-mediated hepcidin induction and that it may contribute to a number of liver pathologies in addition to toxic effects of iron. We believe that our findings will advance the understanding of cellular signaling events in the liver during iron overload of different etiologies. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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15 pages, 1793 KiB

Open AccessArticle

L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia—Report of New Cases

by Beatriz Cadenas, Josep Fita-Torró, Mar Bermúdez-Cortés, Inés Hernandez-Rodriguez, José Luis Fuster, María Esther Llinares, Ana María Galera, Julia Lee Romero, Santiago Pérez-Montero, Cristian Tornador and Mayka Sanchez

Pharmaceuticals 2019, 12(1), 17; https://doi.org/10.3390/ph12010017 - 23 Jan 2019

Cited by 22 | Viewed by 9670

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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14 pages, 2105 KiB

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

by Eka Ginanjar, Lilik Indrawati, Iswari Setianingsih, Djumhana Atmakusumah, Alida Harahap, Ina S. Timan and Joannes J. M. Marx

Pharmaceuticals 2018, 11(3), 85; https://doi.org/10.3390/ph11030085 - 10 Sep 2018

Cited by 10 | Viewed by 10326

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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10 pages, 2073 KiB

Open AccessArticle

Iron Release from Soybean Seed Ferritin Induced by Cinnamic Acid Derivatives

by Xuejiao Sha, Hai Chen, Jingsheng Zhang and Guanghua Zhao

Pharmaceuticals 2018, 11(2), 39; https://doi.org/10.3390/ph11020039 - 4 May 2018

Cited by 11 | Viewed by 5531

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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22 pages, 1571 KiB

Open AccessReview

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

by Zachary J. Hawula, Daniel F. Wallace, V. Nathan Subramaniam and Gautam Rishi

Pharmaceuticals 2019, 12(4), 170; https://doi.org/10.3390/ph12040170 - 25 Nov 2019

Cited by 44 | Viewed by 10946

Abstract

The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of [...] Read more.

The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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35 pages, 1396 KiB

Open AccessReview

What Is Next in This “Age” of Heme-Driven Pathology and Protection by Hemopexin? An Update and Links with Iron

by Luis Montecinos, Jeffrey D. Eskew and Ann Smith

Pharmaceuticals 2019, 12(4), 144; https://doi.org/10.3390/ph12040144 - 24 Sep 2019

Cited by 15 | Viewed by 9152

Abstract

This review provides a synopsis of the published literature over the past two years on the heme-binding protein hemopexin (HPX), with some background information on the biochemistry of the HPX system. One focus is on the mechanisms of heme-driven pathology in the context [...] Read more.

This review provides a synopsis of the published literature over the past two years on the heme-binding protein hemopexin (HPX), with some background information on the biochemistry of the HPX system. One focus is on the mechanisms of heme-driven pathology in the context of heme and iron homeostasis in human health and disease. The heme-binding protein hemopexin is a multi-functional protectant against hemoglobin (Hb)-derived heme toxicity as well as mitigating heme-mediated effects on immune cells, endothelial cells, and stem cells that collectively contribute to driving inflammation, perturbing vascular hemostasis and blood–brain barrier function. Heme toxicity, which may lead to iron toxicity, is recognized increasingly in a wide range of conditions involving hemolysis and immune system activation and, in this review, we highlight some newly identified actions of heme and hemopexin especially in situations where normal processes fail to maintain heme and iron homeostasis. Finally, we present preliminary data showing that the cytokine IL-6 cross talks with activation of the c-Jun N-terminal kinase pathway in response to heme-hemopexin in models of hepatocytes. This indicates another level of complexity in the cell responses to elevated heme via the HPX system when the immune system is activated and/or in the presence of inflammation. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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13 pages, 433 KiB

Open AccessReview

The Efficacy of Iron Chelators for Removing Iron from Specific Brain Regions and the Pituitary—Ironing out the Brain

by Robert R. Crichton, Roberta J. Ward and Robert C. Hider

Pharmaceuticals 2019, 12(3), 138; https://doi.org/10.3390/ph12030138 - 17 Sep 2019

Cited by 26 | Viewed by 6043

Abstract

Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong [...] Read more.

Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong life. More recently, the use of deferiprone to chelate iron from various brain regions in Parkinson’s Disease and Friederich’s Ataxia has yielded encouraging results, although the side effects, in <2% of Parkinson’s Disease(PD) patients, have limited its long-term use. A new class of hydroxpyridinones has recently been synthesised, which showed no adverse effects in preliminary trials. A vital question remaining is whether inflammation may influence chelation efficacy, with a recent study suggesting that high levels of inflammation may diminish the ability of the chelator to bind the excess iron. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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29 pages, 3934 KiB

Open AccessReview

Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features

by L. Tom Vlasveld, Roel Janssen, Edouard Bardou-Jacquet, Hanka Venselaar, Houda Hamdi-Roze, Hal Drakesmith and Dorine W. Swinkels

Pharmaceuticals 2019, 12(3), 132; https://doi.org/10.3390/ph12030132 - 9 Sep 2019

Cited by 40 | Viewed by 6236

Abstract

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin [...] Read more.

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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26 pages, 740 KiB

Open AccessReview

Multilevel Impacts of Iron in the Brain: The Cross Talk between Neurophysiological Mechanisms, Cognition, and Social Behavior

by Ana Ferreira, Pedro Neves and Raffaella Gozzelino

Pharmaceuticals 2019, 12(3), 126; https://doi.org/10.3390/ph12030126 - 29 Aug 2019

Cited by 76 | Viewed by 12500

Abstract

Iron is a critical element for most organisms, which plays a fundamental role in the great majority of physiological processes. So much so, that disruption of iron homeostasis has severe multi-organ impacts with the brain being particularly sensitive to such modifications. More specifically, [...] Read more.

Iron is a critical element for most organisms, which plays a fundamental role in the great majority of physiological processes. So much so, that disruption of iron homeostasis has severe multi-organ impacts with the brain being particularly sensitive to such modifications. More specifically, disruption of iron homeostasis in the brain can affect neurophysiological mechanisms, cognition, and social behavior, which eventually contributes to the development of a diverse set of neuro-pathologies. This article starts by exploring the mechanisms of iron action in the brain and follows with a discussion on cognitive and behavioral implications of iron deficiency and overload and how these are framed by the social context. Subsequently, we scrutinize the implications of the disruption of iron homeostasis for the onset and progression of psychosocial disorders. Lastly, we discuss the links between biological, psychological, and social dimensions and outline potential avenues of research. The study of these interactions could ultimately contribute to a broader understanding of how individuals think and act under physiological and pathophysiological conditions. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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9 pages, 785 KiB

Open AccessReview

Iron Deficiency as a Therapeutic Target in Cardiovascular Disease

by Samira Lakhal-Littleton

Pharmaceuticals 2019, 12(3), 125; https://doi.org/10.3390/ph12030125 - 28 Aug 2019

Cited by 14 | Viewed by 5053

Abstract

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on [...] Read more.

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on their effectiveness in other cardiovascular diseases are lacking or conflicting. Realising the potential of iron therapies in cardiovascular disease requires understanding of the mechanisms through which iron deficiency affects cardiovascular function, and the cell types in which such mechanisms operate. That understanding has been enhanced by recent insights into the roles of hepcidin and iron regulatory proteins (IRPs) in cellular iron homeostasis within cardiovascular cells. These studies identify intracellular iron deficiency within the cardiovascular tissue as an important contributor to the disease process, and present novel therapeutic strategies based on targeting the machinery of cellular iron homeostasis rather than direct iron supplementation. This review discusses these new insights and their wider implications for the treatment of cardiovascular diseases, focusing on two disease conditions: chronic heart failure and pulmonary arterial hypertension. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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16 pages, 553 KiB

Open AccessReview

Impairment of the Developing Human Brain in Iron Deficiency: Correlations to Findings in Experimental Animals and Prospects for Early Intervention Therapy

by Veronika Markova, Charlotte Holm, Anja Bisgaard Pinborg, Lars Lykke Thomsen and Torben Moos

Pharmaceuticals 2019, 12(3), 120; https://doi.org/10.3390/ph12030120 - 14 Aug 2019

Cited by 21 | Viewed by 4449

Abstract

Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In [...] Read more.

Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In early embryonic life, iron is already needed for proper development of the brain with the proliferation, migration, and differentiation of neuro-progenitor cells. This is underpinned by the widespread expression of transferrin receptors in the developing brain, which, in later life, is restricted to cells of the blood–brain and blood–cerebrospinal fluid barriers and neuronal cells, hence ensuring a sustained iron supply to the brain, even in the fully developed brain. In embryonic human life, iron deficiency is thought to result in a lower brain weight, with the impaired formation of myelin. Studies of fully developed infants that have experienced iron deficiency during development reveal the chronic and irreversible impairment of cognitive, memory, and motor skills, indicating widespread effects on the human brain. This review highlights the major findings of recent decades on the effects of gestational and lactational iron deficiency on the developing human brain. The findings are correlated to findings of experimental animals ranging from rodents to domestic pigs and non-human primates. The results point towards significant effects of iron deficiency on the developing brain. Evidence would be stronger with more studies addressing the human brain in real-time and the development of blood biomarkers of cerebral disturbance in iron deficiency. Cerebral iron deficiency is expected to be curable with iron substitution therapy, as the brain, privileged by the cerebral vascular transferrin receptor expression, is expected to facilitate iron extraction from the circulation and enable transport further into the brain. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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21 pages, 1241 KiB

Open AccessReview

Role of Dietary Flavonoids in Iron Homeostasis

by Marija Lesjak and Surjit K. S. Srai

Pharmaceuticals 2019, 12(3), 119; https://doi.org/10.3390/ph12030119 - 8 Aug 2019

Cited by 39 | Viewed by 10437

Abstract

Balancing systemic iron levels within narrow limits is critical for human health, as both iron deficiency and overload lead to serious disorders. There are no known physiologically controlled pathways to eliminate iron from the body and therefore iron homeostasis is maintained by modifying [...] Read more.

Balancing systemic iron levels within narrow limits is critical for human health, as both iron deficiency and overload lead to serious disorders. There are no known physiologically controlled pathways to eliminate iron from the body and therefore iron homeostasis is maintained by modifying dietary iron absorption. Several dietary factors, such as flavonoids, are known to greatly affect iron absorption. Recent evidence suggests that flavonoids can affect iron status by regulating expression and activity of proteins involved the systemic regulation of iron metabolism and iron absorption. We provide an overview of the links between different dietary flavonoids and iron homeostasis together with the mechanism of flavonoids effect on iron metabolism. In addition, we also discuss the clinical relevance of state-of-the-art knowledge regarding therapeutic potential that flavonoids may have for conditions that are low in iron such as anaemia or iron overload diseases. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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14 pages, 705 KiB

Open AccessReview

Ferritin in Kidney and Vascular Related Diseases: Novel Roles for an Old Player

by József Balla, György Balla and Abolfazl Zarjou

Pharmaceuticals 2019, 12(2), 96; https://doi.org/10.3390/ph12020096 - 21 Jun 2019

Cited by 22 | Viewed by 5143

Abstract

Iron is at the forefront of a number of pivotal biological processes due to its ability to readily accept and donate electrons. However, this property may also catalyze the generation of free radicals with ensuing cellular and tissue toxicity. Accordingly, throughout evolution numerous [...] Read more.

