Current status of iron metabolism: Clinical and therapeutic implications

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"documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2017;148:218-24" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 92 "formatos" => array:3 [ "EPUB" => 1 "HTML" => 81 "PDF" => 10 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Revisión" "titulo" => "Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "218" "paginaFinal" => "224" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Current status of iron metabolism: Clinical and therapeutic implications" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figura 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1578 "Ancho" => 1685 "Tamanyo" => 228326 ] ] "descripcion" => array:1 [ "es" => "Síntesis de hepcidina. El eje principal que controla la síntesis de hepcidina es el bone morphogenetic protein-hemojuvelina-sons of mothers against decapentaplegic (BMP-HJV-SMAD). La transferrina unida al hierro (Tf-Fe2) es un sensor de los hepatocitos para el control de la transcripción de hepcidina. La unión de Tf-Fe2 con los receptores de la transferrina (TfR1 y TfR2) y con la proteína de la hemocromatosis humana (HFE) se correlaciona inversamente con los niveles de saturación de la transferrina por el hierro, de tal manera que, si los niveles aumentan, la HFE es desplazada de TfR1 al TfR2 para activar BMP. Esta activación facilita la unión de BMP6 con sus receptores 1 y 2 (BMPR1 y BMPR2), en presencia de hemojuvelina (HJV) y de neoginina (NEO), y pone en marcha la fosforilización de SMAD 1/5/8, la transcripción del gen hepcidin antimicrobial peptide (HAMP) y la síntesis de hepcidina. Otro mediador importante en la síntesis de hepcidina es la inflamación a través de la IL6 y activina B (Act-B) por vía janus kinasa- signal transducer and activator of transcription (JAK-STAT3) y BMP. La principal señal inhibidora de hepcidina proviene de la médula ósea durante la eritropoyesis activa y tiene lugar a través de distintas proteínas entre las que sobresalen la eritroferrona (ERFE), el growth differentiation factor (GDF15) y el twisted gastrulation BMP signaling modulator (TWSG1), que inhiben la vía SMAD. La matriptasa-2 (MT-2), codificada por el gen TMPRSS6, también tiene un efecto inhibitorio sobre la transcripción de hepcidina por escisión de la HJV, impidiendo la activación del complejo BMP. Otras señales inhibidoras de la síntesis de hepcidina provienen de las situaciones que generan hipoxia tisular y de la administración de factores estimulantes de la eritropoyesis como la eritropoyetina (EPO)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Susana Conde Diez, Ricardo de las Cuevas Allende, Eulogio Conde García" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Susana" "apellidos" => "Conde Diez" ] 1 => array:2 [ "nombre" => "Ricardo" "apellidos" => "de las Cuevas Allende" ] 2 => array:2 [ "nombre" => "Eulogio" "apellidos" => "Conde García" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020617301675" "doi" => "10.1016/j.medcle.2017.03.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301675?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316306649?idApp=UINPBA00004N" "url" => "/00257753/0000014800000005/v1_201702231707/S0025775316306649/v1_201702231707/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020617301705" "issn" => "23870206" "doi" => "10.1016/j.medcle.2017.03.002" "estado" => "S300" "fechaPublicacion" => "2017-03-08" "aid" => "3888" "copyright" => "Elsevier España, S.L.U." 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It can be considered in cases of very severe reaction and if the formulation cannot be changed and/or if the planned treatment has been almost completed." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pere Barba, José Luis Dapena, Pau Montesinos, Susana Rives" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Pere" "apellidos" => "Barba" ] 1 => array:2 [ "nombre" => "José Luis" "apellidos" => "Dapena" ] 2 => array:2 [ "nombre" => "Pau" "apellidos" => "Montesinos" ] 3 => array:2 [ "nombre" => "Susana" "apellidos" => "Rives" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S002577531630673X" "doi" => "10.1016/j.medcli.2016.12.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S002577531630673X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301705?idApp=UINPBA00004N" "url" => "/23870206/0000014800000005/v1_201704020027/S2387020617301705/v1_201704020027/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020617301699" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.12.053" "estado" => "S300" "fechaPublicacion" => "2017-03-08" "aid" => "3886" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2017;148:215-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1 "PDF" => 1 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial article" "titulo" => "Outcome of critically ill patients" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "215" "paginaFinal" => "217" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Pronóstico de los enfermos en situación crítica" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sebastián Iribarren Diarasarri" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Sebastián" "apellidos" => "Iribarren Diarasarri" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775316306716" "doi" => "10.1016/j.medcli.2016.12.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316306716?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301699?idApp=UINPBA00004N" "url" => "/23870206/0000014800000005/v1_201704020027/S2387020617301699/v1_201704020027/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Current status of iron metabolism: Clinical and therapeutic implications" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "218" "paginaFinal" => "224" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Susana Conde Diez, Ricardo de las Cuevas Allende, Eulogio Conde García" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Susana" "apellidos" => "Conde Diez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Ricardo" "apellidos" => "de las Cuevas Allende" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "Eulogio" "apellidos" => "Conde García" "email" => array:2 [ 0 => "euconde@humv.es" 1 => "condee@unican.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Medicina de Familia, Servicio Cántabro de Salud, Santander (Cantabria), Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Medicina de Familia, Servicio Cántabro de Salud, Centro de Salud Bajo Asón, Ampuero (Cantabria), Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Hematología, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander (Cantabria), Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1041 "Ancho" => 1734 "Tamanyo" => 124041 ] ] "descripcion" => array:1 [ "en" => "Body iron homeostasis. The interaction of hepcidin with ferroportin (FPN) controls the main efflux of iron into plasma." ] ] ] "textoCompleto" => "IntroductionIron is an essential nutrient in the body which plays a central role in cellular energy metabolism, anaerobic respiration, synthesis of haemoglobin and nucleotide synthesis, additionally, it is also involved in many other processes of exudative metabolism and cellular immune response.<a class="elsevierStyleCrossRef" href="#bib0295">1</a> In the adult, the total amount of iron in the body is 3–4g, of which 65% is in haemoglobin, 25% in deposit organs (liver, reticuloendothelial system macrophages and bone marrow) and the remaining 10% in myoglobin, cytochromes, peroxidase and catalases.<a class="elsevierStyleCrossRef" href="#bib0300">2</a> Every day, 1–2mg/d of iron is absorbed from the diet, which is the same amount lost daily, but it should be noted that the organism does not have an active iron excretion mechanism, so that control of the duodenal absorption plays a vital role in iron homeostasis.<a class="elsevierStyleCrossRef" href="#bib0305">3</a> Plasma iron circulates bound to transferrin and it comes from the iron which is absorbed and the iron that comes from deposit organs, which release it into the plasma through ferroportin.<a class="elsevierStyleCrossRefs" href="#bib0295">1–3</a> Their accumulation leads to iron overload that is toxic and can damage tissues and cause cell death by free radical formation and lipid peroxidation. For this reason, the circulating iron is never found in free form, it is always attached to other molecules, mainly transferrin, but when concentrations of plasma iron are high and transferrin is saturated, the excess iron is bound to other plasma molecules of low molecular weight such as citrate, acetate and albumin.<a class="elsevierStyleCrossRef" href="#bib0300">2</a>The iron in the body follows a cycle consisting of duodenal absorption, distribution through the plasma bound to transferrin and transfer to cells via the transferrin receptor, located in the cytoplasmic membrane, for use in different metabolic processes or for storing it in deposit organs.<a class="elsevierStyleCrossRefs" href="#bib0295">1–3</a> When red blood cells age, they are destroyed in macrophages, mainly in the spleen, and iron is reused after passing through the plasma (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Foods containing ferric iron which, after being reduced to the ferrous form, it is absorbed by duodenal enterocytes and subsequently released into plasma through ferroportin (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Regulation of iron homeostasis. Hepcidin-ferroportin axisHepcidin is the main hormone that regulates iron metabolism. It is synthesized in the liver and its main mission is to control the arrival of iron in plasma from food through enterocytes, macrophages, which contain the iron coming from recycled senescent red blood cells, and that released from the deposits (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Ferroportin is responsible for the efflux of iron from enterocytes, macrophages and hepatocytes into the plasma. Hepcidin binds to ferroportin for its destruction by endocytosis into the cell's lysosomes resulting, on the one hand, in a hyposideremia by lowering the iron transferred to the plasma and, on the other hand, to the accumulation of iron as ferritin enterocytes, macrophages and hepatocytes.<a class="elsevierStyleCrossRefs" href="#bib0295">1–3</a> The control of iron homeostasis by hepcidin is a classic endocrine regulation system; in the words of Ganz, the relationship of hepcidin with iron is similar to that of insulin with glucose.<a class="elsevierStyleCrossRef" href="#bib0310">4</a> Hepcidin is therefore the principal regulator of iron and plays a key role in all its abnormalities, whether having to do with deficiency or excess. Hepcidin deficiency causes iron overload, while its excess favours iron sequestration in the liver and macrophages and contributes to the development of iron deficiency anaemias or because of its misuse in anaemia of chronic disease.<a class="elsevierStyleCrossRef" href="#bib0315">5</a> In these cases, a functional iron deficiency anaemia occurs because iron reserves are not available for erythropoiesis.<a class="elsevierStyleCrossRefs" href="#bib0315">5,6</a> Increased hepcidin also occurs in chronic inflammatory processes by an increase in IL6, which also represents a host defence mechanism against infection by limiting the availability of extracellular iron to microorganisms.<a class="elsevierStyleCrossRef" href="#bib0315">5</a> Hepcidin production is negatively regulated by erythropoiesis through mediators that prevent its production when iron is required for haemoglobin synthesis.<a class="elsevierStyleCrossRef" href="#bib0315">5</a> Hepcidin is an acute phase reactant that responds to a variety of inflammatory mediators and signals that activate transcription through different signalling pathways.<a class="elsevierStyleCrossRef" href="#bib0315">5</a>Regulation of hepcidin expressionHepcidin, encoded by the gene HAMP, is the hormone that regulates iron metabolism. It is a 25-amino acid peptide produced by hepatocytes interacting with the ferroportin found in the cell membrane of enterocytes, macrophages and hepatocytes.<a class="elsevierStyleCrossRef" href="#bib0325">7</a> Regulation of hepcidin is a multifactorial process involving different stimulatory and inhibitory signals which, in various ways, control its final transcript.<a class="elsevierStyleCrossRefs" href="#bib0325">7,8</a> Hepcidin is regulated by plasma iron through a feedback mechanism which involves intra and extracellular iron sensors coupled to one or more signal transduction pathways. Iron-bound transferrin (Fe2-Tf) (holotransferrin) is a hepatocyte sensor converging in a complex heterotetrameric signalling associated with the hepatocyte membrane made up of transferrin receptors (TfR1 and TfR2), human hemochromatosis protein (HFE), BMP ligands (bone morphogenetic protein), 2 kinase receptors of BMP (BMPR1 and BMPR2), a BMP coreceptor (hemojuvelin [HJV]) and a facilitator (neoginin).<a class="elsevierStyleCrossRefs" href="#bib0325">7–10</a> There is also an increase in hepcidin in IL-6-mediated inflammatory processes. Conversely, an effective erythropoiesis in bone marrow decreases hepcidin levels, ensuring the supply of iron for erythrocyte production. Therefore, hepcidin levels reflect the integration of multiple activating and inhibitory signals involved in iron regulation (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Activating signalsBMP-HJV-SMAD is the main axis controlling hepcidin synthesis. In situations of iron deficiency, the Fe2-Tf complex binds to the TfR1 receptor, which is not capable of activating the BMP-SMAD pathway and therefore hepcidin is not synthesized, something which facilitates the arrival of iron into plasma. When iron deficiency is corrected, holotransferrin joins the TfR2 receptor, forming a complex with HFE<a class="elsevierStyleCrossRefs" href="#bib0295">1,7–11</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). The role of HFE is to promote the association and stabilization with TfR2, activate HJV and BMP to bind to its receptors (BMPR1 and BMPR2), in the presence of neoginin, promoting SMAD1/5/8 phosphorylation, HAMP transcription and finally hepcidin synthesis<a class="elsevierStyleCrossRefs" href="#bib0350">12,13</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Another important mediator in hepcidin synthesis is the inflammation through IL6 and other cytokines (IL1, IL22) and activin B (Act-B) which activate the JAK-STAT3 and BMP signalling pathway<a class="elsevierStyleCrossRefs" href="#bib0325">7,9</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).Inhibitory signalsThe main hepcidin inhibitory signal comes from erythropoiesis and is related to different proteins such as erythroferrone, growth differentiation factor 15 (GDF15) and twisted gastrulation BMP signalling modulator (TWSG1) that inhibits the SMAD pathway<a class="elsevierStyleCrossRef" href="#bib0325">7</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Matriptase-2 also has an inhibiting effect on hepcidin, encoded by the TMPRSS6 gene, as it blocks HJV and prevents BMP complex activation.<a class="elsevierStyleCrossRef" href="#bib0340">10</a> Other inhibitory signals of hepcidin synthesis are tissue hypoxia and erythropoiesis stimulating factors such as erythropoietin (EPO).<a class="elsevierStyleCrossRefs" href="#bib0295">1,2</a>Disorders associated with hepcidin abnormalitiesFerroportin and hepcidin abnormalities, whether by interaction or aberrant expression, cause or contribute to triggering a large number of iron related disorders ranging from anaemia due to iron deficiency to iron overload diseases.<a class="elsevierStyleCrossRefs" href="#bib0360">14,15</a>Diseases associated with an excess of hepcidinA high level of hepcidin generates hyposideremia with the consequent reduction in erythropoiesis due to insufficient supply of iron, which leads to the development of anaemia in chronic diseases.