Basic Understanding of Iron Metabolism / 임상소아혈액종양

Iron is critical for almost all living organisms because it serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism. Disruption of iron homeostasis is associated with a wide range of diseases. Thus mammals have developed sophisticated mechanisms to maintain optimal range of iron concentration. Iron regulation involves processes at the systemic and cellular levels. These processes are regulated by hepcidin and iron regulatory proteins. Hepcidin modulates systemic iron homeostasis with ability to impede cellular iron export via interaction with the iron export protein, ferroportin. Whereas, iron regulatory proteins control cellular iron homeostasis by translational regulation of proteins which involve iron metabolism. Recent advances in the study of iron metabolism have shown promising results that hepcidin-targeted strategies may help to improve the diagnosis and treatment of iron related diseases. Although these strategies are now under development, ongoing studies can help to elucidate its application possibilities.

Estudio prospectivo de la concentración de hierro sérico en donantes de plasma durante un año / Prospective study during a year of the iron concentration in plasma donors

Introducción: los donantes regulares de plasmaféresis, tienen pérdidas de masa eritrocitaria que pueden afectar, en dependencia de las individualidades, sus reservas de hierro. Objetivo: determinar comportamiento evolutivo durante un año de la sideremia en donantes de plasmaféresis. Método: se realizó un estudio observacional descriptivo en 200 donantes de plasma del Banco de Sangre Provincial de Cienfuegos. Se cuantificó de forma seriada la concentración de hierro sérico. Se relacionó la cantidad de individuos con valores bajos del mineral y variables sexo, edad, tiempo donando plasma, frecuencia de donaciones y concentración de hemoglobina. Resultados: los valores grupales promedio de hierro sérico mostraron tendencia a disminuir dentro de la normalidad, aunque se constató en un pequeño grupo déficit de hierro latente y en otro ligera anemia, más frecuente en mujeres, y mayores de 44 años, relacionado con mayor intensidad en cada ciclo de donación y tiempo de permanencia como donante de plasma. Conclusiones: sin llegar a establecer relación causal directa, los resultados de la investigación apuntan hacia el desarrollo de déficit progresivo de hierro en los donantes regulares de plasma,por balance negativo del mineral. Es preciso observar con mayor acercamiento la donación de plasma, que como proceso ético e inocuo, evite efectos no deseados en los donantes(AU)

Introduction: Regular plasmapheresis donors have erythrocytemas losses that can affect, depending on individualities, their iron stores. Aim: To determine evolutionary behavior during one year of serum iron in plasmapheresis donors. Method: A descriptive observational study was carried out on 200 plasma donors from the Provincial Blood Bank of Cienfuegos. The serum iron concentration was serially quantified. The number of individuals with low values of the mineral and variables gender, age, time donating plasma, frequency of donations and hemoglobin concentration were related. Results: The serum iron average showed a tendency to decrease within normal range, although it was found in a small group of latent iron deficiency and in another slight anemia, more frequent in women, and over 44 years old, related to greater intensity in each donation cycle and time of permanence as a plasma donor. Conclusions: Without establishing a direct causal relationship, the results of the research point to the development of progressive iron deficiency in regular plasma donors, due to the negative balance of the mineral. The donation of plasma, as an ethical and harmless process, should be monitored more closely, avoiding undesirable effects on donors(AU)

Regulación de la hepcidina y homeostasis del hierro: avances y perspectivas / Regulation of hepcidin and iron homeostasis: progress and prospects

El estudio de los desórdenes genéticos del metabolismo del hierro, la identificación de sus transportadores y el descubrimiento de la hepcidina, hormona reguladora de la homeostasia del hierro, han contribuido grandemente a aumentar los conocimientos sobre este metabolismo y han cambiado sustancialmente la visión sobre las enfermedades relacionadas con alteraciones del metabolismo férrico. En la última década, no solo se han esclarecido elementos de la patogénesis de estas enfermedades, sino que ya se vislumbran aplicaciones terapéuticas de estos avances. Así, ya se habla de una nueva era basada en el tratamiento de los desórdenes de la homeostasia del hierro a través de la modulación de la hepcidina