Iron is at the forefront of a number of pivotal biological processes due to its ability to readily accept and donate electrons. However, this property may also catalyze the generation of free radicals with ensuing cellular and tissue toxicity. Accordingly, throughout evolution numerous pathways and proteins have evolved to minimize the potential hazardous effects of iron cations and yet allow for readily available iron cations in a wide variety of fundamental metabolic processes. One of the extensively studied proteins in the context of systemic and cellular iron metabolisms is ferritin. While clinicians utilize serum ferritin to monitor body iron stores and inflammation, it is important to note that the vast majority of ferritin is located intracellularly. Intracellular ferritin is made of two different subunits (heavy and light chain) and plays an imperative role as a safe iron depot. In the past couple of decades our understanding of ferritin biology has remarkably improved. Additionally, a significant body of evidence has emerged describing the significance of the kidney in iron trafficking and homeostasis. Here, we briefly discuss some of the most important findings that relate to the role of iron and ferritin heavy chain in the context of kidney-related diseases and, in particular, vascular calcification, which is a frequent complication of chronic kidney disease. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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10 pages, 655 KiB

Open AccessReview

Ironing out Macrophage Immunometabolism

by Stefania Recalcati, Elena Gammella and Gaetano Cairo

Pharmaceuticals 2019, 12(2), 94; https://doi.org/10.3390/ph12020094 - 19 Jun 2019

Cited by 24 | Viewed by 4855

Abstract

Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. [...] Read more.

Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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11 pages, 498 KiB

Open AccessReview

Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

by Shashank Masaldan, Abdel Ali Belaidi, Scott Ayton and Ashley I. Bush

Pharmaceuticals 2019, 12(2), 93; https://doi.org/10.3390/ph12020093 - 19 Jun 2019

Cited by 72 | Viewed by 7375

Abstract

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). [...] Read more.

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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28 pages, 3354 KiB

Open AccessReview

Iron Supplementation Therapy, A Friend and Foe of Mycobacterial Infections?

by Rafiou Agoro and Catherine Mura

Pharmaceuticals 2019, 12(2), 75; https://doi.org/10.3390/ph12020075 - 17 May 2019

Cited by 24 | Viewed by 7610

Abstract

Iron is an essential element that is required for oxygen transfer, redox, and metabolic activities in mammals and bacteria. Mycobacteria, some of the most prevalent infectious agents in the world, require iron as growth factor. Mycobacterial-infected hosts set up a series of defense [...] Read more.

Iron is an essential element that is required for oxygen transfer, redox, and metabolic activities in mammals and bacteria. Mycobacteria, some of the most prevalent infectious agents in the world, require iron as growth factor. Mycobacterial-infected hosts set up a series of defense mechanisms, including systemic iron restriction and cellular iron distribution, whereas mycobacteria have developed sophisticated strategies to acquire iron from their hosts and to protect themselves from iron’s harmful effects. Therefore, it is assumed that host iron and iron-binding proteins, and natural or synthetic chelators would be keys targets to inhibit mycobacterial proliferation and may have a therapeutic potential. Beyond this hypothesis, recent evidence indicates a host protective effect of iron against mycobacterial infections likely through promoting remodeled immune response. In this review, we discuss experimental procedures and clinical observations that highlight the role of the immune response against mycobacteria under various iron availability conditions. In addition, we discuss the clinical relevance of our knowledge regarding host susceptibility to mycobacteria in the context of iron availability and suggest future directions for research on the relationship between host iron and the immune response and the use of iron as a therapeutic agent. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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31 pages, 355 KiB

Open AccessReview

The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review

by Andrew E. Armitage and Diego Moretti

Pharmaceuticals 2019, 12(2), 59; https://doi.org/10.3390/ph12020059 - 16 Apr 2019

Cited by 34 | Viewed by 7079

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)

11 pages, 1011 KiB

Open AccessReview

Iron in Lung Pathology

by Vida Zhang, Elizabeta Nemeth and Airie Kim

Pharmaceuticals 2019, 12(1), 30; https://doi.org/10.3390/ph12010030 - 15 Feb 2019

Cited by 33 | Viewed by 6413

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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22 pages, 747 KiB

Open AccessReview

Neurodegeneration with Brain Iron Accumulation Disorders: Valuable Models Aimed at Understanding the Pathogenesis of Iron Deposition

by Sonia Levi and Valeria Tiranti

Pharmaceuticals 2019, 12(1), 27; https://doi.org/10.3390/ph12010027 - 9 Feb 2019

Cited by 63 | Viewed by 8191

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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28 pages, 2648 KiB

