scholarly journals Hepcidin: SNP-Like Polymorphisms Present in Iron Metabolism and Clinical Complications of Iron Accumulation and Deficiency

2017 ◽  
Author(s):  
Cadiele Oliana Reichert ◽  
Joel da Cunha ◽  
Débora Levy ◽  
Luciana Morganti Ferreira Maselli ◽  
Sérgio Paulo Bydlowski ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Accumulation ◽  
Clinical Complications

scholarly journals Soybean Ferritin Expression in Saccharomyces cerevisiae Modulates Iron Accumulation and Resistance to Elevated Iron Concentrations

2016 ◽  
Vol 82 (10) ◽  
pp. 3052-3060 ◽  
Author(s):  
Rosa de Llanos ◽  
Carlos Andrés Martínez-Garay ◽  
Josep Fita-Torró ◽  
Antonia María Romero ◽  
María Teresa Martínez-Pastor ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Iron Deficiency ◽  
Iron Metabolism ◽  
Soybean Seed ◽  
Iron Accumulation ◽  
Yeast Cells ◽  
Nutritional Disorder ◽  
Iron Storage ◽  
Content Type ◽  
Iron Concentrations

ABSTRACTFungi, including the yeastSaccharomyces cerevisiae, lack ferritin and use vacuoles as iron storage organelles. This work explored how plant ferritin expression influenced baker's yeast iron metabolism. Soybean seed ferritin H1 (SFerH1) and SFerH2 genes were cloned and expressed in yeast cells. Both soybean ferritins assembled as multimeric complexes, which bound yeast intracellular ironin vivoand, consequently, induced the activation of the genes expressed during iron scarcity. Soybean ferritin protected yeast cells that lacked the Ccc1 vacuolar iron detoxification transporter from toxic iron levels by reducing cellular oxidation, thus allowing growth at high iron concentrations. Interestingly, when simultaneously expressed inccc1Δ cells, SFerH1 and SFerH2 assembled as heteropolymers, which further increased iron resistance and reduced the oxidative stress produced by excess iron compared to ferritin homopolymer complexes. Finally, soybean ferritin expression led to increased iron accumulation in both wild-type andccc1Δ yeast cells at certain environmental iron concentrations.IMPORTANCEIron deficiency is a worldwide nutritional disorder to which women and children are especially vulnerable. A common strategy to combat iron deficiency consists of dietary supplementation with inorganic iron salts, whose bioavailability is very low. Iron-enriched yeasts and cereals are alternative strategies to diminish iron deficiency. Animals and plants possess large ferritin complexes that accumulate, detoxify, or buffer excess cellular iron. However, the yeastSaccharomyces cerevisiaelacks ferritin and uses vacuoles as iron storage organelles. Here, we explored how soybean ferritin expression influenced yeast iron metabolism, confirming that yeasts that express soybean seed ferritin could be explored as a novel strategy to increase dietary iron absorption.

scholarly journals New Mutations in HFE2 and TFR2 Genes Causing Non HFE-Related Hereditary Hemochromatosis

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1980
Author(s):  
Gonzalo Hernández ◽  
Xenia Ferrer-Cortès ◽  
Veronica Venturi ◽  
Melina Musri ◽  
Martin Floor Pilquil ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Iron Metabolism ◽  
Hereditary Hemochromatosis ◽  
Genetic Data ◽  
Common Type ◽  
Iron Deposition ◽  
Nonsense Mutations ◽  
Clinical Complications ◽  
Specialized Center ◽  
New Mutations

Hereditary hemochromatosis (HH) is an iron metabolism disease clinically characterized by excessive iron deposition in parenchymal organs such as liver, heart, pancreas, and joints. It is caused by mutations in at least five different genes. HFE hemochromatosis is the most common type of hemochromatosis, while non-HFE related hemochromatosis are rare cases. Here, we describe six new patients of non-HFE related HH from five different families. Two families (Family 1 and 2) have novel nonsense mutations in the HFE2 gene have novel nonsense mutations (p.Arg63Ter and Asp36ThrfsTer96). Three families have mutations in the TFR2 gene, one case has one previously unreported mutation (Family A—p.Asp680Tyr) and two cases have known pathogenic mutations (Family B and D—p.Trp781Ter and p.Gln672Ter respectively). Clinical, biochemical, and genetic data are discussed in all these cases. These rare cases of non-HFE related hereditary hemochromatosis highlight the importance of an earlier molecular diagnosis in a specialized center to prevent serious clinical complications.