The study of genetic disorders of iron metabolism, identification of transporters and the discovery of hepcidin- a hormone regulating iron homeostasis- have contributed greatly to increase awareness of this metabolism. Substantially, the vision on diseases related to disorders of iron metabolism has been changed. In the last decade, elements of the pathogenesis of these diseases have not only been clarified, but therapeutic applications of these advances are looming. Thus, there are expectations of a new era based on the treatment of iron homeostasis disorders through hepcidin modulation

key regulator for iron homeostasis in chronic hepatitis C

Hepcidin is a small, cysteine-rich cationic peptide produced by hepatocytes. There is a single human hepcidin gene; whose essential role in iron homeostasis was confirmed by identifying homozygous frameshift or nonsense mutations in affected individuals with severe Juvenile hemochromatosis. IL-6 may be the mediator of hepcidin induction by inflammation. Hypoferremia is a common response to systemic infections or generalized inflammatory disorders, anemia of chronic disease occurs in patients with acute and chronic immune activation and represents an important clinical problem. The study will attempt to determine the hepatic hepcidin expression levels in patients with chronic hepatitis C virus infection. Fifty patients with chronic hepatitis C virus infection [CHCV], their age between [20- 55] years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, before interferon and Ribavirin therapy, and ten healthy individuals were included to serve as controls. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigations. CBCs and serological assay for serum ferritin, iron, transferrin [s-TFR] levels, Liver biopsy for hepcidin mRNA levels and iron deposits in liver by [PCR] polymerase chain reaction. All subjects gave written informed consent for enrolment in the study, which was approved by the Research Ethical Committee of the General Organization for Teaching Hospitals and Institutes. Liver biopsy was taken from healthy subjects during abdominal surgery. Our results revealed that hepatic hepcidin expression is considered highly valid marker in case of CHCV infection. Our study concluded that there's a highly significant inverse correlation between hepcidin versus liver iron, serum iron and serum transferrin but there's no significant correlation versus ferritin. Hepcidin measuring and manipulating hepcidin levels will, in the future, have a role in diagnosing and treating any number of iron related disorders. Hepcidin itself has antimicrobial properties of uncertain importance so that careful clinical trials will be required to define appropriate indications of hepcidin antagonists

Métodos de determinação da biodisponibilidade do ferro: ênfase na utilização de radionuclídeo 59 / Methods for determining the bioavailability of iron: emphasis on the use of 59

Iron deficiency can be caused by imbalance between the available amount of the mineral and the body requirement. Thus, the study of iron bioavailability has been of growing interest from the nutritional point of view, due to its recognized role in the physiological and biochemical regulation, besides the contribution to the establishment of recommendations for intake of this element depending on the individuals? requirements and disease prevention. In the assessment of bioavailability, one should use methodologies depicting the chemical forms, allowing for a thorough ana lysis of the results and repeating the physiological conditions as much as possible. Therefore, radioisotopes are ideal tracers due to the specifi city of their identifi cation and quantification. This procedure is usually characterized by good precision, due to the greater analytical sensitivity and the ability for detection ?in vivo?. This work aims to elucidate the use of radioisotopes in various methodologies for studies of iron bioavailability in animals.

La anemia por deficiencia de hierro puede ser causada por desequilibrio en la cantidad biodisponible y su necesidad orgánica. Debidoa eso, la biodisponibilidad de hierro ha sido objeto de creciente interés desde el punto de vista nutricional por el reconocido papel en laregulación fisiológica y bioquímica, además de contribuir a la fijación de la ingestión recomendada de este elemento en función de las necesidades de los individuos y para prevenir enfermedades. En la evaluación dela biodisponibilidad deberán ser utilizadas metodologías que procuren dilucidar las formas químicas, que permitan un análisis cuidadosode los resultados y que reproduzcan lo más fielmente posible las condiciones fisiológicas. Por eso, los radioisótopos trazadores son ideales,por la especificidad con que son identificados y cuantificados. Este trabajo tuvo por objetivo dilucidar la utilización de radioisótopos en diversas metodologías para estudios de biodisponibilidad de hierro en animales.