Open AccessReview

Iron Homeostasis in the Lungs—A Balance between Health and Disease

by Joana Neves, Thomas Haider, Max Gassmann and Martina U. Muckenthaler

Pharmaceuticals 2019, 12(1), 5; https://doi.org/10.3390/ph12010005 - 1 Jan 2019

Cited by 61 | Viewed by 11703

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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20 pages, 33844 KiB

Open AccessReview

Iron Regulation: Macrophages in Control

by Nyamdelger Sukhbaatar and Thomas Weichhart

Pharmaceuticals 2018, 11(4), 137; https://doi.org/10.3390/ph11040137 - 14 Dec 2018

Cited by 146 | Viewed by 15967

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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24 pages, 324 KiB

Open AccessReview

Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases

by Verena Petzer, Igor Theurl and Günter Weiss

Pharmaceuticals 2018, 11(4), 135; https://doi.org/10.3390/ph11040135 - 11 Dec 2018

Cited by 32 | Viewed by 5257

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)

14 pages, 1119 KiB

Open AccessReview

Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects

by Olivier Loréal, Thibault Cavey, François Robin, Moussa Kenawi, Pascal Guggenbuhl and Pierre Brissot

Pharmaceuticals 2018, 11(4), 131; https://doi.org/10.3390/ph11040131 - 26 Nov 2018

Cited by 11 | Viewed by 7299

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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14 pages, 951 KiB

Open AccessReview

Brain Iron Homeostasis: A Focus on Microglial Iron

by Israel C. Nnah and Marianne Wessling-Resnick

Pharmaceuticals 2018, 11(4), 129; https://doi.org/10.3390/ph11040129 - 23 Nov 2018

Cited by 78 | Viewed by 9586

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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13 pages, 1430 KiB

Open AccessReview

Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia

by Mateusz Szudzik, Rafał R. Starzyński, Aneta Jończy, Rafał Mazgaj, Małgorzata Lenartowicz and Paweł Lipiński

Pharmaceuticals 2018, 11(4), 128; https://doi.org/10.3390/ph11040128 - 22 Nov 2018

Cited by 42 | Viewed by 8979 | Correction

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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30 pages, 1417 KiB

Open AccessReview

Hepcidin Therapeutics

by Angeliki Katsarou and Kostas Pantopoulos

Pharmaceuticals 2018, 11(4), 127; https://doi.org/10.3390/ph11040127 - 21 Nov 2018

Cited by 77 | Viewed by 11799

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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18 pages, 1460 KiB

Open AccessReview

Emerging and Dynamic Biomedical Uses of Ferritin

by Brian Chiou and James R. Connor

Pharmaceuticals 2018, 11(4), 124; https://doi.org/10.3390/ph11040124 - 13 Nov 2018

Cited by 77 | Viewed by 14175

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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14 pages, 3002 KiB

Open AccessReview

Reductive Mobilization of Iron from Intact Ferritin: Mechanisms and Physiological Implication

by Fadi Bou-Abdallah, John J. Paliakkara, Galina Melman and Artem Melman

Pharmaceuticals 2018, 11(4), 120; https://doi.org/10.3390/ph11040120 - 5 Nov 2018

Cited by 47 | Viewed by 6358

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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20 pages, 2749 KiB

Open AccessReview

The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value

by Antonella Roetto, Mariarosa Mezzanotte and Rosa Maria Pellegrino

Pharmaceuticals 2018, 11(4), 115; https://doi.org/10.3390/ph11040115 - 23 Oct 2018

Cited by 19 | Viewed by 6152

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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16 pages, 1085 KiB

Open AccessReview

The Role of NCOA4-Mediated Ferritinophagy in Health and Disease

by Naiara Santana-Codina and Joseph D. Mancias

Pharmaceuticals 2018, 11(4), 114; https://doi.org/10.3390/ph11040114 - 23 Oct 2018

Cited by 221 | Viewed by 17575

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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14 pages, 783 KiB