<a class="elsevierStyleCrossRefs" href="#bib0365">15,16</a>Chronic diseases present with moderate normocytic and normochromic anaemia but sometimes it may be microcytic and hypochromic. Anaemia is not only the result of elevated hepcidin, there is also a direct effect of cytokines on the production and half-life of red blood cells.<a class="elsevierStyleCrossRef" href="#bib0315">5</a> In chronic kidney disease (CKD), an elevated hepcidin is the result of a combination of inflammation and inadequate kidney clearance.<a class="elsevierStyleCrossRefs" href="#bib0340">10,17</a> In neoplasms, anaemia is associated with disease and treatments, but high levels of hepcidin and cytokines also play an important role.<a class="elsevierStyleCrossRef" href="#bib0300">2</a> In addition, 10% of the elderly develop anaemia due to nutritional defects, bleeding, chronic inflammation, renal failure, MDS and increased hepcidin.<a class="elsevierStyleCrossRefs" href="#bib0295">1,2</a> Finally, iron-refractory iron deficiency anaemia must be included in this section, a genetic anaemia characterized by a mutation in the TMPRR6 gene encoding matriptase-2.<a class="elsevierStyleCrossRef" href="#bib0340">10</a> The genetic defect is autosomal recessive and occurs with elevated hepcidin levels due to the absence of matriptase-2, resulting in an accumulation of HJV and activation of BMP pathway.<a class="elsevierStyleCrossRef" href="#bib0340">10</a>Diseases associated with hepcidin decrease or resistanceA hepcidin production deficiency results in iron overload which is usually genetic and is due to mutations in the HFE or TfR2 gene (adult hemochromatosis) or the HJV or HAMP genes (juvenile hemochromatosis).<a class="elsevierStyleCrossRefs" href="#bib0380">18,19</a> This decrease of hepcidin contributes to the normal operation of ferroportin, which results in enterocyte iron absorption and increased release of iron from macrophages, which causes hypersideremia with subsequent increase in transferrin saturation, and the appearance of iron bound to proteins other than transferrin, called non-transferrin-bound iron (NTBI).<a class="elsevierStyleCrossRefs" href="#bib0325">7,15</a> As there is no regulatory mechanism for excreting iron in humans, excess iron is deposited in tissues that express carriers for NTBI, mainly the liver, heart, pancreas and other endocrine glands, causing function failure in the affected organ.Hemochromatosis is the most common cause of genetic iron overload. There are many mutations that lead to the clinical syndrome previously mentioned, but the most common is inherited as an autosomal recessive trait, affecting the HFE gene, which encodes the HFE protein (Type 1 Hemochromatosis). The most common subtype affects homozygous patients with Cys282Tyr mutation (type 1A). Heterozygous patients may have mixed Cys282Tyr/His63Asp mutations (type 1B). There are also cases that have mutations in genotypes other than HFE, for example, Ser65Cys (Type 1C).<a class="elsevierStyleCrossRefs" href="#bib0355">13,18,19</a> More penetrating and severe forms of hereditary hemochromatosis are rare and are caused by mutations in genes HJV (type 2A), hepcidin (type 2B), or TfR2 (type 3).<a class="elsevierStyleCrossRefs" href="#bib0335">9,18</a> Mutations in the gene that controls TfR2 prevent this from binding to HFE and consequently, the BMP-HJV-SMAD complex is not activated and hepcidin is not synthesized.<a class="elsevierStyleCrossRef" href="#bib0380">18</a> Another rare form of hemochromatosis is due to mutations in the ferroportin gene (type 4). These mutations, C326S and SLC11A3, lead to a hepcidin-resistant ferroportin, so that the iron is exported to the circulation, even in the presence of elevated levels of hepcidin.<a class="elsevierStyleCrossRefs" href="#bib0380">18,20</a> Phlebotomy is the treatment of choice in iron overload and it is estimated that 1mg of iron is lost with each millilitre of red cells removed and, therefore, the mobilization of excess iron accumulated in the tissues is promoted to restore erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0300">2</a>β-Thalassemia is another disease that occurs with anaemia, iron overload and low levels of hepcidin. Iron overload is the leading cause of morbidity and mortality in these patients, both in non-transfusion-dependent thalassemia as well as in the dependent one. Defective β-globin chain production during erythropoiesis results in the precipitation of α-chains produced in excess and many erythroid precursors may die early, which results in an ineffective erythropoiesis.<a class="elsevierStyleCrossRefs" href="#bib0395">21,22</a> To minimize anaemia, a series of compensatory mechanisms are activated, such as an increase in erythropoietin which causes a erythroblastic hyperplasia, extramedullary haematopoiesis, splenomegaly and increased intestinal absorption of iron which, in the absence of transfusion, is the cause of iron overload.<a class="elsevierStyleCrossRef" href="#bib0405">23</a> The decrease in hepcidin levels is the result of increased suppressor factors, erythroferrone and GDF15 during the development of erythroblasts.<a class="elsevierStyleCrossRef" href="#bib0330">8</a> Transfusions partially correct anaemia and hepcidin suppression, but provide very high amounts of iron with the RBCs transfused. Iron overload in β-thalassemia is treated with iron chelators.Hepcidin in the diagnosis of iron abnormalitiesIf hepcidin plays a central role in the pathogenesis of many iron disorders, it seems logical that its quantification should become a useful tool for the diagnosis and clinical management of associated diseases. The size of hepcidin in its circulating bioactive form is 25 amino acids and the N-terminal degradation or storage of samples at room temperature results in smaller isoforms (hepcidin-24, -23, -22 and -20 amino acids) whose meaning is not known.<a class="elsevierStyleCrossRef" href="#bib0295">1</a> Circulating hepcidin binds to one alpha-2-macroglobulin and to albumin, it is excreted by the kidney and reabsorbed in the proximal tubules.<a class="elsevierStyleCrossRef" href="#bib0410">24</a>The development of tests to quantify hepcidin levels in biological samples is a not yet resolved challenge. Absolute hepcidin levels differ widely, up to 10 times in the general population and between the different clinical trials, so each laboratory should establish its own reference values. These differences may be due to the fact that hepcidin is influenced by many physiological and pathological stimuli that promote or inhibit its synthesis and because it adheres to plastics.<a class="elsevierStyleCrossRef" href="#bib0410">24</a> Hepcidin determination can be performed on serum, plasma or urine by immunoassay or by mass spectrometry. The quantification of hepcidin by immunoassay may be more appropriate for large-scale studies due to its high performance and relatively low cost. However, immunoassays quantify the total hepcidin, without distinguishing between the complete hepcidin (hepcidin-25) and the smaller isoforms (hepcidin-20, -22, -23 and -24), besides, its concentrations are usually higher in CKD due to a dysfunction in hepcidin clearance.<a class="elsevierStyleCrossRef" href="#bib0410">24</a> Urinary hepcidin measurement correlates with plasma hepcidin, but urinary detection may be distorted by the high concentration of small isoforms and in CKD.<a class="elsevierStyleCrossRef" href="#bib0410">24</a>Hepcidin as a therapeutic targetHepcidin is the main target of diseases related to iron metabolism disorders and, therefore, new hepcidin agonists or antagonist drug therapies are being researched.<a class="elsevierStyleCrossRefs" href="#bib0340">10,11</a> The interest of these studies is huge, as evidenced by the fact that in July 2016 there were 120 registered clinical trials of hepcidin in ClinicalTrials.gov.Hepcidin agonistsIncrease levels of circulating hepcidin may be beneficial in patients with processes that occur with iron overload, such as hemochromatosis and thalassemia. This could be achieved with drugs that have a hepcidin-like activity or stimulating its endogenous production, but the design of a hepcidin similar to that of oneself does not seem to be the solution, because its half-life is very short and because of the costs involved in its production.<a class="elsevierStyleCrossRef" href="#bib0340">10</a>MinihepcidinsThey have a hepcidin-like action with a better bioavailability and a longer circulating half-life. Their action is exerted by binding to ferroportin and blocking the efflux of iron from enterocytes, macrophages and hepatocytes, leading to decreased plasma iron levels.<a class="elsevierStyleCrossRefs" href="#bib0345">11,25–27</a> Its efficacy has been demonstrated in knockout HAMP −/− mice, a model of severe hemochromatosis with lack of hepcidin, in which a plasma iron reduction and tissue iron overload normalization is achieved.<a class="elsevierStyleCrossRef" href="#bib0425">27</a> In thalassaemic mice, treatment with minihepcidins decreases iron overload and improves all haematological parameters.<a class="elsevierStyleCrossRefs" href="#bib0415">25–27</a> This is the result of iron restriction, leading to a decrease in aggregate formation and intracellular inclusion bodies and prevents oxidative stress in erythrocytes, damage in DNA, organelle and cell membrane, with improved erythropoiesis and anaemia correction.<a class="elsevierStyleCrossRefs" href="#bib0300">2,20</a>Hepcidin endogenous production stimulatorsAnother way to increase hepcidin production is based on the design of TMPRSS6 antagonists. RNA technologies are used, mainly antisense oligonucleotides that could silence the mRNA of TMPRSS6 thereby stabilizing HJV, stimulating BMP-HJV-SMAD pathway and increasing the synthesis of endogenous hepcidin.<a class="elsevierStyleCrossRefs" href="#bib0345">11,28</a> These drugs have also been effective in treating iron overload in knockout mice and in the treatment of anaemia and iron overload in thalassemia mouse model (th3/+).<a class="elsevierStyleCrossRef" href="#bib0435">29</a> In addition to increasing the levels of hepcidin, they improve iron overload, reduce splenomegaly and, surprisingly, ineffective erythropoiesis is corrected in thalassaemic mice with homozygous inactivation of TMPRSS6.<a class="elsevierStyleCrossRefs" href="#bib0435">29,30</a>Hepcidin antagonistsThe high concentration of hepcidin causes iron entrapment in the cells of the reticuloendothelial system and is the leading cause of effective iron deficiency in anaemia of chronic disease, therefore, pharmacological suppression of hepcidin would facilitate iron mobilization, promoting erythropoiesis and anaemia correction. The strategies that are being considered for this purpose are directed to change the BMP-SMAD or IL6/STAT3 axes, interfere in hepcidin-ferroportin binding and enhance their suppressive mechanisms<a class="elsevierStyleCrossRefs" href="#bib0340">10,11,16,31,32</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Inhibition of bone morphogenetic protein pathwayThe BMP-HJV-SMAD pathway is the main axis which controls the synthesis of hepcidin and, therefore, inhibiting the BMP pathway would decrease HAMP expression and blood concentrations of hepcidin. Various molecules have been directed against HJV as a target. On the one hand, several monoclonal antibodies (mAbs) targeting the HJV (ABT-207, h5F9-AM8 and h5F9-23) protein that prevent the binding of BMP with BMPR, block the SMAD pathway and correct anaemia in rats with chronic inflammatory processes<a class="elsevierStyleCrossRefs" href="#bib0455">33,34</a> have been investigated. A similar effect is achieved with a fusion protein between the soluble HJV (sHJV) and the Fc fragment of immunoglobulins (sHJV-Fc) that binds to BMP and prevents BMPR activation.<a class="elsevierStyleCrossRefs" href="#bib0345">11,35</a> The same applies to a BMP receptor 1 (BMPR1) inhibitor, the LDN-193189, in rats and human hepatoma cells<a class="elsevierStyleCrossRef" href="#bib0470">36</a> and with an anti-BPM6 MAb.<a class="elsevierStyleCrossRef" href="#bib0475">37</a> Another way of inhibiting the BMP pathway is blocking or silencing the genes regulating hepcidin synthesis with antisense oligonucleotides that interfere with RNA and silence the mRNA (siRNA) of hepcidin-encoding genes, TfR2 and HJV.<a class="elsevierStyleCrossRefs" href="#bib0470">36,38</a> The administration of these siRNAs decreases hepcidin concentrations and corrects anaemia in a chronic inflammatory anaemia mouse model.<a class="elsevierStyleCrossRefs" href="#bib0370">16,39</a> Furthermore, it is known that human mutations in the genes encoding hepcidin, the HJV and TfR2, are associated with iron overload diseases, so in these cases, the effects on the corresponding targets of these oligonucleotides and siRNAs may not be effective.<a class="elsevierStyleCrossRef" href="#bib0340">10</a>Heparin is another known hepcidin inhibitor through BMP6 sequestration and the subsequent blocking of the SMAD pathway, but its anticoagulant activity limits the therapeutic use as an hepcidin inhibitor. This action of heparin has been demonstrated in mice and in patients receiving heparin to prevent deep venous thrombosis which has achieved an increase in serum iron and transferrin saturation and a reduction in C-reactive protein.<a class="elsevierStyleCrossRef" href="#bib0490">40</a> Several modified heparin analogues have been designed to minimize its anticoagulant effect, maintaining their inhibitory effect on hepcidin expression to treat anaemia of inflammatory processes.<a class="elsevierStyleCrossRefs" href="#bib0490">40,41</a>Suppression of the inflammatory pathwayBlocking IL6 with xiltuximab<a class="elsevierStyleCrossRef" href="#bib0500">42</a> and IL6 receptor with tocilizumab<a class="elsevierStyleCrossRef" href="#bib0505">43</a> prevent STAT3 phosphorylation and hepcidin concentration decrease and blood iron (level) normalization in monkeys with arthritis and in patients with Castleman's disease. Similar effects were achieved with a chemical inhibitor of JAK2, the AG490, blocking the IL6-STAT3 pathway.<a class="elsevierStyleCrossRef" href="#bib0510">44</a> The main drawback of anti-cytokine treatments is that they induce immunosuppression, with impairment of the host defences and an increased risk of infections.<a class="elsevierStyleCrossRef" href="#bib0345">11</a>Potentiation of erythropoiesisIncreased erythropoiesis is accompanied by a suppression of hepcidin, which could represent a new strategy for the treatment of anaemia of chronic disease. High doses of EPO may be able to overcome the observed resistance to EPO in these diseases, probably by partial suppression of hepcidin.<a class="elsevierStyleCrossRef" href="#bib0515">45</a> Similarly, prolylhydroxylase inhibitors, which stabilize the factors, induce hypoxia and increase EPO synthesis, decrease hepcidin levels and increase haemoglobin in patients with CKD.<a class="elsevierStyleCrossRef" href="#bib0520">46</a>Neutralization of circulating hepcidinThe bioactive neutralization of hepcidin may be achieved by direct binding or sequestration of the circulating hormone with MAb, anticalines or L-RNA aptamers (called Spiegelmers, in German, ‘mirror’). The main advantage of these hepcidin neutralizers is their high specificity and picomolar affinity to bind to their targets, but the main challenge they must overcome to demonstrate their efficacy is the high rate of hepcidin production present in humans, so that would require massive doses of therapeutic agents in order to achieve their goal.<a class="elsevierStyleCrossRef" href="#bib0340">10</a> However, it has been shown that the intermittent or partial neutralization of hepcidin activity may be sufficient to achieve the desired therapeutic effects.<a class="elsevierStyleCrossRefs" href="#bib0340">10,47</a> A human anti-hepcidin antibody, 12B9m, has been evaluated in transgenic mice with inflammatory anaemia caused by Brucella abortus and in monkeys. Neutralization of hepcidin by MAb increased erythropoiesis and haemoglobin levels.