A anemia ferropriva pode ser causada pelo desequilíbrio na quantidade biodisponível e a sua necessidade orgânica. Assim, o estudode biodisponibilidade do ferro tem sido alvo de crescente interesse do ponto de vista nutricional, pelo reconhecido papel na regulaçãofisiológica e bioquímica, além de contribuir no estabelecimento das recomendações de ingestão deste elemento em função das necessidades dos indivíduos e para prevenir doenças. Na avaliação da biodisponibilidade, deverão ser utilizadas metodologias que procurem elucidar as formas químicas, que permitam uma análise criteriosados resultados e que reproduzam o mais possível as condições fisiológicas. Assim, os radioisótopos são traçadores ideais pela especificidade com que são identificados e quantificados. Esseprocedimento é normalmente caracterizado por boa precisão, devido à maior sensibilidade analítica e à capacidade de detecção in vivo. Opresente trabalho objetiva elucidar a utilização dos radioisótopos em diversas metodologias para estudos de biodisponibilidade de ferro emanimais.

Protective effect and mechanism of hepcidin in rats with alcoholic liver damage / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the mechanism of how iron-regulatory protein (hepcidin) affect iron overload in alcoholic liver disease (ALD).</p><p><b>METHODS</b>Thirty male wistar rats were randomly divided into 3 groups: Lieber-Decarli liquid without alcohol group (control group), Lieber-Decarli liquid with alcohol (alcohol group) and hepcidin intraperitoneally injected group (hepcidin group), each rat was fed for 6 weeks. The Serum concentration of Alanine Aminotransferase (ALT), Aspartate Amino Transferase (AST), Iron, Total Iron Binding capacity (TIBC), Ferritin, Malonyl Dialdehyde (MDA) and Hepcidin were determined. Hepatic tissue was examined by hematoxylin and eosin staining, prussian blue iron staining and immunohistochemistry staining.</p><p><b>RESULTS</b>(1) Serum concentration of ALT in control group, alcohol group and hepcidin group were (25.2 ± 4.6) U/L, (37.9 ± 14.3) U/L and (40.9 ± 14.1) U/L (F = 4.907, P < 0.05), respectively. Serum AST among three groups were (32.3 ± 13.4) U/L, (55.0 ± 18.6) U/L and (48.3 ± 26.0) U/L (F = 3.742, P < 0.05), respectively. The secretions of ferritin were (224.72 ± 85.49) ng/ml, (345.59 ± 124.75) ng/ml and (339.47 ± 138.47) ng/ml (F = 3.539, P < 0.05). The serum concentrations of TIBC were (147.30 ± 31.98) μmol/L, (148.04 ± 58.74) μmol/L and (143.28 ± 37.38) μmol/L (F = 1.209, P > 0.05), respectively. The serum concentrations of iron were (55.64 ± 13.32) μmol/L, (60.37 ± 25.89) μmol/L and (49.77 ± 17.64) μmol/L (F = 0.651, P > 0.05), respectively. The serum concentration of MDA were (5.84 ± 2.17) nmol/ml, (6.51 ± 2.23) nmol/ml and (4.27 ± 2.68) nmol/ml (F = 2.782, P > 0.05), respectively. The serum concentration of Hepcidin were (155.96 ± 44.91)ng/ml, (124.11 ± 31.98) ng/ml and (114.96 ± 25.81) ng/ml (F = 3.839, P < 0.05), respectively. (2) Significant fat change observed in the liver of alcohol group. The positive granulations of iron staining were (0.8 ± 1.0), (1.2 ± 1.6) and (1.1 ± 1.1) (F = 0.254, P > 0.05), respectively. No differences found of liver iron express among the three groups. Intraperitoneal injection of hepcidin increased hepcidin expression in liver which was inhibited by alcohol (F = 4.139, P < 0.05).</p><p><b>CONCLUSIONS</b>ALD rats with lower hepcidin expression in liver can result in iron metabolism disorder. Ectogenic hepcidin can protect liver against alcohol damage by inhibiting lipid peroxidation.</p>

Actualizacion: deficiencia de hierro y zinc en niños / Update: iron and zinc deficiency in children

ivel mundial, en Bolivia el 82% de los niños de 6 a 23 meses son anémicos. El retardo de crecimiento es un problema frecuente en países en desarrollo, el 32% de los niños bolivianos lo sufren, esta prevalencia es la más altade Sudamérica.