Open AccessReview

Links Between Iron and Lipids: Implications in Some Major Human Diseases

by Stephanie Rockfield, Ravneet Chhabra, Michelle Robertson, Nabila Rehman, Richa Bisht and Meera Nanjundan

Pharmaceuticals 2018, 11(4), 113; https://doi.org/10.3390/ph11040113 - 22 Oct 2018

Cited by 56 | Viewed by 5557

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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14 pages, 648 KiB

Open AccessReview

Potential Treatment of Retinal Diseases with Iron Chelators

by Wanting Shu and Joshua L. Dunaief

Pharmaceuticals 2018, 11(4), 112; https://doi.org/10.3390/ph11040112 - 22 Oct 2018

Cited by 36 | Viewed by 6222

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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15 pages, 2064 KiB

Open AccessReview

Protective Role of Histidine Supplementation Against Oxidative Stress Damage in the Management of Anemia of Chronic Kidney Disease

by Mayra Vera-Aviles, Eleni Vantana, Emmy Kardinasari, Ngat L. Koh and Gladys O. Latunde-Dada

Pharmaceuticals 2018, 11(4), 111; https://doi.org/10.3390/ph11040111 - 21 Oct 2018

Cited by 67 | Viewed by 10090

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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24 pages, 7176 KiB

Open AccessReview

Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores

by Maria Rangel, Tânia Moniz, André M. N. Silva and Andreia Leite

Pharmaceuticals 2018, 11(4), 110; https://doi.org/10.3390/ph11040110 - 20 Oct 2018

Cited by 9 | Viewed by 4996

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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22 pages, 635 KiB

Open AccessReview

New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases

by Marco T. Nuñez and Pedro Chana-Cuevas

Pharmaceuticals 2018, 11(4), 109; https://doi.org/10.3390/ph11040109 - 19 Oct 2018

Cited by 103 | Viewed by 10229

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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18 pages, 707 KiB

Open AccessReview

Influence of Iron on Bone Homeostasis

by Enikő Balogh, György Paragh and Viktória Jeney

Pharmaceuticals 2018, 11(4), 107; https://doi.org/10.3390/ph11040107 - 18 Oct 2018

Cited by 125 | Viewed by 14684

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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15 pages, 1262 KiB

Open AccessReview

Oxidative Stress and Cardiovascular Complications in Chronic Kidney Disease, the Impact of Anaemia

by Faisal Nuhu and Sunil Bhandari

Pharmaceuticals 2018, 11(4), 103; https://doi.org/10.3390/ph11040103 - 11 Oct 2018

Cited by 46 | Viewed by 6536

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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20 pages, 1791 KiB

Open AccessReview

Gut Microbiota and Iron: The Crucial Actors in Health and Disease

by Bahtiyar Yilmaz and Hai Li

Pharmaceuticals 2018, 11(4), 98; https://doi.org/10.3390/ph11040098 - 5 Oct 2018

Cited by 193 | Viewed by 20105

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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23 pages, 2387 KiB

Open AccessReview

Sucrosomial^® Iron: A New Generation Iron for Improving Oral Supplementation

by Susana Gómez-Ramírez, Elisa Brilli, Germano Tarantino and Manuel Muñoz

Pharmaceuticals 2018, 11(4), 97; https://doi.org/10.3390/ph11040097 - 4 Oct 2018

Cited by 85 | Viewed by 18380

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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14 pages, 1620 KiB

Open AccessReview

Anemia and Iron Deficiency in Cancer Patients: Role of Iron Replacement Therapy

by Fabiana Busti, Giacomo Marchi, Sara Ugolini, Annalisa Castagna and Domenico Girelli

Pharmaceuticals 2018, 11(4), 94; https://doi.org/10.3390/ph11040094 - 30 Sep 2018

Cited by 100 | Viewed by 26714

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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15 pages, 1311 KiB

Open AccessReview

Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

by David Alsina, Rosa Purroy, Joaquim Ros and Jordi Tamarit

Pharmaceuticals 2018, 11(3), 89; https://doi.org/10.3390/ph11030089 - 19 Sep 2018