Hemochromatosis and Wilson Disease

2019 ◽  
pp. 176-177
Author(s):  
Josephina A. Vossen
Keyword(s):  
Computed Tomography ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Standard Method ◽  
Wilson Disease ◽  
Structural Changes ◽  
Systemic Disease ◽  
Copper Metabolism ◽  
Iron Accumulation ◽  
Psychiatric Disturbances

Chapter 38 discusses hemochromatosis and Wilson disease. Hemochromatosis is a systemic disease of iron metabolism leading to iron overload, causing organ and joint iron accumulation. This eventually results in tissue damage and organ failure. Wilson disease, also known as hepatolenticular degeneration, is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances. Wilson disease is often fatal if not recognized and treated. Radiography is the standard method for detecting structural changes associated with hemochromatosis arthropathy and Wilson disease. Similar findings are detected with computed tomography. Ultrasound and MRI are not routinely used in diagnosis.

scholarly journals Does Ceruloplasmin Defend Against Neurodegenerative Diseases?

2019 ◽  
Vol 17 (6) ◽  
pp. 539-549 ◽  
Author(s):  
Bo Wang ◽  
Xiao-Ping Wang
Keyword(s):  
Neurodegenerative Diseases ◽  
Iron Metabolism ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Genetic Disorder ◽  
Protective Role ◽  
The Body ◽  
Iron Accumulation ◽  
Ferroxidase Activity ◽  
Abnormal Metabolism

Ceruloplasmin (CP) is the major copper transport protein in plasma, mainly produced by the liver. Glycosylphosphatidylinositol-linked CP (GPI-CP) is the predominant form expressed in astrocytes of the brain. A growing body of evidence has demonstrated that CP is an essential protein in the body with multiple functions such as regulating the homeostasis of copper and iron ions, ferroxidase activity, oxidizing organic amines, and preventing the formation of free radicals. In addition, as an acute-phase protein, CP is induced during inflammation and infection. The fact that patients with genetic disorder aceruloplasminemia do not suffer from tissue copper deficiency, but rather from disruptions in iron metabolism shows essential roles of CP in iron metabolism rather than copper. Furthermore, abnormal metabolism of metal ions and oxidative stress are found in other neurodegenerative diseases, such as Wilson’s disease, Alzheimer’s disease and Parkinson’s disease. Brain iron accumulation and decreased activity of CP have been shown to be associated with neurodegeneration. We hypothesize that CP may play a protective role in neurodegenerative diseases. However, whether iron accumulation is a cause or a result of neurodegeneration remains unclear. Further research on molecular mechanisms is required before a consensus can be reached regarding a neuroprotective role for CP in neurodegeneration. This review article summarizes the main physiological functions of CP and the current knowledge of its role in neurodegenerative diseases.

Suppression of Erythroid-Specific 5-Aminolevulinate Synthase Using Short-Interfering RNA Alters Iron Metabolism and Inhibits Terminal Differentiation of Human Erythroleukemia Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1632-1632
Author(s):  
Kazumichi Furuyama ◽  
Kiriko Kaneko ◽  
Zhang Yongzhao ◽  
Patrick D. Vargas V. ◽  
Shigeru Sassa ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Mrna Level ◽  
Critical Role ◽  
Erythroid Differentiation ◽  
Iron Accumulation ◽  
Erythroid Cell ◽  
Erythroid Cells ◽  
Aminolevulinate Synthase ◽  
Heme Synthesis ◽  
Tgf Β1