Nuevas moléculas que regulan el metabolismo de hierro / New molecules that regulate iron metabolism

La homeostasis del hierro constituye un mecanismo complejo, hasta hace poco prácticamente desconocido y generador de grandes incertidumbres. El descubrimiento de nuevas moléculas que intervienen en la regulación de su metabolismo - como las proteínas de transporte de membrana, de circulación y/ o de almacenamiento-, junto al hallazgo de nuevos conocimientos en la regulación de los ARNm - responsables de la trascripción de estas nuevas proteínas, de regulación pos-transcripcional y/o pre-traducción-, han permitido comprender un poco más la fisiología de este ponderado metabolismo del hierro y la fisio-patología de las afecciones desencadenadas por las alteraciones y/o mutaciones de los genes responsables de la síntesis de estas proteínas.

Expression of mitochondrial ferritin in K562 leukemic cell during TPA-induced cell differentiation / 中国实验血液学杂志

Mitochondrial ferritin (MtF), a new player in iron metabolism, first identified in 2001, is highly homologous to ferritin both structurally and functionally. Preliminary studies have suggested that MtF might play very important roles in the regulation of mitochondrial iron homeostasis. Leukemic cells, just like other malignant cells, demand more iron for their greater proliferation potential. However, little is known about what roles MtF might play in leukemic cell iron metabolism and cell proliferation. The aim of this study was to investigate the expression of MtF, transferrin receptor 1 (TfR1) and ferritin (Fn) mRNAs in K562 leukemic cells during TPA-induced cell differentiation and to explore the interrelationship between the expression levels of these iron metabolism-related molecules. K562 cells cultured with or without TPA (16 nmol/L) were collected at 24, 72 and 120 hours respectively. Cell differentiation toward monocyte lineage was confirmed by microscopic study (Wright's staining) and flow cytometry. Semiquantitative RT-PCR was performed to determine mRNA expression, with house-keeping gene beta-actin as control reference. This study revealed that over 95% of K562 cells showed morphological features of monocyte/macrophage, and the expression of CD64 on cell surface increased significantly at day 5 with TPA treatment. K562 cells could express a certain level of MtF before TPA-induced differentiation. With increase of TPA-induced cell differentiation, MtF mRNA expressions were downregulated progressively. After 5 days of induced cell differentiation, expression levels of MtF and TfR1 mRNA were just 50.3% and 68.2% of that before TPA treatment. While Fn mRNA expression increased to 1.97 folds of that before TPA treatment. It is concluded that MtF expression is downregulated during TPA-induced K562 cell differentiation, with concomitant downregulation of TfR1 and upregulation of Fn. The coordinated expression regulation of these key iron metabolism-related molecules during cell differentiation may in turn inhibit TfR1-mediated iron uptake via endocytosis and thus adversely affect cell proliferation potential.

Detection of the labile iron pool in leukemia cells and its significance / 中国实验血液学杂志

To explore a rapid and easy method to detect labile iron of pool (LIP) in cells, HL-60 and K562 cells were cultured at a concentration 1 x 10(6)/ml in RPMI 1640 containing 10% heat-inactivated fetal bovine serum. The iron deprivation was induced by adding desferrioxamine (DFO) 10 - 100 micromol/L for 0 - 48 hours. The intracellular LIP was measured by probe calcein-AM. Calcein fluorescence was monitored in 1420 multilabel counter. The results indicated that when HL-60 and K562 cells were incubated with different concentrations of DFO, the calcein fluorescence intensity was higher than that of control group at 12, 24 and 48 hours (P < 0.05). Fluorescence value of representing LIP in DFO groups was lower than that in the control group. In conclusion, DFO can decrease LIP in leukemia cells. The approach used in this study may provide a simple and reliable method for detection of intracellular iron homeostasis.