<a class="elsevierStyleCrossRef" href="#bib0530">48</a> Currently, clinical trials are being conducted with another anti-hepcidin antibody, LY2787106, in patients with anaemia associated with cancer.<a class="elsevierStyleCrossRef" href="#bib0340">10</a>Anticalines are small proteins designed by genetic engineering targeting various biological ligands.<a class="elsevierStyleCrossRef" href="#bib0525">47</a> One of these compounds is the PRS-080, which binds to human hepcidin with subnanomolar affinity, achieving an effective mobilization of iron and hypersideremia in primates.<a class="elsevierStyleCrossRef" href="#bib0535">49</a> Aptamers (Spiegelmers) are l-oligonucleotides designed against the mirror image of the target, to which they bind with high affinity. They are stable in the circulation and immunologically passive because their structure contains l-ribose, instead of d-ribose, which gives them a high degradation resistance due to nucleases.<a class="elsevierStyleCrossRef" href="#bib0540">50</a> NOX-H94 neutralizes human hepcidin and increases plasma iron and transferrin saturation.<a class="elsevierStyleCrossRef" href="#bib0540">50</a>Ferroportin as a target. Blocking hepcidin-ferroportin interactionHepcidin binding to ferroportin takes place in an extracellular region of ferroportin containing the sulfhydryl residue Cys326 surrounded by hydrophobic residues.<a class="elsevierStyleCrossRef" href="#bib0340">10</a> Blocking this interaction prevents endocytosis and ferroportin destruction, which favours the efflux of iron from cells into plasma. A humanized antiferroportin MAb, the LY2928057, is being evaluated. It targets this region and prevents hepcidin binding the carrier without interfering with the efflux of iron through ferroportin,<a class="elsevierStyleCrossRef" href="#bib0545">51</a> increasing plasma iron levels in cynomolgus monkeys. Fursultiamine is a thiol compound that prevents hepcidin binding to ferroportin in vitro and in vivo in mice.<a class="elsevierStyleCrossRef" href="#bib0550">52</a>Other inhibitors of hepcidinTNF-α inhibitors (golimumab or infliximab) also decrease the synthesis of hepcidin and improve the anaemia of chronic disease through an indirect effect on IL653,54 and vitamin D, testosterone and 17-estradiol, which prevents SMAD55-57 phosphorylation. Finally, it should be noted that some extracts of Chinese medicinal plants, such as Caulis spatholobi, called jixueteng, have a potent inhibitor effect on HAMP expression through SMAD 1/5/858 phosphorylation suppression.ConclusionsWe have reviewed the mechanisms that regulate iron homeostasis and hepcidin expression, as well as diseases related to its excess or decrease and the advantages of its quantification in the diagnosis of these diseases. The importance of hepcidin as a therapeutic target focusing on different compounds aimed at correcting iron overload or block/inhibit hepcidin in order to cure the anaemia of chronic disease has been analyzed. Numerous clinical trials are being conducted and it is expected that they will be soon applied to clinical practice, but which of the different therapeutic approaches will have more chances of success is not yet known.Authorship/collaborationSCD, RCA and ECG have contributed to the literature review, writing and discussion of the content of the work. ECG has made the final text review.Conflicts of interestThere are no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres823607" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec820278" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres823608" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec820277" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Regulation of iron homeostasis. Hepcidin-ferroportin axis" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Regulation of hepcidin expression" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Activating signals" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Inhibitory signals" ] ] ] 7 => array:3 [ "identificador" => "sec0030" "titulo" => "Disorders associated with hepcidin abnormalities" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Diseases associated with an excess of hepcidin" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Diseases associated with hepcidin decrease or resistance" ] ] ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Hepcidin in the diagnosis of iron abnormalities" ] 9 => array:3 [ "identificador" => "sec0050" "titulo" => "Hepcidin as a therapeutic target" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0055" "titulo" => "Hepcidin agonists" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Minihepcidins" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Hepcidin endogenous production stimulators" ] ] ] 1 => array:3 [ "identificador" => "sec0070" "titulo" => "Hepcidin antagonists" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Inhibition of bone morphogenetic protein pathway" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Suppression of the inflammatory pathway" ] 2 => array:2 [ "identificador" => "sec0085" "titulo" => "Potentiation of erythropoiesis" ] 3 => array:2 [ "identificador" => "sec0090" "titulo" => "Neutralization of circulating hepcidin" ] 4 => array:2 [ "identificador" => "sec0095" "titulo" => "Ferroportin as a target. Blocking hepcidin-ferroportin interaction" ] 5 => array:2 [ "identificador" => "sec0100" "titulo" => "Other inhibitors of hepcidin" ] ] ] ] ] 10 => array:2 [ "identificador" => "sec0105" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0110" "titulo" => "Authorship/collaboration" ] 12 => array:2 [ "identificador" => "sec0115" "titulo" => "Conflicts of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-09-22" "fechaAceptado" => "2016-10-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec820278" "palabras" => array:5 [ 0 => "Iron metabolism" 1 => "Hepcidin" 2 => "Ferroportin" 3 => "Hepcidin agonists" 4 => "Hepcidin antagonists" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec820277" "palabras" => array:5 [ 0 => "Metabolismo del hierro" 1 => "Hepcidina" 2 => "Ferroportina" 3 => "Agonistas de la hepcidina" 4 => "Antagonistas de la hepcidina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases. The most important inhibitory signals are related to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesized has helped design new pharmacological treatments whose main target is the hepcidin. In the near future, there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La hepcidina es el principal regulador del metabolismo del hierro y el factor patogénico más importante en sus trastornos. La deficiencia de hepcidina provoca sobrecarga de hierro, mientras que su exceso da lugar o contribuye al desarrollo de anemias por déficit o restricción de hierro en las enfermedades crónicas. Conocemos los mecanismos implicados en la síntesis de hepcidina y, en condiciones fisiológicas, hay un equilibrio entre las señales activadoras e inhibidoras que regulan su síntesis. Las primeras incluyen las relacionadas con la concentración plasmática de hierro y con las enfermedades inflamatorias. Las señales inhibidoras más importantes están relacionadas con la eritropoyesis activa y con la matriptasa-2. Conocer cómo se sintetiza la hepcidina ha servido para diseñar nuevos tratamientos farmacológicos cuya diana principal es la hepcidina. En un futuro próximo, se dispondrá de tratamientos eficaces dirigidos a corregir el defecto de muchos de los trastornos del metabolismo del hierro." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Conde Diez S, de las Cuevas Allende R, Conde García E. Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas. Med Clin (Barc). 2017;148:218–224." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1041 "Ancho" => 1734 "Tamanyo" => 124041 ] ] "descripcion" => array:1 [ "en" => "Body iron homeostasis. The interaction of hepcidin with ferroportin (FPN) controls the main efflux of iron into plasma." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1237 "Ancho" => 2350 "Tamanyo" => 328082 ] ] "descripcion" => array:1 [ "en" => "Dietary iron is absorbed by duodenal enterocytes. Nonheme iron occurs primarily in the ferric state (Fe 3+) in the intestine and is reduced to ferrous iron (Fe 2+) by the action of ferrireductases, especially duodenal cytochrome b (Dcytb). Ferrous iron passes through the duodenal enterocytes of the divalent metal transporter-1 (DMT1). Once in the enterocyte, the ferrous iron can be stored in it as ferritin or can be released into the bloodstream through ferroportin (FPN). Ferrous iron is oxidized by a ferroxidase identified as hephaestin, which after converting into ferric iron, it binds to transferrin and thus circulates in plasma. Furthermore, senescent erythrocytes are phagocytosed by macrophages, primarily in the spleen, but also in the liver and the bone marrow (BM). During erythropoiesis, erythroblasts acquire iron for haemoglobin synthesis from transferrin via transferrin receptors. Excess iron is stored in the liver and in macrophages as ferritin, which is oxidized to hemosiderin. Hepcidin plays a key role in the release of iron from the deposits depending on the requirements (e.g.: increased erythropoiesis, etc.)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1586 "Ancho" => 1652 "Tamanyo" => 222274 ] ] "descripcion" => array:1 [ "en" => "Hepcidin synthesis. The main axis that controls the synthesis of hepcidin is bone morphogenetic protein-hemojuvelin-sons of mothers against decapentaplegic (BMP-HJV-SMAD). Transferrin bound to iron (Fe2-Tf) is a hepatocyte sensor for hepcidin transcription control. The binding of Fe2-Tf with transferrin receptors (TfR1 and TfR2) and human hemochromatosis protein (HFE) is inversely correlated with levels of transferrin saturation by iron, so that, if levels increase, HFE is displaced from TfR1 to TfR2 to activate BMP. This activation facilitates the binding of BMP6 with its receptors 1 and 2 (BMPR1 and BMPR2) in the presence of hemojuvelin (HJV) and neoginin (NEO), and launches SMAD 1/5/8 phosphorylation, hepcidin antimicrobial peptide (HAMP) gene transcription and the synthesis of hepcidin. Inflammation is another important mediator in hepcidin synthesis through IL6 and activin B (Act-B) via janus kinase-signal transducer and activator of transcription (JAK-STAT3) and BMP. The main hepcidin inhibitory signal comes from the bone marrow during active erythropoiesis and takes place through different proteins, highlighting erythroferrone (ErFe), growth differentiation factor (GDF15) and twisted gastrulation BMP signalling modulator (TWSG1), which inhibit the SMAD pathway. Matriptase-2 (MT-2), encoded by the gene TMPRSS6, also has an inhibitory effect on hepcidin transcription through HJV cleavage, preventing BMP complex activation. Other inhibitory signals of hepcidin synthesis come from situations that generate tissue hypoxia and from the administration of erythropoiesis stimulating factors such as erythropoietin (EPO)." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "MAb: monoclonal antibody; MRNA: messenger ribonucleic acid; BMP: bone morphogenetic protein; BMPR: bone morphogenetic protein receptor; FPN: ferroportin; HJV: hemojuvelin; sHJV-Fc: fusion protein between the soluble HJV and the Fc fragment of immunoglobulins; IL: interleukin; SMAD: sons of mothers against decapentaplegic; STAT3: signal transducer and activator of transcription 3; TfR2: transferrin receptor 2; TNF: tumour necrosis factor.siHep, siHJV, siTfR2: oligonucleotides silencing mRNA expression in genes encoding hepcidin, HJV or TfR2." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Inhibitor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Action and target \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">References \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">BMPs/BMPR/HJV complex</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Anti-HJV MAb (ABT-207, h5F9-AM8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitor of BMPs/SMAD pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0455">33,34</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• sHJV-Fc \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitor of BMPs/SMAD pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0345">11,35</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• LDN-193189 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BMPR1 phosphorylation inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0470">36</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Anti-BPM6 MAb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BMP6 sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0475">37</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• siHep, siHJV, siTfR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepcidin mRNA degradation, HJV or TfR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0470">36,38</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Modified heparin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitors of BMPs/SMAD pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0490">40,41</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">IL6/SATAT3 pathway</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Anti-IL6 (xiltuximab) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IL6 sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0500">42</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Anti-IL6R (tocilizumab) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IL6 receptor sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0505">43</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• AG490 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">STAT3 phosphorylation inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0510">44</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Antihepcidin agents</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Antihepcidin MAb (12B9m) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepcidin protein sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0530">48</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Anticalines (PRS-080) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepcidin protein sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0535">49</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Aptamers (Spiegelmers: NOX-H94) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepcidin protein sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0540">50</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Hepcidin-ferroportin interaction</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Antiferroportin MAb (LY2928057) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepcidin-ferroportin binding interference \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0545">51</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Fursultiamine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cys326-HS sequestration (FPN-hepcidin binding) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0550">52</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Other inhibitors</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• TNF-α MAb (infliximab, golimumab) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Indirect effect of IL6 suppression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0555">53,54</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Vitamin D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SMAD 1/5/8 phosphorylation suppressed. Vitamin D recep \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0565">55</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• 17-Estradiol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SMAD 1/5/8 phosphorylation suppressed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0570">56</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Testosterone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SMAD 1/5/8 phosphorylation suppressed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0575">57</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Chinese medicinal plant extract: Caulis spatholobi (Jixueteng) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SMAD 1/5/8 phosphorylation suppressed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0580">58</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1384833.