International Journal of Molecular Sciences

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15 pages, 1601 KiB

Open AccessArticle

Effect of 8-Day Fasting on Leukocytes Expression of Genes and Proteins Involved in Iron Metabolism in Healthy Men

by Andżelika Borkowska, Maja Tomczyk, Małgorzata Żychowska, Wiesław Pilis, Michał Zych and Jędrzej Antosiewicz

Int. J. Mol. Sci. 2021, 22(6), 3248; https://doi.org/10.3390/ijms22063248 - 23 Mar 2021

Cited by 4 | Viewed by 3414

Abstract

The popularity of fasting and restricted food intake is increasing. While the body’s adaptability to dietary insufficiency is crucial for health, molecular mechanisms of adaptive changes are not well understood. Here, we compared the effects of fasting and exercise on the expression of [...] Read more.

The popularity of fasting and restricted food intake is increasing. While the body’s adaptability to dietary insufficiency is crucial for health, molecular mechanisms of adaptive changes are not well understood. Here, we compared the effects of fasting and exercise on the expression of leukocyte genes and proteins involved in the storage, export, and acquisition of iron, an essential element with physiological roles. Healthy men participated in the study (age, 30–70 years; body weight, 60–100 kg; body mass index, 20–29.9 kg/m²). The participants performed an exercise test with a gradually increasing intensity until the individual maximum exercise capacity was reached, before and after 8-d fast. Blood samples were collected before, immediately after, and 3 h after exercise. Gene expression was analyzed by reverse-transcription quantitative polymerase chain reaction and protein levels were analyzed by immunobloting. Eight days of total starvation diet affected the body composition and decreased exercise capacity. Further, fasting decreased the expression of genes associated with iron storage and export, and increased the expression of genes involved in iron acquisition. Conversely, only PCBP2 protein increased after fasting; however, an upward trend was apparent for all proteins. In conclusion, the body adapts to starvation by adjusting iron economy. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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16 pages, 3496 KiB

Open AccessArticle

Matriptase-2 and Hemojuvelin in Hepcidin Regulation: In Vivo Immunoblot Studies in Mask Mice

by Jan Krijt, Jana Frýdlová, Iuliia Gurieva, Petr Přikryl, Martin Báječný, Andrea U. Steinbicker, Martin Vokurka and Jaroslav Truksa

Int. J. Mol. Sci. 2021, 22(5), 2650; https://doi.org/10.3390/ijms22052650 - 6 Mar 2021

Cited by 7 | Viewed by 3084

Abstract

Matriptase-2, a serine protease expressed in hepatocytes, is a negative regulator of hepcidin expression. The purpose of the study was to investigate the interaction of matriptase-2 with hemojuvelin protein in vivo. Mice lacking the matriptase-2 proteolytic activity (mask mice) display decreased content [...] Read more.

Matriptase-2, a serine protease expressed in hepatocytes, is a negative regulator of hepcidin expression. The purpose of the study was to investigate the interaction of matriptase-2 with hemojuvelin protein in vivo. Mice lacking the matriptase-2 proteolytic activity (mask mice) display decreased content of hemojuvelin protein. Vice versa, the absence of hemojuvelin results in decreased liver content of matriptase-2, indicating that the two proteins interact. To further characterize the role of matriptase-2, we investigated iron metabolism in mask mice fed experimental diets. Administration of iron-enriched diet increased liver iron stores as well as hepcidin expression. Treatment of iron-overloaded mask mice with erythropoietin increased hemoglobin and hematocrit, indicating that the response to erythropoietin is intact in mask mice. Feeding of an iron-deficient diet to mask mice significantly increased spleen weight as well as the splenic content of erythroferrone and transferrin receptor proteins, indicating stress erythropoiesis. Liver hepcidin expression was decreased; expression of Id1 was not changed. Overall, the results suggest a complex interaction between matriptase-2 and hemojuvelin, and demonstrate that hepcidin can to some extent be regulated even in the absence of matriptase-2 proteolytic activity. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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19 pages, 3391 KiB

Open AccessArticle

Distinct Effects of Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells

by Edina Pandur, Kitti Tamási, Ramóna Pap, Gergely Jánosa and Katalin Sipos

Int. J. Mol. Sci. 2021, 22(3), 1497; https://doi.org/10.3390/ijms22031497 - 2 Feb 2021

Cited by 13 | Viewed by 4701

Abstract

Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by [...] Read more.

Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by secreting pro-inflammatory cytokines. In bacterial infection, macrophages decrease the serum iron concentration by removing iron from the blood, acting as one of the most important regulatory cells of iron homeostasis. We examined whether the Gram-positive and Gram-negative cell wall components from various bacterial strains affect the cytokine production and iron transport, storage and utilization of THP-1 monocytes in different ways. We found that S. aureus lipoteichoic acid (LTA) was less effective in activating pro-inflammatory cytokine expression that may related to its effect on fractalkine production. LTA-treated cells increased iron uptake through divalent metal transporter-1, but did not elevate the expression of cytosolic and mitochondrial iron storage proteins, suggesting that the cells maintained iron efflux via the ferroportin iron exporter. E. coli and P. aeruginosa lipopolysaccharides (LPSs) acted similarly on THP-1 cells, but the rates of the alterations of the examined proteins were different. E. coli LPS was more effective in increasing the pro-inflammatory cytokine production, meanwhile it caused less dramatic alterations in iron metabolism. P. aeruginosa LPS-treated cells produced a smaller amount of pro-inflammatory cytokines, but caused remarkable elevation of both cytosolic and mitochondrial iron storage proteins and intracellular iron content compared to E. coli LPS. These results prove that LPS molecules from different bacterial sources alter diverse molecular mechanisms in macrophages that prepossess the outcome of the bacterial infection. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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15 pages, 1051 KiB

Open AccessArticle

HIF1A: A Putative Modifier of Hemochromatosis

by Sara Pelucchi, Giulia Ravasi, Cristina Arosio, Mario Mauri, Rocco Piazza, Raffaella Mariani and Alberto Piperno

Int. J. Mol. Sci. 2021, 22(3), 1245; https://doi.org/10.3390/ijms22031245 - 27 Jan 2021

Cited by 6 | Viewed by 2827

Abstract

HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed [...] Read more.

HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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19 pages, 16376 KiB

Open AccessArticle

Exacerbation of Neonatal Hemolysis and Impaired Renal Iron Handling in Heme Oxygenase 1-Deficient Mice

by Aleksandra Bednarz, Paweł Lipiński, Rafał R. Starzyński, Mateusz Tomczyk, Izabela Kraszewska, Sylwia Herman, Kacper Kowalski, Ewelina Gruca, Aneta Jończy, Rafał Mazgaj, Mateusz Szudzik, Zenon Rajfur, Zbigniew Baster, Alicja Józkowicz and Małgorzata Lenartowicz

Int. J. Mol. Sci. 2020, 21(20), 7754; https://doi.org/10.3390/ijms21207754 - 20 Oct 2020

Cited by 5 | Viewed by 3014

Abstract

In most mammals, neonatal intravascular hemolysis is a benign and moderate disorder that usually does not lead to anemia. During the neonatal period, kidneys play a key role in detoxification and recirculation of iron species released from red blood cells (RBC) and filtered [...] Read more.

In most mammals, neonatal intravascular hemolysis is a benign and moderate disorder that usually does not lead to anemia. During the neonatal period, kidneys play a key role in detoxification and recirculation of iron species released from red blood cells (RBC) and filtered out by glomeruli to the primary urine. Activity of heme oxygenase 1 (HO1), a heme-degrading enzyme localized in epithelial cells of proximal tubules, seems to be of critical importance for both processes. We show that, in HO1 knockout mouse newborns, hemolysis was prolonged despite a transient state and exacerbated, which led to temporal deterioration of RBC status. In neonates lacking HO1, functioning of renal molecular machinery responsible for iron reabsorption from the primary urine (megalin/cubilin complex) and its transfer to the blood (ferroportin) was either shifted in time or impaired, respectively. Those abnormalities resulted in iron loss from the body (excreted in urine) and in iron retention in the renal epithelium. We postulate that, as a consequence of these abnormalities, a tight systemic iron balance of HO1 knockout neonates may be temporarily affected. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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17 pages, 2656 KiB