Translational control of ceruloplasmin gene expression: Beyond the IRE

Translational control is a common regulatory mechanism for the expression of iron-related proteins. For example, three enzymes involved in erythrocyte development are regulated by three different control mechanisms: globin synthesis is modulated by heme-regulated translational inhibitor; erythroid 5-aminolevulinate synthase translation is inhibited by binding of the iron regulatory protein to the iron response element in the 5'-untranslated region (UTR); and 15-lipoxygenase is regulated by specific proteins binding to the 3'-UTR. Ceruloplasmin (Cp) is a multi-functional, copper protein made primarily by the liver and by activated macrophages. Cp has important roles in iron homeostasis and in inflammation. Its role in iron metabolism was originally proposed because of its ferroxidase activity and because of its ability to stimulate iron loading into apo-transferrin and iron efflux from liver. We have shown that Cp mRNA is induced by interferon (IFN)-ã in U937 monocytic cells, but synthesis of Cp protein is halted by translational silencing. The silencing mechanism requires binding of a cytosolic inhibitor complex, IFN-Gamma-Activated Inhibitor of Translation (GAIT), to a specific GAIT element in the Cp 3'-UTR. Here, we describe our studies that define and characterize the GAIT element and elucidate the specific trans-acting proteins that bind the GAIT element. Our experiments describe a new mechanism of translational control of an iron-related protein and may shed light on the role that macrophage-derived Cp plays at the intersection of iron homeostasis and inflammation.

Iron at the center of ferritin, metal/oxygen homeostasis and novel dietary strategies

Bioiron _ central to respiration, photosynthesis and DNA synthesis and complicated by radical chemistry with oxygen _ depends on ferritin, the super family of protein nanocages (maxi-ferritins in humans, animals, plants and bacteria, and mini-ferritins, also called DPS proteins, in bacteria) for iron and oxygen control. Regulation of ferritin synthesis, best studied in animals, uses DNA transcription and mRNA translation check points. Ferritin is a member of both the "oxidant stress response" gene family that includes thioredoxin reductase and quinine reductase, and a member of the iron responsive gene family that includes ferroportin and mt-aconitase ferritin DNA regulation responds preferentially to oxidant response inducers and ferritin mRNA to iron inducers; heme confers regulator synergy. Ferritin proteins manage iron and oxygen, with ferroxidase sites and iron + oxygen substrates to form mineral of both Fe and O atoms; maxi-ferritins contribute more to cellular iron metabolism and mini-ferritins to stress responses. Iron recovery from ferritin is controlled by gated protein pores, possibly contributing to iron absorption from ferritin, a significant dietary iron source. Ferritin gene regulation is a model for integrating DNA/mRNA controls, while ferritin protein function is central to molecular nutrition cellular metabolism at the crossroads of iron and oxygen in biology.

Hepcidina: nueva molécula, nuevos horizontes / Hepcidine: a new molecule opening up new horizons

En los últimos años se han descubierto al menos 7 nuevas moléculas relacionadas con la homeostasia del hierro, lo que cambia la visión clásica acerca del metabolismo de este mineral. Probablemente sea la hepcidina la más interesante de todas, por considerarse un regulador negativo de la absorción del hierro en el intestino delgado y de su liberación por los macrófagos. Esta proteína es un péptido antimicrobiano rico en cisteínas, producido en el hígado, que se estima como considerado como un elemento clave en la regulación de la absorción y cinética del hierro en el organismo. Su expresión es regulada por el hierro y el estímulo inflamatorio, por lo que es considerada una reactante de fase aguda. La hepcidina se presenta como un candidato atractivo para mediador en la anemia de los procesos crónicos y en otros trastornos del metabolismo férrico, lo que le confiere a esta molécula un futuro prometedor en el diagnóstico y tratamiento de estos estados patológicos

The cellular mechanisms of body iron homeostasis

Cells tightly regulate iron levels through the activity of iron regulatory proteins (IRPs) that bind to RNA motifs called iron responsive elements (IREs). When cells become iron-depleted, IRPs bind to IREs present in the mRNAs of ferritin and the transferrin receptor, resulting in diminished translation of the ferritin mRNA and increased translation of the transferrin receptor mRNA. Similarly, body iron homeostasis is maintained through the control of intestinal iron absorption. Intestinal epithelia cells sense body iron through the basolateral endocytosis of plasma transferrin. Transferrin endocytosis results in enterocytes whose iron content will depend on the iron saturation of plasma transferrin. Cell iron levels, in turn, inversely correlate with intestinal iron absorption. In this study, we examined the relationship between the regulation of intestinal iron absorption and the regulation of intracellular iron levels by Caco-2 cells. We asserted that IRP activity closely correlates with apical iron uptake and transepithelial iron transport. Moreover, overexpression of IRE resulted in a very low labile or reactive iron pool and increased apical to basolateral iron flux. These results show that iron absorption is primarily regulated by the size of the labile iron pool, which in turn is regulated by the IRE/IRP system.