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Hepcidin inhibitors and their corresponding targets." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:58 [ 0 => array:3 [ "identificador" => "bib0295" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systemic iron homeostasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T. Ganz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/physrev.00008.2013" "Revista" => array:6 [ "tituloSerie" => "Physiol Rev" "fecha" => "2013" "volumen" => "93" "paginaInicial" => "1721" "paginaFinal" => "1741" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24137020" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0300" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepcidin and iron disorders: new biology and clinical approches" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Arezes" 1 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Int J Lab Hem" "fecha" => "2015" "volumen" => "37" "paginaInicial" => "92" "paginaFinal" => "98" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0305" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disorders of iron metabolism. Part I: molecular basis of iron homeostasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Muñoz" 1 => "J.A. García-Erce" 2 => "A.F. Remacha" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jcp.2010.079046" "Revista" => array:6 [ "tituloSerie" => "J Clin Pathol" "fecha" => "2011" "volumen" => "64" "paginaInicial" => "281" "paginaFinal" => "286" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21177266" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0310" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Iron, erythropoiesis, and host defense: A ménage à trois" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T. Ganz" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:2 [ "tituloSerie" => "Am Soc Hematol E Donnall Thomas Lecture" "fecha" => "2014" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0315" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anemia of inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E. Nemeth" 1 => "T. Ganz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.hoc.2014.04.005" "Revista" => array:6 [ "tituloSerie" => "Hematol Oncol Clin North Am" "fecha" => "2014" "volumen" => "28" "paginaInicial" => "671" "paginaFinal" => "681" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25064707" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0320" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Physiology of iron metabolism" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Waldvogel-Abramowski" 1 => "G. Waeber" 2 => "C. Gassner" 3 => "A. Buser" 4 => "B.M. Frey" 5 => "B. Favrat" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000362888" "Revista" => array:6 [ "tituloSerie" => "Transfus Med Hemother" "fecha" => "2014" "volumen" => "41" "paginaInicial" => "213" "paginaFinal" => "221" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25053935" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0325" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepcidina and iron homeostasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T. Ganz" 1 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbamcr.2012.01.014" "Revista" => array:6 [ "tituloSerie" => "Biochim Biophys Acta" "fecha" => "2012" "volumen" => "1823" "paginaInicial" => "1434" "paginaFinal" => "1443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22306005" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0330" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of erythroferrone as an erythroid regulator of iron metabolism" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L. Kautz" 1 => "G. Jung" 2 => "E.V. Valore" 3 => "S. Rivella" 4 => "E. Nemeth" 5 => "T. Ganz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng.2996" "Revista" => array:6 [ "tituloSerie" => "Nat Genet" "fecha" => "2014" "volumen" => "46" "paginaInicial" => "678" "paginaFinal" => "684" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24880340" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0335" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. Pietrangelo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2015.06.045" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2015" "volumen" => "149" "paginaInicial" => "1240" "paginaFinal" => "1251" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26164493" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0340" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The pathophisiology and pharmacology of hepcidin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P. Ruchala" 1 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.tips.2014.01.004" "Revista" => array:6 [ "tituloSerie" => "Trends Pharmacol Sci" "fecha" => "2014" "volumen" => "35" "paginaInicial" => "155" "paginaFinal" => "161" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24552640" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0345" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available in: www.md-journal.com" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepcidin A promising therapeutic target for iron disorders. A systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J. Liu" 1 => "B. Sun" 2 => "H. Yin" 3 => "S. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MD.0000000000003150" "Revista" => array:4 [ "tituloSerie" => "Medicine (Baltimore)" "fecha" => "2016" "volumen" => "95" "paginaInicial" => "e3150" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0350" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X.G. Wu" 1 => "Y. Wang" 2 => "Q. Wu" 3 => "W.H. Cheng" 4 => "W. Liu" 5 => "Y. Zhao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2014-01-552281" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2014" "volumen" => "124" "paginaInicial" => "1335" "paginaFinal" => "1343" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24904118" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0355" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "How mutant HFE causes hereditary hemochromatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M.U. Muckenthaler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2014-07-581744" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2014" "volumen" => "124" "paginaInicial" => "1212" "paginaFinal" => "1213" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25147378" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0360" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Iron-deficiency anemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "C. Camaschella" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra1401038" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2015" "volumen" => "372" "paginaInicial" => "1832" "paginaFinal" => "1843" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25946282" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0365" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disorders of iron metabolism. Part II: iron deficiency and iron overlad" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Muñoz" 1 => "J.A. García-Erce" 2 => "A.F. Remacha" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jcp.2010.086991" "Revista" => array:6 [ "tituloSerie" => "J Clin Pathol" "fecha" => "2011" "volumen" => "64" "paginaInicial" => "287" "paginaFinal" => "296" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21177268" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0370" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepcidin regulation in the anemia of inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.Y. Wang" 1 => "J.L. Babitt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MOH.0000000000000236" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Hematol" "fecha" => "2016" "volumen" => "23" "paginaInicial" => "189" "paginaFinal" => "197" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26886082" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0375" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nuevas expectativas en el tratamiento de la anemia en la enfermedad renal crónica" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.M. López-Gómez" 1 => "S. Abad" 2 => "A. Vega" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.nefro.2016.03.006" "Revista" => array:6 [ "tituloSerie" => "Nefrologia" "fecha" => "2016" "volumen" => "36" "paginaInicial" => "232" "paginaFinal" => "236" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27137103" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0380" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Haemochromatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L.W. Powell" 1 => "R.C. Seckington" 2 => "Y. Deugnier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(15)01315-X" "Revista" => array:7 [ "tituloSerie" => "Lancet" "fecha" => "2016" "volumen" => "388" "paginaInicial" => "706" "paginaFinal" => "716" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26975792" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0140673605177411" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0385" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemocromatosis hereditaria. Problemas en el diagnóstico y tratamiento" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Altés" 1 => "C. Sanz" 2 => "M. Bruguera" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Med Clin (Barc)" "fecha" => "2015" "volumen" => "144" "paginaInicial" => "424" "paginaFinal" => "428" ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0390" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The molecular basis of hepcidin-resistant hereditary hemochromatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Fernandes" 1 => "G.C. Preza" 2 => "Y. Phung" 3 => "J. Kaplan" 4 => "T. Ganz" 5 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2008-03-146134" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2009" "volumen" => "114" "paginaInicial" => "437" "paginaFinal" => "443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19383972" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0395" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of ineffective erythropoiesis in non-transfusion-dependent thalassemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S. Rivella" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0268-960X(12)70005-X" "Revista" => array:6 [ "tituloSerie" => "Blood Rev" "fecha" => "2012" "volumen" => "26" "paginaInicial" => "S12" "paginaFinal" => "S15" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22631035" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0400" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ineffective erythropoiesis and regulation of iron status in iron loading anaemias" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C. Camaschella" 1 => "A. Nai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/bjh.13820" "Revista" => array:6 [ "tituloSerie" => "Br J Haematol" "fecha" => "2016" "volumen" => "172" "paginaInicial" => "512" "paginaFinal" => "523" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26491866" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0405" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Morbidities in non-transfusion-dependent thalassemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A.N. Saliba" 1 => "A.T. Taher" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/nyas.13083" "Revista" => array:6 [ "tituloSerie" => "Ann N Y Acad Sci" "fecha" => "2016" "volumen" => "1368" "paginaInicial" => "82" "paginaFinal" => "94" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27186941" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0410" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Swinkels hepcidin in the diagnosis of iron disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D. Girelli" 1 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2015-12-639112" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2016" "volumen" => "127" "paginaInicial" => "2809" "paginaFinal" => "2813" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27044621" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0415" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Manipulation of the hepcidin pathway for therapeutics purpose" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E. Fung" 1 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3324/haematol.2013.084624" "Revista" => array:6 [ "tituloSerie" => "Haematologica" "fecha" => "2013" "volumen" => "98" "paginaInicial" => "1667" "paginaFinal" => "1676" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24186312" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0420" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacological targeting of the hepcidin/ferroportin axis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G. Sabastiani" 1 => "N. Wilkinson" 2 => "K. Pantopoulos" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fphar.2016.00160" "Revista" => array:5 [ "tituloSerie" => "Front Pharmacol" "fecha" => "2016" "volumen" => "7" "paginaInicial" => "160" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27445804" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0425" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepcidin. Minireview" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.S. Palaneeswari" 1 => "M. Ganesh" 2 => "T. Karthikeyan" 3 => "A.J. Devi" 4 => "S.V. Mythili" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7860/JCDR/2013/6420.3273" "Revista" => array:6 [ "tituloSerie" => "J Clin Diagn Res" "fecha" => "2013" "volumen" => "7" "paginaInicial" => "1767" "paginaFinal" => "1771" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24086909" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0430" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "A. Nai" 1 => "A. Pagani" 2 => "G. Mandelli" 3 => "M.R. Lidonnici" 4 => "L. Silvestri" 5 => "G. Ferrari" 6 => "C. Camaschell" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-01-401885" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2012" "volumen" => "119" "paginaInicial" => "5021" "paginaFinal" => "5029" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22490684" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0435" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(−/−) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.J. Schmidt" 1 => "I. Toudjarska" 2 => "A.K. Sendamarai" 3 => "T. Racie" 4 => "S. Milstein" 5 => "B.R. Bettencourt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-09-453977" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2013" "volumen" => "121" "paginaInicial" => "1200" "paginaFinal" => "1208" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23223430" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0440" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibiting the hepcidin inhibitor for treatment of iron overload" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "L. Silvestri" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-12-472597" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2013" "volumen" => "121" "paginaInicial" => "1068" "paginaFinal" => "1069" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23411732" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0445" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T. Ganz" 1 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Hematology Am Soc Hematol Educ Program" "fecha" => "2011" "paginaInicial" => "538" "paginaFinal" => "542" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0450" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Modulation of