Open AccessArticle

Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage

by Christina Mertens, Laura Kuchler, Anna Sola, Roser Guiteras, Stephan Grein, Bernhard Brüne, Andreas von Knethen and Michaela Jung

Int. J. Mol. Sci. 2020, 21(20), 7527; https://doi.org/10.3390/ijms21207527 - 13 Oct 2020

Cited by 23 | Viewed by 3946

Abstract

During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal [...] Read more.

During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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18 pages, 2328 KiB

Open AccessArticle

Distinct TP53 Mutation Types Exhibit Increased Sensitivity to Ferroptosis Independently of Changes in Iron Regulatory Protein Activity

by Laurie R. Thompson, Thais G. Oliveira, Evan R. Hermann, Winyoo Chowanadisai, Stephen L. Clarke and McKale R. Montgomery

Int. J. Mol. Sci. 2020, 21(18), 6751; https://doi.org/10.3390/ijms21186751 - 15 Sep 2020

Cited by 28 | Viewed by 4740

Abstract

The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. In addition to loss of tumor suppressor functions, mutations in TP53 promote cancer progression by altering cellular iron acquisition and metabolism. A newly identified role for TP53 in the [...] Read more.

The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. In addition to loss of tumor suppressor functions, mutations in TP53 promote cancer progression by altering cellular iron acquisition and metabolism. A newly identified role for TP53 in the coordination of iron homeostasis and cancer cell survival lies in the ability for TP53 to protect against ferroptosis, a form of iron-mediated cell death. The purpose of this study was to determine the extent to which TP53 mutation status affects the cellular response to ferroptosis induction. Using H1299 cells, which are null for TP53, we generated cell lines expressing either a tetracycline inducible wild-type (WT) TP53 gene, or a representative mutated TP53 gene from six exemplary “hotspot” mutations in the DNA binding domain (R273H, R248Q, R282W, R175H, G245S, and R249S). TP53 mutants (R273H, R248Q, R175H, G245S, and R249S) exhibited increased sensitivity ferroptosis compared to cells expressing WT TP53. As iron-mediated lipid peroxidation is critical for ferroptosis induction, we hypothesized that iron acquisition pathways would be upregulated in mutant TP53-expressing cells. However, only cells expressing the R248Q, R175H, and G245S TP53 mutation types exhibited statistically significant increases in spontaneous iron regulatory protein (IRP) RNA binding activity following ferroptosis activation. Moreover, changes in the expression of downstream IRP targets were inconsistent with the observed differences in sensitivity to ferroptosis. These findings reveal that canonical iron regulatory pathways are bypassed during ferroptotic cell death. These results also indicate that induction of ferroptosis may be an effective therapeutic approach for tumor cells expressing distinct TP53 mutation types. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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16 pages, 2305 KiB

Open AccessArticle

Exercise Training and Vitamin C Supplementation Affects Ferritin mRNA in Leukocytes without Affecting Prooxidative/Antioxidative Balance in Elderly Women

by Małgorzata Żychowska, Agata Grzybkowska, Monika Wiech, Robert Urbański, Wanda Pilch, Anna Piotrowska, Olga Czerwińska-Ledwig and Jędrzej Antosiewicz

Int. J. Mol. Sci. 2020, 21(18), 6469; https://doi.org/10.3390/ijms21186469 - 5 Sep 2020

Cited by 6 | Viewed by 3582

Abstract

Physical training and antioxidant supplementation may influence iron metabolism through reduced oxidative stress and subsequent lowering of mRNA levels of genes that are easily induced by this stress, including those responsible for iron homeostasis. Fifteen elderly women participated in our 12-week experiment, involving [...] Read more.