Cited by 30 | Viewed by 7492

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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21 pages, 12719 KiB

Open AccessReview

Mitochondrial Targeting in Neurodegeneration: A Heme Perspective

by Veronica Fiorito, Deborah Chiabrando and Emanuela Tolosano

Pharmaceuticals 2018, 11(3), 87; https://doi.org/10.3390/ph11030087 - 18 Sep 2018

Cited by 27 | Viewed by 5546

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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17 pages, 383 KiB

Open AccessReview

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

by Ana Cordeiro Gomes, Ana C. Moreira, Gonçalo Mesquita and Maria Salomé Gomes

Pharmaceuticals 2018, 11(3), 84; https://doi.org/10.3390/ph11030084 - 1 Sep 2018

Cited by 33 | Viewed by 6628

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)

20 pages, 1673 KiB

Open AccessReview

Intravenous Irons: From Basic Science to Clinical Practice

by Sunil Bhandari, Dora I. A. Pereira, Helen F. Chappell and Hal Drakesmith

Pharmaceuticals 2018, 11(3), 82; https://doi.org/10.3390/ph11030082 - 27 Aug 2018

Cited by 61 | Viewed by 13247

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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13 pages, 1561 KiB

Open AccessFeature PaperConcept Paper

Unraveling Hepcidin Plasma Protein Binding: Evidence from Peritoneal Equilibration Testing

by Laura E. Diepeveen, Coby M. Laarakkers, Hilde P.E. Peters, Antonius E. van Herwaarden, Hans Groenewoud, Joanna IntHout, Jack F. Wetzels, Rachel P.L. van Swelm and Dorine W. Swinkels

Pharmaceuticals 2019, 12(3), 123; https://doi.org/10.3390/ph12030123 - 23 Aug 2019

Cited by 9 | Viewed by 3869

Abstract

Peptide hormone hepcidin regulates systemic iron metabolism and has been described to be partially bound to α2-macroglobulin and albumin in blood. However, the reported degree of hepcidin protein binding varies between <3% and ≈89%. Since protein-binding may influence hormone function and quantification, better [...] Read more.

Peptide hormone hepcidin regulates systemic iron metabolism and has been described to be partially bound to α2-macroglobulin and albumin in blood. However, the reported degree of hepcidin protein binding varies between <3% and ≈89%. Since protein-binding may influence hormone function and quantification, better insight into the degree of hepcidin protein binding is essential to fully understand the biological behavior of hepcidin and interpretation of its measurement in patients. Here, we used peritoneal dialysis to assess human hepcidin protein binding in a functional human setting for the first time. We measured freely circulating solutes in blood and peritoneal fluid of 14 patients with end-stage renal disease undergoing a peritoneal equilibration test to establish a curve describing the relation between molecular weight and peritoneal clearance. Calculated binding percentages of total cortisol and testosterone confirmed our model. The protein-bound fraction of hepcidin was calculated to be 40% (±23%). We, therefore, conclude that a substantial proportion of hepcidin is freely circulating. Although a large inter-individual variation in hepcidin clearance, besides patient-specific peritoneal transport characteristics, may have affected the accuracy of the determined binding percentage, we describe an important step towards unraveling human hepcidin plasma protein binding in vivo including the caveats that need further research. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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1 pages, 175 KiB

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

by Mateusz Szudzik, Rafał R. Starzyński, Aneta Jończy, Rafał Mazgaj, Małgorzata Lenartowicz and Paweł Lipiński

Pharmaceuticals 2019, 12(1), 22; https://doi.org/10.3390/ph12010022 - 29 Jan 2019

Cited by 3 | Viewed by 3094

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 [...]

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(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

11 pages, 915 KiB

Open AccessHypothesis

How Eliminating Malaria May Also Prevent Iron Deficiency in African Children

by John Muthii Muriuki and Sarah H. Atkinson

Pharmaceuticals 2018, 11(4), 96; https://doi.org/10.3390/ph11040096 - 1 Oct 2018

Cited by 14 | Viewed by 6710

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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