Abstract Erythroid-specific 5-aminolevulinate synthase (ALAS2) is the first and the rate limiting enzyme for heme biosynthesis in erythroid cells. ALAS2 plays a critical role in hemoglobin synthesis and erythrocyte maturation, since targeting the ALAS2 gene results in embryonic death in mice because of severe anemia. In humans, heritable mutations of the ALAS2 gene are responsible for X-linked sideroblastic anemia (XLSA). However, the effect of suppressed expression of ALAS2 on erythroid cell differentiation has not been examined in human cells. We therefore addressed this question, by stably suppressing ALAS2 mRNA with short-interfering RNA (siRNA) in a human erythroleukemia cell line, YN-1. After cloning of cells expressing low ALAS2 (ALAS2low cells), cells were induced to undergo erythroid differentiation by treatment with transforming growth factor beta1 (TGF-β1). Gene expression profiles of induced and uninduced cells were examined, including genes involved in globin synthesis and iron metabolism. Hemoglobin production, as judged by o-dianisidine staining, was significantly lower in ALAS2low cells than in control cells both before and after erythroid differentiation. Both alpha and gamma globin mRNA levels were also reduced in ALAS2low cells, compared with control cells. Decreased heme synthesis as well as reduced globin production in ALAS2low erythroid cells are consistent with our previous findings in murine erythroleukemia cells studied by antisense technology (Meguro K, et al. Blood86:940–948, 1995), and extends our previous conclusion on the critical role of ALAS2 in heme and globin formation to human erythroid cells. Transferrin receptor (TFR) mRNA level was decreased in ALAS2low cells, and remained low following TGF-β1 treatment, whereas its level was increased in control cells during erythroid differentiation, which reflects enhanced iron uptake by differentiated control cells. Decreased TFR mRNA level in ALAS2low cells may suggest iron accumulation, since TFR mRNA is known to be unstable when intracellular iron level is increased. Notably, mitochondrial ferritin (MtF) mRNA level was decreased in control cells after differentiation, reflecting utilization of mitochondrial iron for heme synthesis, but it did not change in ALAS2low cells following TGF-β1 treatment. As accumulation of MtF protein is known to occur in iron-overloaded erythroid cells of patients with XLSA, our finding also suggests that there may be intramitochondrial iron accumulation in ALAS2low cells even after differentiation. In contrast to MtF mRNA, the level of cytosolic ferritin heavy chain mRNA was similar both in ALAS2low cells and control cells. These findings suggest that MtF levels, rather than cytosolic ferritin levels, may be a sensitive and specific indicator for iron accumulation in mitochondria. This study shows the critical role of ALAS2 not only in heme synthesis and hemoglobin formation, but also in iron metabolism in erythroid cells during their cell differentiation. An ALAS2low erythroid cell line, such as ALAS2-suppressed YN-1, will provide a good model for the study of relationship between heme biosynthesis and iron metabolism during terminal differentiation of human erythroid cells.

Upregulation of Renal Iron Metabolism in Sickle Cell Disease Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1276-1276
Author(s):  
Guelaguetza Vazquez-Meves ◽  
Namita Kumari ◽  
Nowah Afangbedji ◽  
Alfia Khaibullina ◽  
Zena Quezado ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Epithelial Cells ◽  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Globin Gene ◽  
Proximal Tubules ◽  
Iron Accumulation ◽  
Cell Disease ◽  
Intracellular Iron ◽  
Iron Storage