Physical training and antioxidant supplementation may influence iron metabolism through reduced oxidative stress and subsequent lowering of mRNA levels of genes that are easily induced by this stress, including those responsible for iron homeostasis. Fifteen elderly women participated in our 12-week experiment, involving six weeks of training without supplementation and six weeks of training supported by oral supplementation of 1000 mg of vitamin C daily. The participants were divided into two groups (n = 7 in group 1 and n = 8 in group 2). In group 1, we applied vitamin C supplementation in the first six weeks of training, while in group 2 during the remaining six weeks of training. In both phases, the health-related training occurred three times per week. Training accompanied by vitamin C supplementation did not affect prooxidative/antioxidative balance but significantly decreased ferritin heavy chain (FTH) and ferritin light chain (FTL) mRNA in leukocytes (for FTH mRNA from 2^64.24 to 2^11.06, p = 0.03 in group 1 and from 2^60.54 to 2^16.03, p = 0.01 in group 2, for FTL mRNA from 2^20.22 to 2^4.53, p = 0.01 in group 2). We concluded that vitamin C supplementation might have caused a decrease in gene expression of two important antioxidative genes (FTH, FTL) and had no effect on plasma prooxidative/antioxidative balance. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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18 pages, 3183 KiB

Open AccessArticle

Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration

by Paolo Santambrogio, Maddalena Ripamonti, Chiara Paolizzi, Celeste Panteghini, Miryam Carecchio, Luisa Chiapparini, Marzia Raimondi, Alicia Rubio, Ivano Di Meo, Anna Cozzi, Stefano Taverna, Giuseppe De Palma, Valeria Tiranti and Sonia Levi

Int. J. Mol. Sci. 2020, 21(10), 3664; https://doi.org/10.3390/ijms21103664 - 22 May 2020

Cited by 23 | Viewed by 4196

Abstract

Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme [...] Read more.

Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal globus pallidus was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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14 pages, 1211 KiB

Open AccessArticle

Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis

by Marc Vila Cuenca, Giacomo Marchi, Anna Barqué, Clara Esteban-Jurado, Alessandro Marchetto, Alejandro Giorgetti, Viorica Chelban, Henry Houlden, Nicholas W Wood, Chiara Piubelli, Marina Dorigatti Borges, Dulcinéia Martins de Albuquerque, Kleber Yotsumoto Fertrin, Ester Jové-Buxeda, Jordi Sanchez-Delgado, Neus Baena-Díez, Birute Burnyte, Algirdas Utkus, Fabiana Busti, Gintaras Kaubrys, Eda Suku, Kamil Kowalczyk, Bartosz Karaszewski, John B. Porter, Sally Pollard, Perla Eleftheriou, Patricia Bignell, Domenico Girelli and Mayka Sanchez Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(7), 2374; https://doi.org/10.3390/ijms21072374 - 30 Mar 2020

Cited by 27 | Viewed by 5691

Abstract

Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) [...] Read more.

Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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17 pages, 2490 KiB

Open AccessArticle

Liver Iron Retention Estimated from Utilization of Oral and Intravenous Radioiron in Various Anemias and Hemochromatosis in Humans

by Annelies J. van Vuren, Richard van Wijk, Eduard J. van Beers and Joannes J.M. Marx

Int. J. Mol. Sci. 2020, 21(3), 1077; https://doi.org/10.3390/ijms21031077 - 6 Feb 2020

Cited by 3 | Viewed by 3332

Abstract

Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of ⁵⁹Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron [...] Read more.

Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of ⁵⁹Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron uptake after oral and intravenous ⁵⁹Fe administration. We present data from patients with iron deficiency (ID; N = 47), hereditary hemochromatosis (HH; N = 121) and non-transfusion-dependent hereditary anemia (HA; N = 40). Mean mucosal iron uptake and mucosal iron transfer (±SD) were elevated in patients with HH (59 ± 18%, 80 ± 15% respectively), HA (65 ± 17%, 74 ± 18%) and ID (84 ± 14%, 94 ± 6%) compared to healthy controls (43 ± 19%, 64 ± 18%) (p < 0.05) resulting in increased iron retention after 14 days compared to healthy controls in all groups (p < 0.01). The fraction of retained iron utilized for red cell production was 0.37 ± 0.17 in untreated HA, 0.55 ± 0.20 in untreated HH and 0.99 ± 0.22 in ID (p < 0.01). Interestingly, compared to red blood cell iron utilization after oral iron administration, red blood cell iron utilization was higher after injection of transferrin-bound iron in HA and HH. Liver iron retention was considerably higher in HH and HA compared to ID. We hypothesize that albumin serves as a scavenger of absorbed Fe(II) for delivering albumin-bound Fe(III) to hepatocytes. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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Review