hepcidin to treat iron deregulation: potential clinical applications" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "N.L. Blanchette" 1 => "D.H. Manz" 2 => "F.M. Torti" 3 => "S.V. Torti" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1586/17474086.2016.1124757" "Revista" => array:6 [ "tituloSerie" => "Expert Rev Hematol" "fecha" => "2016" "volumen" => "9" "paginaInicial" => "169" "paginaFinal" => "186" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26669208" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0455" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-repulsive guidance molecule C (RGMc) antibodies increases serum iron in rats and cynomolgus monkeys by hepcidin downregulation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Böser" 1 => "D. Seemann" 2 => "M.J. Liguori" 3 => "L. Fan" 4 => "L. Huang" 5 => "M. Hafner" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1208/s12248-015-9770-4" "Revista" => array:7 [ "tituloSerie" => "AAPS J" "fecha" => "2015" "volumen" => "17" "paginaInicial" => "930" "paginaFinal" => "938" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25896304" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0022347607008785" "estado" => "S300" "issn" => "00223476" ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0460" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-hemojuvelin antibody corrects anemia caused by inappropriately high hepcidin levels" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Kovac" 1 => "P. Böser" 2 => "Y. Cui" 3 => "D. Ferring-Appel" 4 => "D. Casarrubea" 5 => "L. Huang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3324/haematol.2015.140772" "Revista" => array:6 [ "tituloSerie" => "Haematologica" "fecha" => "2016" "volumen" => "101" "paginaInicial" => "e173" "paginaFinal" => "e176" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26944476" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0465" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I. Theurl" 1 => "A. Schroll" 2 => "T. Sonnweber" 3 => "M. Nairz" 4 => "M. Theurl" 5 => "W. Willenbacher" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2011-03-345066" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2011" "volumen" => "118" "paginaInicial" => "4977" "paginaFinal" => "4984" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21730356" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0470" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.U. Steinbicker" 1 => "C. Sachidanandan" 2 => "A.J. Vonner" 3 => "R.Z. Yusuf" 4 => "D.Y. Deng" 5 => "C.S. Lai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2010-10-313064" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2011" "volumen" => "117" "paginaInicial" => "4915" "paginaFinal" => "4923" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21393479" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0475" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Corradini" 1 => "P.J. Schmidt" 2 => "D. Meynard" 3 => "C. Garuti" 4 => "G. Montosi" 5 => "S. Chen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2010.07.044" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2010" "volumen" => "139" "paginaInicial" => "1721" "paginaFinal" => "1729" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20682319" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0480" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "www.frontiersin.org" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepcidin antagonists for potential treatments of disorders with hepcidin excess" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Poli" 1 => "M. Asperti" 2 => "P. Ruzzenenti" 3 => "M. Regoni" 4 => "P. Arosio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fphar.2014.00086" "Revista" => array:5 [ "tituloSerie" => "Front Pharmacol" "fecha" => "2014" "volumen" => "5" "paginaInicial" => "86" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24808863" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0485" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of siRNA delivery enhancers by a chemical library screen" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Gilleron" 1 => "P. Paramasivam" 2 => "A. Zeigerer" 3 => "W. Querbes" 4 => "G. Marsico" 5 => "C. Andree" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/nar/gkv762" "Revista" => array:6 [ "tituloSerie" => "Nucleic Acids Res" "fecha" => "2015" "volumen" => "43" "paginaInicial" => "7984" "paginaFinal" => "8001" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26220182" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0490" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Poli" 1 => "M. Asperti" 2 => "A. Naggi" 3 => "N. Campostrini" 4 => "D. Girelli" 5 => "M. Corbella" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2013-07-515221" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2014" "volumen" => "123" "paginaInicial" => "1564" "paginaFinal" => "1573" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24398330" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0495" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oversulfated heparins with low anticoagulant activity are strong and fast inhibitors of hepcidin expression in vitro and in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Poli" 1 => "M. Asperti" 2 => "P. Ruzzenenti" 3 => "L. Mandelli" 4 => "N. Campostrini" 5 => "G. Martini" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bcp.2014.09.007" "Revista" => array:6 [ "tituloSerie" => "Biochem Pharmacol" "fecha" => "2014" "volumen" => "92" "paginaInicial" => "467" "paginaFinal" => "475" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25241290" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0500" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Analysis of inflammatory and anemia-related biomarkers in a randomized, double-blind, placebo-controlled study of siltuximab (anti-IL6 monoclonal antibody) in patients with multicentric Castleman disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Casper" 1 => "S. Chaturvedi" 2 => "N. Munshi" 3 => "R. Wong" 4 => "M. Qi" 5 => "M. Schaffer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/1078-0432.CCR-15-0134" "Revista" => array:6 [ "tituloSerie" => "Clin Cancer Res" "fecha" => "2015" "volumen" => "21" "paginaInicial" => "4294" "paginaFinal" => "4304" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26124203" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0505" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.N. Song" 1 => "N. Tomosugi" 2 => "H. Kawabata" 3 => "T. Ishikawa" 4 => "T. Nishikawa" 5 => "K. Yoshizaki" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2010-03-271791" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2010" "volumen" => "116" "paginaInicial" => "3627" "paginaFinal" => "3634" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20644113" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0510" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "AG490: an inhibitor of hepcidin expression in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.P. Zhang" 1 => "Z. Wang" 2 => "L.X. Wang" 3 => "S.J. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3748/wjg.v17.i45.5032" "Revista" => array:6 [ "tituloSerie" => "World J Gastroenterol" "fecha" => "2011" "volumen" => "17" "paginaInicial" => "5032" "paginaFinal" => "5034" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22174555" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0515" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hyporesponsiveness to erythropoietin: causes and management" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. Elliott" 1 => "D. Mishler" 2 => "R. Agarwal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.ackd.2008.12.004" "Revista" => array:6 [ "tituloSerie" => "Adv Chronic Kidney Dis" "fecha" => "2009" "volumen" => "16" "paginaInicial" => "94" "paginaFinal" => "100" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19233068" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0520" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Provenzano" 1 => "A. Besarab" 2 => "C.H. Sun" 3 => "S.A. Diamond" 4 => "J.H. Durham" 5 => "J.L. Cangiano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2215/CJN.06890615" "Revista" => array:6 [ "tituloSerie" => "Clin J Am Soc Nephrol" "fecha" => "2016" "volumen" => "11" "paginaInicial" => "982" "paginaFinal" => "991" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27094610" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0525" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved mass spectrometry assay for plasma hepcidin: detection and characterization of a novel hepcidin isoform" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.M. Laarakkers" 1 => "E.T. Wiegerinck" 2 => "S. Klaver" 3 => "M. Kolodziejczyk" 4 => "H. Gille" 5 => "A.M. Hohlbaum" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0075518" "Revista" => array:5 [ "tituloSerie" => "PLoS One" "fecha" => "2013" "volumen" => "8" "paginaInicial" => "e75518" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24124495" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0530" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.S. Cooke" 1 => "B. Hinkle" 2 => "H. Salimi-Moosavi" 3 => "I. Foltz" 4 => "C. King" 5 => "P. Rathanaswami" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2013-06-505792" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2013" "volumen" => "122" "paginaInicial" => "3054" "paginaFinal" => "3061" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23945155" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0535" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Iron mobilization and pharmacodynamic marker measurements in non-human primates following administration of PRS-080, a novel and highly specific anti-hepcidin therapeutic [abstract]" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Hohlbaum" 1 => "H. Gille" 2 => "J. Christian" 3 => "A. Allersdorfer" 4 => "J. Jaworski" 5 => "J. Burrows" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Am J Hematol" "fecha" => "2013" "volumen" => "5" "paginaInicial" => "E41" ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0540" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Schwoebel" 1 => "L.T. van Eijk" 2 => "D. Zboralski" 3 => "S. Sell" 4 => "K. Buchner" 5 => "C. Maasch" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-09-456756" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2013" "volumen" => "121" "paginaInicial" => "2311" "paginaFinal" => "2315" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23349391" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0545" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "LY2928057, an antibody targeting ferroportin, is a potent inhibitor of hepcidin activity and increases iron mobilization in normal cynomolgus monkeys" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.R. Witcher" 1 => "D. Leung" 2 => "K.A. Hill" 3 => "D.C. de Rosa" 4 => "J. Xu" 5 => "J. Manetta" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Blood" "fecha" => "2013" "volumen" => "122" "paginaInicial" => "3433" ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0550" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High-throughput screening of small molecules identifies hepcidin antagonists" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E. Fung" 1 => "P. Sugianto" 2 => "J. Hsu" 3 => "R. Damoiseaux" 4 => "T. Ganz" 5 => "E. Nemeth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1124/mol.112.083428" "Revista" => array:6 [ "tituloSerie" => "Mol Pharmacol" "fecha" => "2013" "volumen" => "83" "paginaInicial" => "681" "paginaFinal" => "690" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23292796" "web" => "Medline" ] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0555" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of subcutaneous and intravenous golimumab on inflammatory biomarkers in patients with rheumatoid arthritis: results of a phase 1, randomized, open-label trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.K. Doyle" 1 => "M.U. Rahman" 2 => "B. Frederick" 3 => "C.A. Birbara" 4 => "D. de Vries" 5 => "G. Teodter" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/kes381" "Revista" => array:6 [ "tituloSerie" => "Rheumatology" "fecha" => "2013" "volumen" => "52" "paginaInicial" => "1214" "paginaFinal" => "1219" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23418046" "web" => "Medline" ] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0560" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tumour necrosis factor alpha downregulates human hemojuvelin expression via a novel response element within its promoter" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.F. Salama" 1 => "H.K. Bayele" 2 => "S.S. Srai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1423-0127-19-1" "Revista" => array:6 [ "tituloSerie" => "J Biomed Sci" "fecha" => "2012" "volumen" => "19" "paginaInicial" => "1" "paginaFinal" => "12" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22212150" "web" => "Medline" ] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0565" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Suppression of iron-regulatory hepcidin by vitamin D" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Bacchetta" 1 => "J.J. Zaritsky" 2 => "J.L. Sea" 3 => "R.F. Chun" 4 => "T.S. Lisse" 5 => "K. Zavala" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2013040355" "Revista" => array:6 [ "tituloSerie" => "J Am Soc Nephrol" "fecha" => "2014" "volumen" => "25" "paginaInicial" => "564" "paginaFinal" => "572" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24204002" "web" => "Medline" ] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0570" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "17β-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Q. Yang" 1 => "J. Jian" 2 => "S. Katz" 3 => "S.B. Abramson" 4 => "X. Huang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/en.2011-2045" "Revista" => array:6 [ "tituloSerie" => "Endocrinology" "fecha" => "2012" "volumen" => "153" "paginaInicial" => "3170" "paginaFinal" => "3178" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22535765" "web" => "Medline" ] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0575" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W. Guo" 1 => "E. Bachman" 2 => "M. Li" 3 => "C.N. Roy" 4 => "J. Blusztajn" 5 => "S. Wong" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/acel.12052" "Revista" => array:6 [ "tituloSerie" => "Aging Cell" "fecha" => "2013" "volumen" => "12" "paginaInicial" => "280" "paginaFinal" => "291" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23399021" "web" => "Medline" ] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0580" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Screening identifies the Chinese medicinal plant caulis spatholobi as an effective HAMP expression inhibitor" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Guan" 1 => "P. An" 2 => "Z. Zhang" 3 => "F. Zhang" 4 => "Y. Tu" 5 => "Q. Wu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3945/jn.113.174201" "Revista" => array:6 [ "tituloSerie" => "J Nutr" "fecha" => "2013" "volumen" => "143" "paginaInicial" => "1061" "paginaFinal" => "1066" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23700338" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000014800000005/v1_201704020027/S2387020617301675/v1_201704020027/en/main.assets" "Apartado" => array:4 [ "identificador" => "44147" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000014800000005/v1_201704020027/S2387020617301675/v1_201704020027/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301675?idApp=UINPBA00004N"]

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Current status of iron metabolism: Clinical and therapeutic implications

Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas

Susana Conde Dieza, Ricardo de las Cuevas Allendeb, Eulogio Conde Garcíac,

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euconde@humv.es
condee@unican.es

Corresponding author.