Abstract BACKGROUND: Hemolysis and frequent blood transfusions lead to the iron overload and organ iron accumulation in patients with red blood cells disorders. The pattern of iron accumulation within different organs is disease specific. Abnormalities of renal iron metabolism and cortical iron deposition is characteristic for sickle cell disease (SCD) but not for β-thalassemia. Renal iron deposition does not correlate with iron overload and blood transfusion. Iron is reabsorbed from primary urine in the renal proximal epithelial cells and released into the renal intersitium by ferroportin. Iron-regulating hormone, hepcidin controls ferroportin expression. Binding of hepcidin to the ferroportin induces ferroportin degradation and intracellular iron accumulation. Low concentrations of circulating hepcidin are common in SCD patients and do not explain paradoxical renal iron accumulation. SCD mice accumulate iron in the epithelial cells of proximal tubules and may be a suitable model to study iron metabolism in SCD. OBJECTIVES: To characterize proteins of the renal iron metabolism in SCD mouse model. METHODS: The SCD (Townes) mice do not express mouse α- or β-globin alleles, but carry two copies of a human α1-globin gene and two copies of a human Aγ-globin and βS-globin genes. These animals synthesize approximately 94% human sickle (HbS) and 6% human fetal hemoglobin (HbF), and no murine hemoglobin. Control animals carry two copies of the human α1-globin gene and two copies of the human hemoglobin gamma (Aγ) gene and the human wildtype hemoglobin beta (βA) gene. Kidneys were collected from 5 months old SCD and control mice. Renal cortex was used for RNA and protein isolation. Levels of renal hepcidin, ferroportin, transferrin receptor (TFR1), divalent cation receptor (DMT1), ferritin and hepheastin were determined by q-RT-PCR, WB and ELISA. Paraffin-embedded sections were used for immunostaining. Perl's Prussian blue staining was used for detection of renal iron accumulation. RESULTS:We detected significant accumulation of iron in the epithelial cells of proximal tubules in SCD mice. Expression of renal hepcidin was increased in SCD mice compared to controls. Surprisingly mRNA levels of all other proteins involved in renal iron metabolism (ferroportin, TFR1, DMT1, ferritin and hephaestin) were decreased in SCD mice kidney. In contrast, we found increased protein levels of transferrin receptor (iron importer), ferritin (iron storage protein) and slightly increased level of ferroportin (iron exporter). We also observed significant renal macrophages infiltration in SCD mice. CONCLUSIONS: Increased levels of renal hepcidin expression in SCD mice may be associated with renal inflammation. Higher levels of locally expressed hepcidin may lead to the partial degradation of the iron exporter (ferroportin). Increased levels of iron importers (TFR1 and DMT1) and no significant change in ferroportin expression can cumulatively saturate iron storage in ferritin and lead to the accumulation of intracellular iron. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants 1P50HL118006, 1R01HL125005 and 5G12MD007597. The content is solely the responsibility of the authors and does not necessarily represent the official view of NHLBI, NIMHD or NIH. Disclosures Quezado: IONIS Pharmaceuticals: Research Funding.

scholarly journals Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Satoru Oshiro ◽  
Masaki S. Morioka ◽  
Masataka Kikuchi
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Lateral Sclerosis

Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs). Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD) and Parkinson's disease (PD), circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS). Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.

scholarly journals Transferrin receptor regulates malignancies and the stemness of hepatocellular carcinoma-derived cancer stem-like cells by affecting iron accumulation

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243812
Author(s):  
Chong Xiao ◽  
Xi Fu ◽  
Yuting Wang ◽  
Hong Liu ◽  
Yifang Jiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Cancer Metastasis ◽  
Regulatory Protein ◽  
Disease Recurrence ◽  
Iron Accumulation ◽  
Upstream Regulator ◽  
Ros Accumulation ◽  
Liver Hepatocellular Carcinoma

Background Iron metabolism is essential because it plays regulatory roles in various physiological and pathological processes. Disorders of iron metabolism balance are related to various cancers, including hepatocellular carcinoma. Cancer stem-like cells (CSCs) exert critical effects on chemotherapy failure, cancer metastasis, and subsequent disease recurrence and relapse. However, little is known about how iron metabolism affects liver CSCs. Here, we investigated the expression of transferrin receptor 1 (TFR1) and ferroportin (FPN), two iron importers, and an upstream regulator, iron regulatory protein 2 (IRP2), in liver hepatocellular carcinoma (LIHC) and related CSCs. Methods The expression levels of TFR1, FPN and IRP2 were analysed using the GEPIA database. CSCs were derived from parental LIHC cells cultured in serum-free medium. After TFR1 knockdown, ROS accumulation and malignant behaviours were measured. The CCK-8 assay was performed to detect cell viability after TFR1 knockdown and erastin treatment. Results TFR1 expression was upregulated in LIHC tissue and CSCs derived from LIHC cell lines, prompting us to investigate the roles of TFR1 in regulating CSCs. Knockdown of TFR1 expression decreased iron accumulation and inhibited malignant behaviour. Knockdown of TFR1 expression decreased reactive oxygen species (ROS) accumulation induced by erastin treatment and maintained mitochondrial function, indicating that TFR1 is critical in regulating erastin-induced cell death in CSCs. Additionally, knockdown of TFR1 expression decreased sphere formation by decreasing iron accumulation in CSCs, indicating a potential role for TFR1 in maintaining stemness. Conclusion These findings, which revealed TFR1 as a critical regulator of LIHC CSCs in malignant behaviour and stemness that functions by regulating iron accumulation, may have implications to improve therapeutic approaches.

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