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18 pages, 2241 KiB

Open AccessReview

EnvIRONmental Aspects in Myelodysplastic Syndrome

by Verena Petzer, Igor Theurl, Günter Weiss and Dominik Wolf

Int. J. Mol. Sci. 2021, 22(10), 5202; https://doi.org/10.3390/ijms22105202 - 14 May 2021

Cited by 5 | Viewed by 4053

Abstract

Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes [...] Read more.

Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (TET2), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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15 pages, 1479 KiB

Open AccessReview

Is Chelation Therapy a Potential Treatment for Parkinson’s Disease?

by Roberta J. Ward, David T. Dexter, Antonio Martin-Bastida and Robert R. Crichton

Int. J. Mol. Sci. 2021, 22(7), 3338; https://doi.org/10.3390/ijms22073338 - 24 Mar 2021

Cited by 19 | Viewed by 4458

Abstract

Iron loading in some brain regions occurs in Parkinson’s Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that [...] Read more.

Iron loading in some brain regions occurs in Parkinson’s Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that iron is sequestered within cells as a result of the “anaemia of chronic disease” and remains unavailable to the chelator. In this review, the extent of neuroinflammation in PD is discussed together with the role played by glia cells, specifically microglia and astrocytes, in controlling iron metabolism during inflammation, together with the results of MRI studies. The current use of chelators in clinical medicine is presented together with a discussion of two clinical trials of PD patients where an iron chelator was administered and showed encouraging results. It is proposed that the use of anti-inflammatory drugs combined with an iron chelator might be a better approach to increase chelator efficacy. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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13 pages, 3423 KiB

Open AccessReview

The Role of GSH in Intracellular Iron Trafficking

by Robert Hider, Mayra Vera Aviles, Yu-Lin Chen and Gladys Oluyemisi Latunde-Dada

Int. J. Mol. Sci. 2021, 22(3), 1278; https://doi.org/10.3390/ijms22031278 - 28 Jan 2021

Cited by 33 | Viewed by 4643

Abstract

Evidence is reviewed for the role of glutathione in providing a ligand for the cytosolic iron pool. The possibility of histidine and carnosine forming ternary complexes with iron(II)glutathione is discussed and the physiological significance of these interactions considered. The role of carnosine in [...] Read more.

Evidence is reviewed for the role of glutathione in providing a ligand for the cytosolic iron pool. The possibility of histidine and carnosine forming ternary complexes with iron(II)glutathione is discussed and the physiological significance of these interactions considered. The role of carnosine in muscle, brain, and kidney physiology is far from established and evidence is presented that the iron(II)-binding capability of carnosine relates to this role. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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19 pages, 983 KiB

Open AccessReview

Iron Therapy in Chronic Kidney Disease: Days of Future Past

by Kuo-Hua Lee, Yang Ho and Der-Cherng Tarng

Int. J. Mol. Sci. 2021, 22(3), 1008; https://doi.org/10.3390/ijms22031008 - 20 Jan 2021

Cited by 15 | Viewed by 11226

Abstract

Anemia affects millions of patients with chronic kidney disease (CKD) and prompt iron supplementation can lead to reductions in the required dose of erythropoiesis-stimulating agents, thereby reducing medical costs. Oral and intravenous (IV) traditional iron preparations are considered far from ideal, primarily due [...] Read more.