a Medicina de Familia, Servicio Cántabro de Salud, Santander (Cantabria), Spain

b Medicina de Familia, Servicio Cántabro de Salud, Centro de Salud Bajo Asón, Ampuero (Cantabria), Spain

c Servicio de Hematología, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander (Cantabria), Spain

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1&#8211;2<span class="elsevierStyleHsp" style=""></span>mg&#47;d of iron is absorbed from the diet&#44; which is the same amount lost daily&#44; but it should be noted that the organism does not have an active iron excretion mechanism&#44; so that control of the duodenal absorption plays a vital role in iron homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">3</span></a> Plasma iron circulates bound to transferrin and it comes from the iron which is absorbed and the iron that comes from deposit organs&#44; which release it into the plasma through ferroportin&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#8211;3</span></a> Their accumulation leads to iron overload that is toxic and can damage tissues and cause cell death by free radical formation and lipid peroxidation&#46; For this reason&#44; the circulating iron is never found in free form&#44; it is always attached to other molecules&#44; mainly transferrin&#44; but when concentrations of plasma iron are high and transferrin is saturated&#44; the excess iron is bound to other plasma molecules of low molecular weight such as citrate&#44; acetate and albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The iron in the body follows a cycle consisting of duodenal absorption&#44; distribution through the plasma bound to transferrin and transfer to cells via the transferrin receptor&#44; located in the cytoplasmic membrane&#44; for use in different metabolic processes or for storing it in deposit organs&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#8211;3</span></a> When red blood cells age&#44; they are destroyed in macrophages&#44; mainly in the spleen&#44; and iron is reused after passing through the plasma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Foods containing ferric iron which&#44; after being reduced to the ferrous form&#44; it is absorbed by duodenal enterocytes and subsequently released into plasma through ferroportin &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Regulation of iron homeostasis&#46; Hepcidin-ferroportin axis</span><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Hepcidin</span> is the main hormone that regulates iron metabolism&#46; It is synthesized in the liver and its main mission is to control the arrival of iron in plasma from food through enterocytes&#44; macrophages&#44; which contain the iron coming from recycled senescent red blood cells&#44; and that released from the deposits &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; <span class="elsevierStyleItalic">Ferroportin</span> is responsible for the efflux of iron from enterocytes&#44; macrophages and hepatocytes into the plasma&#46; Hepcidin binds to ferroportin for its destruction by endocytosis into the cell&#39;s lysosomes resulting&#44; on the one hand&#44; in a hyposideremia by lowering the iron transferred to the plasma and&#44; on the other hand&#44; to the accumulation of iron as ferritin enterocytes&#44; macrophages and hepatocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#8211;3</span></a> The control of iron homeostasis by hepcidin is a classic endocrine regulation system&#59; in the words of Ganz&#44; the relationship of hepcidin with iron is similar to that of insulin with glucose&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">4</span></a> Hepcidin is therefore the principal regulator of iron and plays a key role in all its abnormalities&#44; whether having to do with deficiency or excess&#46; Hepcidin deficiency causes iron overload&#44; while its excess favours iron sequestration in the liver and macrophages and contributes to the development of iron deficiency anaemias or because of its misuse in anaemia of chronic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> In these cases&#44; a functional iron deficiency anaemia occurs because iron reserves are not available for erythropoiesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">5&#44;6</span></a> Increased hepcidin also occurs in chronic inflammatory processes by an increase in IL6&#44; which also represents a host defence mechanism against infection by limiting the availability of extracellular iron to microorganisms&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> Hepcidin production is negatively regulated by erythropoiesis through mediators that prevent its production when iron is required for haemoglobin synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> Hepcidin is an acute phase reactant that responds to a variety of inflammatory mediators and signals that activate transcription through different signalling pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Regulation of hepcidin expression</span><p id="par0020" class="elsevierStylePara elsevierViewall">Hepcidin&#44; encoded by the gene HAMP&#44; is the hormone that regulates iron metabolism&#46; It is a 25-amino acid peptide produced by hepatocytes interacting with the ferroportin found in the cell membrane of enterocytes&#44; macrophages and hepatocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">7</span></a> Regulation of hepcidin is a multifactorial process involving different stimulatory and inhibitory signals which&#44; in various ways&#44; control its final transcript&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">7&#44;8</span></a> Hepcidin is regulated by plasma iron through a <span class="elsevierStyleItalic">feedback</span> mechanism which involves intra and extracellular iron sensors coupled to one or more signal transduction pathways&#46; Iron-bound transferrin &#40;Fe2-Tf&#41; &#40;holotransferrin&#41; is a hepatocyte sensor converging in a complex heterotetrameric signalling associated with the hepatocyte membrane made up of transferrin receptors &#40;TfR1 and TfR2&#41;&#44; human hemochromatosis protein &#40;HFE&#41;&#44; BMP ligands &#40;<span class="elsevierStyleItalic">bone morphogenetic protein&#41;</span>&#44; 2 kinase receptors of BMP &#40;BMPR1 and BMPR2&#41;&#44; a BMP coreceptor &#40;hemojuvelin &#91;HJV&#93;&#41; and a facilitator &#40;neoginin&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">7&#8211;10</span></a> There is also an increase in hepcidin in IL-6-mediated inflammatory processes&#46; Conversely&#44; an effective erythropoiesis in bone marrow decreases hepcidin levels&#44; ensuring the supply of iron for erythrocyte production&#46; Therefore&#44; hepcidin levels reflect the integration of multiple activating and inhibitory signals involved in iron regulation &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Activating signals</span><p id="par0025" class="elsevierStylePara elsevierViewall">BMP-HJV-SMAD is the main axis controlling hepcidin synthesis&#46; In situations of iron deficiency&#44; the Fe2-Tf complex binds to the TfR1 receptor&#44; which is not capable of activating the BMP-SMAD pathway and therefore hepcidin is not synthesized&#44; something which facilitates the arrival of iron into plasma&#46; When iron deficiency is corrected&#44; holotransferrin joins the TfR2 receptor&#44; forming a complex with HFE<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#44;7&#8211;11</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; The role of HFE is to promote the association and stabilization with TfR2&#44; activate HJV and BMP to bind to its receptors &#40;BMPR1 and BMPR2&#41;&#44; in the presence of neoginin&#44; promoting SMAD1&#47;5&#47;8 phosphorylation&#44; HAMP transcription and finally hepcidin synthesis<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">12&#44;13</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Another important mediator in hepcidin synthesis is the inflammation through IL6 and other cytokines &#40;IL1&#44; IL22&#41; and activin B &#40;Act-B&#41; which activate the JAK-STAT3 and BMP signalling pathway<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">7&#44;9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Inhibitory signals</span><p id="par0030" class="elsevierStylePara elsevierViewall">The main hepcidin inhibitory signal comes from erythropoiesis and is related to different proteins such as erythroferrone&#44; <span class="elsevierStyleItalic">growth differentiation factor 15</span> &#40;GDF15&#41; and <span class="elsevierStyleItalic">twisted gastrulation BMP signalling modulator</span> &#40;TWSG1&#41; that inhibits the SMAD pathway<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">7</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Matriptase-2 also has an inhibiting effect on hepcidin&#44; encoded by the TMPRSS6 gene&#44; as it blocks HJV and prevents BMP complex activation&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a> Other inhibitory signals of hepcidin synthesis are tissue hypoxia and erythropoiesis stimulating factors such as erythropoietin &#40;EPO&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#44;2</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Disorders associated with hepcidin abnormalities</span><p id="par0035" class="elsevierStylePara elsevierViewall">Ferroportin and hepcidin abnormalities&#44; whether by interaction or aberrant expression&#44; cause or contribute to triggering a large number of iron related disorders ranging from anaemia due to iron deficiency to iron overload diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">14&#44;15</span></a></p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Diseases associated with an excess of hepcidin</span><p id="par0040" class="elsevierStylePara elsevierViewall">A high level of hepcidin generates hyposideremia with the consequent reduction in erythropoiesis due to insufficient supply of iron&#44; which leads to the development of anaemia in chronic diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">15&#44;16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Chronic diseases</span> present with moderate normocytic and normochromic anaemia but sometimes it may be microcytic and hypochromic&#46; Anaemia is not only the result of elevated hepcidin&#44; there is also a direct effect of cytokines on the production and half-life of red blood cells&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">5</span></a> In chronic kidney disease &#40;CKD&#41;&#44; an elevated hepcidin is the result of a combination of inflammation and inadequate kidney clearance&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">10&#44;17</span></a> In neoplasms&#44; anaemia is associated with disease and treatments&#44; but high levels of hepcidin and cytokines also play an important role&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a> In addition&#44; 10&#37; of the elderly develop anaemia due to nutritional defects&#44; bleeding&#44; chronic inflammation&#44; renal failure&#44; MDS and increased hepcidin&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">1&#44;2</span></a> Finally&#44; <span class="elsevierStyleItalic">iron-refractory iron deficiency anaemia</span> must be included in this section&#44; a genetic anaemia characterized by a mutation in the TMPRR6 gene encoding matriptase-2&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a> The genetic defect is autosomal recessive and occurs with elevated hepcidin levels due to the absence of matriptase-2&#44; resulting in an accumulation of HJV and activation of BMP pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diseases associated with hepcidin decrease or resistance</span><p id="par0050" class="elsevierStylePara elsevierViewall">A hepcidin production deficiency results in iron overload which is usually genetic and is due to mutations in the HFE or TfR2 gene &#40;adult hemochromatosis&#41; or the HJV or HAMP genes &#40;juvenile hemochromatosis&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">18&#44;19</span></a> This decrease of hepcidin contributes to the normal operation of ferroportin&#44; which results in enterocyte iron absorption and increased release of iron from macrophages&#44; which causes hypersideremia with subsequent increase in transferrin saturation&#44; and the appearance of iron bound to proteins other than transferrin&#44; called <span class="elsevierStyleItalic">non-transferrin-bound iron</span> &#40;NTBI&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">7&#44;15</span></a> As there is no regulatory mechanism for excreting iron in humans&#44; excess iron is deposited in tissues that express carriers for NTBI&#44; mainly the liver&#44; heart&#44; pancreas and other endocrine glands&#44; causing function failure in the affected organ&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Hemochromatosis</span> is the most common cause of genetic iron overload&#46; There are many mutations that lead to the clinical syndrome previously mentioned&#44; but the most common is inherited as an autosomal recessive trait&#44; affecting the HFE gene&#44; which encodes the HFE protein &#40;Type 1 Hemochromatosis&#41;&#46; The most common subtype affects homozygous patients with Cys282Tyr mutation &#40;type 1A&#41;&#46; Heterozygous patients may have mixed Cys282Tyr&#47;His63Asp mutations &#40;type 1B&#41;&#46; There are also cases that have mutations in genotypes other than HFE&#44; for example&#44; Ser65Cys &#40;Type 1C&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">13&#44;18&#44;19</span></a> More penetrating and severe forms of hereditary hemochromatosis are rare and are caused by mutations in genes HJV &#40;type 2A&#41;&#44; hepcidin &#40;type 2B&#41;&#44; or TfR2 &#40;type 3&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">9&#44;18</span></a> Mutations in the gene that controls TfR2 prevent this from binding to HFE and consequently&#44; the BMP-HJV-SMAD complex is not activated and hepcidin is not synthesized&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">18</span></a> Another rare form of hemochromatosis is due to mutations in the ferroportin gene &#40;type 4&#41;&#46; These mutations&#44; C326S and SLC11A3&#44; lead to a hepcidin-resistant ferroportin&#44; so that the iron is exported to the circulation&#44; even in the presence of elevated levels of hepcidin&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">18&#44;20</span></a> Phlebotomy is the treatment of choice in iron overload and it is estimated that 1<span class="elsevierStyleHsp" style=""></span>mg of iron is lost with each millilitre of red cells removed and&#44; therefore&#44; the mobilization of excess iron accumulated in the tissues is promoted to restore erythropoiesis&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">2</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#946;-Thalassemia</span> is another disease that occurs with anaemia&#44; iron overload and low levels of hepcidin&#46; Iron overload is the leading cause of morbidity and mortality in these patients&#44; both in non-transfusion-dependent thalassemia as well as in the dependent one&#46; Defective &#946;-globin chain production during erythropoiesis results in the precipitation of &#945;-chains produced in excess and many erythroid precursors may die early&#44; which results in an ineffective erythropoiesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">21&#44;22</span></a> To minimize anaemia&#44; a series of compensatory mechanisms are activated&#44; such as an increase in erythropoietin which causes a erythroblastic hyperplasia&#44; extramedullary haematopoiesis&#44; splenomegaly and increased intestinal absorption of iron which&#44; in the absence of transfusion&#44; is the cause of iron overload&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">23</span></a> The decrease in hepcidin levels is the result of increased suppressor factors&#44; erythroferrone and GDF15 during the development of erythroblasts&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">8</span></a> Transfusions partially correct anaemia and hepcidin suppression&#44; but provide very high amounts of iron with the RBCs transfused&#46; Iron overload in &#946;-thalassemia is treated with iron chelators&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Hepcidin in the diagnosis of iron abnormalities</span><p id="par0065" class="elsevierStylePara elsevierViewall">If hepcidin plays a central role in the pathogenesis of many iron disorders&#44; it seems logical that its quantification should become a useful tool for the diagnosis and clinical management of associated diseases&#46; The size of hepcidin in its circulating