Anemia affects millions of patients with chronic kidney disease (CKD) and prompt iron supplementation can lead to reductions in the required dose of erythropoiesis-stimulating agents, thereby reducing medical costs. Oral and intravenous (IV) traditional iron preparations are considered far from ideal, primarily due to gastrointestinal intolerability and the potential risk of infusion reactions, respectively. Fortunately, the emergence of novel iron replacement therapies has engendered a paradigm shift in the treatment of iron deficiency anemia in patients with CKD. For example, oral ferric citrate is an efficacious and safe phosphate binder that increases iron stores to maintain hemoglobin levels. Additional benefits include reductions in fibroblast growth factor 23 levels and the activation of 1,25 dihydroxyvitamin D. The new-generation IV iron preparations ferumoxytol, iron isomaltoside 1000, and ferric carboxymaltose are characterized by a reduced risk of infusion reactions and are clinically well tolerated as a rapid high-dose infusion. In patients undergoing hemodialysis (HD), ferric pyrophosphate citrate (FPC) administered through dialysate enables the replacement of ongoing uremic and HD-related iron loss. FPC transports iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Moreover, this paper summarizes recent advancements of hypoxia-inducible factor prolyl hydroxylase inhibitors and future perspectives in renal anemia management. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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18 pages, 1512 KiB

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Regulatory Connections between Iron and Glucose Metabolism

by Carine Fillebeen, Nhat Hung Lam, Samantha Chow, Amy Botta, Gary Sweeney and Kostas Pantopoulos

Int. J. Mol. Sci. 2020, 21(20), 7773; https://doi.org/10.3390/ijms21207773 - 21 Oct 2020

Cited by 42 | Viewed by 10042

Abstract

Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin [...] Read more.

Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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Open AccessReview

Iron Metabolism in Obesity and Metabolic Syndrome

by Álvaro González-Domínguez, Francisco M. Visiedo-García, Jesús Domínguez-Riscart, Raúl González-Domínguez, Rosa M. Mateos and Alfonso María Lechuga-Sancho

Int. J. Mol. Sci. 2020, 21(15), 5529; https://doi.org/10.3390/ijms21155529 - 1 Aug 2020

Cited by 145 | Viewed by 11831

Abstract

Obesity is an excessive adipose tissue accumulation that may have detrimental effects on health. Particularly, childhood obesity has become one of the main public health problems in the 21st century, since its prevalence has widely increased in recent years. Childhood obesity is intimately [...] Read more.

Obesity is an excessive adipose tissue accumulation that may have detrimental effects on health. Particularly, childhood obesity has become one of the main public health problems in the 21st century, since its prevalence has widely increased in recent years. Childhood obesity is intimately related to the development of several comorbidities such as nonalcoholic fatty liver disease, dyslipidemia, type 2 diabetes mellitus, non-congenital cardiovascular disease, chronic inflammation and anemia, among others. Within this tangled interplay between these comorbidities and associated pathological conditions, obesity has been closely linked to important perturbations in iron metabolism. Iron is the second most abundant metal on Earth, but its bioavailability is hampered by its ability to form highly insoluble oxides, with iron deficiency being the most common nutritional disorder. Although every living organism requires iron, it may also cause toxic oxygen damage by generating oxygen free radicals through the Fenton reaction. Thus, iron homeostasis and metabolism must be tightly regulated in humans at every level (i.e., absorption, storage, transport, recycling). Dysregulation of any step involved in iron metabolism may lead to iron deficiencies and, eventually, to the anemic state related to obesity. In this review article, we summarize the existent evidence on the role of the most recently described components of iron metabolism and their alterations in obesity. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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18 pages, 1534 KiB

Open AccessHypothesis

How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children

by Kelvin M. Abuga, John Muthii Muriuki, Thomas N. Williams and Sarah H. Atkinson

Int. J. Mol. Sci. 2020, 21(18), 6976; https://doi.org/10.3390/ijms21186976 - 22 Sep 2020

Cited by 17 | Viewed by 12931

Abstract

Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. [...] Read more.

Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis. Full article

(This article belongs to the Special Issue Transport, Cellular Uptake and Metabolism of Iron: Molecular Aspects and Regulation in Health and Disease)

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