bioactive form is 25 amino acids and the N-terminal degradation or storage of samples at room temperature results in smaller isoforms &#40;hepcidin-24&#44; -23&#44; -22 and -20 amino acids&#41; whose meaning is not known&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">1</span></a> Circulating hepcidin binds to one alpha-2-macroglobulin and to albumin&#44; it is excreted by the kidney and reabsorbed in the proximal tubules&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">24</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The development of tests to quantify hepcidin levels in biological samples is a not yet resolved challenge&#46; Absolute hepcidin levels differ widely&#44; up to 10 times in the general population and between the different clinical trials&#44; so each laboratory should establish its own reference values&#46; These differences may be due to the fact that hepcidin is influenced by many physiological and pathological stimuli that promote or inhibit its synthesis and because it adheres to plastics&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">24</span></a> Hepcidin determination can be performed on serum&#44; plasma or urine by immunoassay or by mass spectrometry&#46; The quantification of hepcidin by immunoassay may be more appropriate for large-scale studies due to its high performance and relatively low cost&#46; However&#44; immunoassays quantify the total hepcidin&#44; without distinguishing between the complete hepcidin &#40;hepcidin-25&#41; and the smaller isoforms &#40;hepcidin-20&#44; -22&#44; -23 and -24&#41;&#44; besides&#44; its concentrations are usually higher in CKD due to a dysfunction in hepcidin clearance&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">24</span></a> Urinary hepcidin measurement correlates with plasma hepcidin&#44; but urinary detection may be distorted by the high concentration of small isoforms and in CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Hepcidin as a therapeutic target</span><p id="par0075" class="elsevierStylePara elsevierViewall">Hepcidin is the main target of diseases related to iron metabolism disorders and&#44; therefore&#44; new hepcidin agonists or antagonist drug therapies are being researched&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">10&#44;11</span></a> The interest of these studies is huge&#44; as evidenced by the fact that in July 2016 there were 120 registered clinical trials of hepcidin in <span class="elsevierStyleItalic">ClinicalTrials&#46;gov</span>&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Hepcidin agonists</span><p id="par0080" class="elsevierStylePara elsevierViewall">Increase levels of circulating hepcidin may be beneficial in patients with processes that occur with iron overload&#44; such as hemochromatosis and thalassemia&#46; This could be achieved with drugs that have a hepcidin-like activity or stimulating its endogenous production&#44; but the design of a hepcidin similar to that of oneself does not seem to be the solution&#44; because its half-life is very short and because of the costs involved in its production&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a></p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Minihepcidins</span><p id="par0085" class="elsevierStylePara elsevierViewall">They have a hepcidin-like action with a better bioavailability and a longer circulating half-life&#46; Their action is exerted by binding to ferroportin and blocking the efflux of iron from enterocytes&#44; macrophages and hepatocytes&#44; leading to decreased plasma iron levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">11&#44;25&#8211;27</span></a> Its efficacy has been demonstrated in <span class="elsevierStyleItalic">knockout HAMP &#8722;&#47;&#8722;</span> mice&#44; a model of severe hemochromatosis with lack of hepcidin&#44; in which a plasma iron reduction and tissue iron overload normalization is achieved&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">27</span></a> In thalassaemic mice&#44; treatment with minihepcidins decreases iron overload and improves all haematological parameters&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">25&#8211;27</span></a> This is the result of iron restriction&#44; leading to a decrease in aggregate formation and intracellular inclusion bodies and prevents oxidative stress in erythrocytes&#44; damage in DNA&#44; organelle and cell membrane&#44; with improved erythropoiesis and anaemia correction&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">2&#44;20</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Hepcidin endogenous production stimulators</span><p id="par0090" class="elsevierStylePara elsevierViewall">Another way to increase hepcidin production is based on the design of TMPRSS6 antagonists&#46; RNA technologies are used&#44; mainly antisense oligonucleotides that could silence the mRNA of <span class="elsevierStyleItalic">TMPRSS6</span> thereby stabilizing HJV&#44; stimulating BMP-HJV-SMAD pathway and increasing the synthesis of endogenous hepcidin&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">11&#44;28</span></a> These drugs have also been effective in treating iron overload in <span class="elsevierStyleItalic">knockout</span> mice and in the treatment of anaemia and iron overload in thalassemia mouse model &#40;th3&#47;&#43;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">29</span></a> In addition to increasing the levels of hepcidin&#44; they improve iron overload&#44; reduce splenomegaly and&#44; surprisingly&#44; ineffective erythropoiesis is corrected in thalassaemic mice with homozygous inactivation of TMPRSS6&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">29&#44;30</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Hepcidin antagonists</span><p id="par0095" class="elsevierStylePara elsevierViewall">The high concentration of hepcidin causes iron entrapment in the cells of the reticuloendothelial system and is the leading cause of effective iron deficiency in anaemia of chronic disease&#44; therefore&#44; pharmacological suppression of hepcidin would facilitate iron mobilization&#44; promoting erythropoiesis and anaemia correction&#46; The strategies that are being considered for this purpose are directed to change the BMP-SMAD or IL6&#47;STAT3 axes&#44; interfere in hepcidin-ferroportin binding and enhance their suppressive mechanisms<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">10&#44;11&#44;16&#44;31&#44;32</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Inhibition of bone morphogenetic protein pathway</span><p id="par0100" class="elsevierStylePara elsevierViewall">The BMP-HJV-SMAD pathway is the main axis which controls the synthesis of hepcidin and&#44; therefore&#44; inhibiting the BMP pathway would decrease HAMP expression and blood concentrations of hepcidin&#46; Various molecules have been directed against HJV as a target&#46; On the one hand&#44; several monoclonal antibodies &#40;mAbs&#41; targeting the HJV &#40;ABT-207&#44; h5F9-AM8 and h5F9-23&#41; protein that prevent the binding of BMP with BMPR&#44; block the SMAD pathway and correct anaemia in rats with chronic inflammatory processes<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">33&#44;34</span></a> have been investigated&#46; A similar effect is achieved with a fusion protein between the soluble HJV &#40;sHJV&#41; and the Fc fragment of immunoglobulins &#40;sHJV-Fc&#41; that binds to BMP and prevents BMPR activation&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">11&#44;35</span></a> The same applies to a BMP receptor 1 &#40;BMPR1&#41; inhibitor&#44; the LDN-193189&#44; in rats and human hepatoma cells<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">36</span></a> and with an anti-BPM6 MAb&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">37</span></a> Another way of inhibiting the BMP pathway is blocking or silencing the genes regulating hepcidin synthesis with antisense oligonucleotides that interfere with RNA and silence the mRNA &#40;siRNA&#41; of hepcidin-encoding genes&#44; TfR2 and HJV&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">36&#44;38</span></a> The administration of these siRNAs decreases hepcidin concentrations and corrects anaemia in a chronic inflammatory anaemia mouse model&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">16&#44;39</span></a> Furthermore&#44; it is known that human mutations in the genes encoding hepcidin&#44; the HJV and TfR2&#44; are associated with iron overload diseases&#44; so in these cases&#44; the effects on the corresponding targets of these oligonucleotides and siRNAs may not be effective&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Heparin is another known hepcidin inhibitor through BMP6 sequestration and the subsequent blocking of the SMAD pathway&#44; but its anticoagulant activity limits the therapeutic use as an hepcidin inhibitor&#46; This action of heparin has been demonstrated in mice and in patients receiving heparin to prevent deep venous thrombosis which has achieved an increase in serum iron and transferrin saturation and a reduction in C-reactive protein&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">40</span></a> Several modified heparin analogues have been designed to minimize its anticoagulant effect&#44; maintaining their inhibitory effect on hepcidin expression to treat anaemia of inflammatory processes&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">40&#44;41</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Suppression of the inflammatory pathway</span><p id="par0110" class="elsevierStylePara elsevierViewall">Blocking IL6 with xiltuximab<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">42</span></a> and IL6 receptor with tocilizumab<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">43</span></a> prevent STAT3 phosphorylation and hepcidin concentration decrease and blood iron &#40;level&#41; normalization in monkeys with arthritis and in patients with Castleman&#39;s disease&#46; Similar effects were achieved with a chemical inhibitor of JAK2&#44; the AG490&#44; blocking the IL6-STAT3 pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">44</span></a> The main drawback of anti-cytokine treatments is that they induce immunosuppression&#44; with impairment of the host defences and an increased risk of infections&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Potentiation of erythropoiesis</span><p id="par0115" class="elsevierStylePara elsevierViewall">Increased erythropoiesis is accompanied by a suppression of hepcidin&#44; which could represent a new strategy for the treatment of anaemia of chronic disease&#46; High doses of EPO may be able to overcome the observed resistance to EPO in these diseases&#44; probably by partial suppression of hepcidin&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">45</span></a> Similarly&#44; prolylhydroxylase inhibitors&#44; which stabilize the factors&#44; induce hypoxia and increase EPO synthesis&#44; decrease hepcidin levels and increase haemoglobin in patients with CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">46</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Neutralization of circulating hepcidin</span><p id="par0120" class="elsevierStylePara elsevierViewall">The bioactive neutralization of hepcidin may be achieved by direct binding or sequestration of the circulating hormone with MAb&#44; anticalines or L-RNA aptamers &#40;called <span class="elsevierStyleItalic">Spiegelmers</span>&#44; in German&#44; &#8216;mirror&#8217;&#41;&#46; The main advantage of these hepcidin neutralizers is their high specificity and picomolar affinity to bind to their targets&#44; but the main challenge they must overcome to demonstrate their efficacy is the high rate of hepcidin production present in humans&#44; so that would require massive doses of therapeutic agents in order to achieve their goal&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a> However&#44; it has been shown that the intermittent or partial neutralization of hepcidin activity may be sufficient to achieve the desired therapeutic effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">10&#44;47</span></a> A human anti-hepcidin antibody&#44; 12B9m&#44; has been evaluated in transgenic mice with inflammatory anaemia caused by <span class="elsevierStyleItalic">Brucella abortus</span> and in monkeys&#46; Neutralization of hepcidin by MAb increased erythropoiesis and haemoglobin levels&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">48</span></a> Currently&#44; clinical trials are being conducted with another anti-hepcidin antibody&#44; LY2787106&#44; in patients with anaemia associated with cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleItalic">Anticalines</span> are small proteins designed by genetic engineering targeting various biological ligands&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">47</span></a> One of these compounds is the PRS-080&#44; which binds to human hepcidin with subnanomolar affinity&#44; achieving an effective mobilization of iron and hypersideremia in primates&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a> Aptamers &#40;<span class="elsevierStyleItalic">Spiegelmers</span>&#41; are <span class="elsevierStyleSmallCaps">l</span>-oligonucleotides designed against the mirror image of the target&#44; to which they bind with high affinity&#46; They are stable in the circulation and immunologically passive because their structure contains <span class="elsevierStyleSmallCaps">l</span>-ribose&#44; instead of <span class="elsevierStyleSmallCaps">d</span>-ribose&#44; which gives them a high degradation resistance due to nucleases&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">50</span></a> NOX-H94 neutralizes human hepcidin and increases plasma iron and transferrin saturation&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">50</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Ferroportin as a target&#46; Blocking hepcidin-ferroportin interaction</span><p id="par0125" class="elsevierStylePara elsevierViewall">Hepcidin binding to ferroportin takes place in an extracellular region of ferroportin containing the sulfhydryl residue Cys326 surrounded by hydrophobic residues&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">10</span></a> Blocking this interaction prevents endocytosis and ferroportin destruction&#44; which favours the efflux of iron from cells into plasma&#46; A humanized antiferroportin MAb&#44; the LY2928057&#44; is being evaluated&#46; It targets this region and prevents hepcidin binding the carrier without interfering with the efflux of iron through ferroportin&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">51</span></a> increasing plasma iron levels in cynomolgus monkeys&#46; Fursultiamine is a thiol compound that prevents hepcidin binding to ferroportin in vitro and in vivo in mice&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Other inhibitors of hepcidin</span><p id="par0130" class="elsevierStylePara elsevierViewall">TNF-&#945; inhibitors &#40;golimumab or infliximab&#41; also decrease the synthesis of hepcidin and improve the anaemia of chronic disease through an indirect effect on IL653&#44;54 and vitamin D&#44; testosterone and 17-estradiol&#44; which prevents SMAD55-57 phosphorylation&#46; Finally&#44; it should be noted that some extracts of Chinese medicinal plants&#44; such as <span class="elsevierStyleItalic">Caulis spatholobi</span>&#44; called jixueteng&#44; have a potent inhibitor effect on HAMP expression through SMAD 1&#47;5&#47;858 phosphorylation suppression&#46;</p></span></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusions</span><p id="par0135" class="elsevierStylePara elsevierViewall">We have reviewed the mechanisms that regulate iron homeostasis and hepcidin expression&#44; as well as diseases related to its excess or decrease and the advantages of its quantification in the diagnosis of these diseases&#46; The importance of hepcidin as a therapeutic target focusing on different compounds aimed at correcting iron overload or block&#47;inhibit hepcidin in order to cure the anaemia of chronic disease has been analyzed&#46; Numerous clinical trials are being conducted and it is expected that they will be soon applied to clinical practice&#44; but which of the different therapeutic approaches will have more chances of success is not yet known&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Authorship&#47;collaboration</span><p id="par0140" class="elsevierStylePara elsevierViewall">SCD&#44; RCA and ECG have contributed to the literature review&#44; writing and discussion of the content of the work&#46; ECG has made the final text review&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicts of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">There are no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:3 [
          "identificador" => "xres823607"
          "titulo" => "Abstract"
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              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec820278"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres823608"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0010"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec820277"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Regulation of iron homeostasis&#46; Hepcidin-ferroportin axis"
        ]
        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Regulation of hepcidin expression"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Activating signals"
            ]
            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Inhibitory signals"
            ]
          ]
        ]
        7 => array:3 [
          "identificador" => "sec0030"
          "titulo" => "Disorders associated with hepcidin abnormalities"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Diseases associated with an excess of hepcidin"
            ]
            1 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Diseases associated with hepcidin decrease or resistance"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Hepcidin in the diagnosis of iron abnormalities"
        ]
        9 => array:3 [
          "identificador" => "sec0050"
          "titulo" => "Hepcidin as a therapeutic target"
          "secciones" => array:2 [
            0 => array:3 [
              "identificador" => "sec0055"
              "titulo" => "Hepcidin agonists"
              "secciones" => array:2 [
                0 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Minihepcidins"
                ]
                1 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Hepcidin endogenous production stimulators"
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "sec0070"
              "titulo" => "Hepcidin antagonists"
              "secciones" => array:6 [
                0 => array:2 [
                  "identificador" => "sec0075"
                  "titulo" => "Inhibition of bone morphogenetic protein pathway"
                ]
                1 => array:2 [
                  "identificador" => "sec0080"
                  "titulo" => "Suppression of the inflammatory pathway"
                ]
                2 => array:2 [
                  "identificador" => "sec0085"
                  "titulo" => "Potentiation of erythropoiesis"
                ]
                3 => array:2 [
                  "identificador" => "sec0090"
                  "titulo" => "Neutralization of circulating hepcidin"
                ]
                4 => array:2 [
                  "identificador" => "sec0095"
                  "titulo" => "Ferroportin as a target&#46; Blocking hepcidin-ferroportin interaction"
                ]
                5 => array:2 [
                  "identificador" => "sec0100"
                  "titulo" => "Other inhibitors of hepcidin"
                ]
              ]
            ]
          ]
        ]
        10 => array:2 [
          "identificador" => "sec0105"
          "titulo" => "Conclusions"
        ]
        11 => array:2 [
          "identificador" => "sec0110"
          "titulo" => "Authorship&#47;collaboration"
        ]
        12 => array:2 [
          "identificador" => "sec0115"
          "titulo" => "Conflicts of interest"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-09-22"
    "fechaAceptado" => "2016-10-26"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec820278"
          "palabras" => array:5 [
            0 => "Iron metabolism"
            1 => "Hepcidin"
            2 => "Ferroportin"
            3 => "Hepcidin agonists"
            4 => "Hepcidin antagonists"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec820277"
          "palabras" => array:5 [
            0 => "Metabolismo del hierro"
            1 => "Hepcidina"
            2 => "Ferroportina"
            3 => "Agonistas de la hepcidina"
            4 => "Antagonistas de la hepcidina"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders&#46; Hepcidin deficiency causes iron overload&#44; whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases&#46; We know the mechanisms involved in the synthesis of hepcidin and&#44; under physiological conditions&#44; there is a balance between activating signals and inhibitory signals that regulate its synthesis&#46; The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases&#46; The most important inhibitory signals are related to active erythropoiesis and to matriptase-2&#46; Knowing how hepcidin is synthesized has helped design new pharmacological treatments whose main target is the hepcidin&#46; In the near future&#44; there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La hepcidina es el principal regulador del metabolismo del hierro y el factor patog&#233;nico m&#225;s importante en sus trastornos&#46; La deficiencia de hepcidina provoca sobrecarga de hierro&#44; mientras que su exceso da lugar o contribuye al desarrollo de anemias por d&#233;ficit o restricci&#243;n de hierro en las enfermedades cr&#243;nicas&#46; Conocemos los mecanismos implicados en la s&#237;ntesis de hepcidina y&#44; en condiciones fisiol&#243;gicas&#44; hay un equilibrio entre las se&#241;ales activadoras e inhibidoras que regulan su s&#237;ntesis&#46; Las primeras incluyen las relacionadas con la concentraci&#243;n plasm&#225;tica de hierro y con las enfermedades inflamatorias&#46; Las se&#241;ales inhibidoras m&#225;s importantes est&#225;n relacionadas con la eritropoyesis activa y con la matriptasa-2&#46; Conocer c&#243;mo se sintetiza la hepcidina ha servido para dise&#241;ar nuevos tratamientos farmacol&#243;gicos cuya diana principal es la hepcidina&#46; En un futuro pr&#243;ximo&#44; se dispondr&#225; de tratamientos eficaces dirigidos a corregir el defecto de muchos de los trastornos del metabolismo del hierro&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Conde Diez S&#44; de las Cuevas Allende R&#44; Conde Garc&#237;a E&#46; Estado actual del metabolismo del hierro&#58; implicaciones cl&#237;nicas y terap&#233;uticas&#46; Med Clin &#40;Barc&#41;&#46; 2017&#59;148&#58;218&#8211;224&#46;</p>"
      ]
    ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Body iron homeostasis&#46; The interaction of hepcidin with ferroportin &#40;FPN&#41; controls the main efflux of iron into plasma&#46;</p>"
        ]
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        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
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        "mostrarFloat" => true
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        "figura" => array:1 [
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Dietary iron is absorbed by duodenal enterocytes&#46; Nonheme iron occurs primarily in the ferric state &#40;Fe 3&#43;&#41; in the intestine and is reduced to ferrous iron &#40;Fe 2&#43;&#41; by the action of ferrireductases&#44; especially duodenal cytochrome b &#40;Dcytb&#41;&#46; Ferrous iron passes through the duodenal enterocytes of the divalent metal transporter-1 &#40;DMT1&#41;&#46; Once in the enterocyte&#44; the ferrous iron can be stored in it as ferritin or can be released into the bloodstream through ferroportin &#40;FPN&#41;&#46; Ferrous iron is oxidized by a ferroxidase identified as hephaestin&#44; which after converting into ferric iron&#44; it binds to transferrin and thus circulates in plasma&#46; Furthermore&#44; senescent erythrocytes are phagocytosed by macrophages&#44; primarily in the spleen&#44; but also in the liver and the bone marrow &#40;BM&#41;&#46; During erythropoiesis&#44; erythroblasts acquire iron for haemoglobin synthesis from transferrin via transferrin receptors&#46; Excess iron is stored in the liver and in macrophages as ferritin&#44; which is oxidized to hemosiderin&#46; Hepcidin plays a key role in the release of iron from the deposits depending on the requirements &#40;e&#46;g&#46;&#58; increased erythropoiesis&#44; etc&#46;&#41;&#46;</p>"
        ]
      ]
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        "etiqueta" => "Fig&#46; 3"
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        "mostrarFloat" => true
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Hepcidin synthesis&#46; The main axis that controls the synthesis of hepcidin is <span class="elsevierStyleItalic">bone morphogenetic protein-hemojuvelin-sons of mothers against decapentaplegic</span> &#40;BMP-HJV-SMAD&#41;&#46; Transferrin bound to iron &#40;Fe2-Tf&#41; is a hepatocyte sensor for hepcidin transcription control&#46; The binding of Fe2-Tf with transferrin receptors &#40;TfR1 and TfR2&#41; and human hemochromatosis protein &#40;HFE&#41; is inversely correlated with levels of transferrin saturation by iron&#44; so that&#44; if levels increase&#44; HFE is displaced from TfR1 to TfR2 to activate BMP&#46; This activation facilitates the binding of BMP6 with its receptors 1 and 2 &#40;BMPR1 and BMPR2&#41; in the presence of hemojuvelin &#40;HJV&#41; and neoginin &#40;NEO&#41;&#44; and launches SMAD 1&#47;5&#47;8 phosphorylation&#44; <span class="elsevierStyleItalic">hepcidin antimicrobial peptide</span> &#40;HAMP&#41; gene transcription and the synthesis of hepcidin&#46; Inflammation is another important mediator in hepcidin synthesis through IL6 and activin B &#40;Act-B&#41; via <span class="elsevierStyleItalic">janus kinase-signal transducer and activator of transcription</span> &#40;JAK-STAT3&#41; and BMP&#46; The main hepcidin inhibitory signal comes from the bone marrow during active erythropoiesis and takes place through different proteins&#44; highlighting erythroferrone &#40;ErFe&#41;&#44; <span class="elsevierStyleItalic">growth differentiation factor</span> &#40;GDF15&#41; and <span class="elsevierStyleItalic">twisted gastrulation BMP signalling modulator</span> &#40;TWSG1&#41;&#44; which inhibit the SMAD pathway&#46; Matriptase-2 &#40;MT-2&#41;&#44; encoded by the gene TMPRSS6&#44; also has an inhibitory effect on hepcidin transcription through HJV cleavage&#44; preventing BMP complex activation&#46; Other inhibitory signals of hepcidin synthesis come from situations that generate tissue hypoxia and from the administration of erythropoiesis stimulating factors such as erythropoietin &#40;EPO&#41;&#46;</p>"
        ]
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        "etiqueta" => "Table 1"
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            "identificador" => "at1"
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            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">MAb&#58; monoclonal antibody&#59; MRNA&#58; messenger ribonucleic acid&#59; BMP&#58; bone morphogenetic protein&#59; BMPR&#58; bone morphogenetic protein receptor&#59; FPN&#58; ferroportin&#59; HJV&#58; hemojuvelin&#59; sHJV-Fc&#58; fusion protein between the soluble HJV and the Fc fragment of immunoglobulins&#59; IL&#58; interleukin&#59; SMAD&#58; sons of mothers against decapentaplegic&#59; STAT3&#58; signal transducer and activator of transcription 3&#59; TfR2&#58; transferrin receptor 2&#59; TNF&#58; tumour necrosis factor&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">siHep&#44; siHJV&#44; siTfR2&#58; oligonucleotides silencing mRNA expression in genes encoding hepcidin&#44; HJV or TfR2&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Action and target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">References&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">BMPs&#47;BMPR&#47;HJV complex</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Anti-HJV MAb &#40;ABT-207&#44; h5F9-AM8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitor of BMPs&#47;SMAD pathway&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">33&#44;34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; sHJV-Fc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitor of BMPs&#47;SMAD pathway&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">11&#44;35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; LDN-193189&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BMPR1 phosphorylation inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Anti-BPM6 MAb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BMP6 sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; siHep&#44; siHJV&#44; siTfR2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepcidin mRNA degradation&#44; HJV or TfR2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">36&#44;38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Modified heparin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitors of BMPs&#47;SMAD pathway&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">40&#44;41</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">IL6&#47;SATAT3 pathway</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Anti-IL6 &#40;xiltuximab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IL6 sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">42</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Anti-IL6R &#40;tocilizumab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IL6 receptor sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">43</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; AG490&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">STAT3 phosphorylation inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">44</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Antihepcidin agents</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Antihepcidin MAb &#40;12B9m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepcidin protein sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Anticalines &#40;PRS-080&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepcidin protein sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">49</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Aptamers <span class="elsevierStyleItalic">&#40;Spiegelmers&#58;</span> NOX-H94&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepcidin protein sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Hepcidin-ferroportin interaction</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Antiferroportin MAb &#40;LY2928057&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepcidin-ferroportin binding interference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Fursultiamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cys326-HS sequestration &#40;FPN-hepcidin binding&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Other inhibitors</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; TNF-&#945; MAb &#40;infliximab&#44; golimumab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Indirect effect of IL6 suppression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">53&#44;54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Vitamin D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SMAD 1&#47;5&#47;8 phosphorylation suppressed&#46; Vitamin D recep&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; 17-Estradiol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SMAD 1&#47;5&#47;8 phosphorylation suppressed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">56</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Testosterone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SMAD 1&#47;5&#47;8 phosphorylation suppressed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Chinese medicinal plant extract&#58; <span class="elsevierStyleItalic">Caulis spatholobi</span> &#40;Jixueteng&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SMAD 1&#47;5&#47;8 phosphorylation suppressed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Hepcidin inhibitors and their corresponding targets&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:58 [
            0 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Systemic iron homeostasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "T&#46; Ganz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/physrev.00008.2013"
                      "Revista" => array:6 [
                        "tituloSerie" => "Physiol Rev"
                        "fecha" => "2013"
                        "volumen" => "93"
                        "paginaInicial" => "1721"
                        "paginaFinal" => "1741"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24137020"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepcidin and iron disorders&#58; new biology and clinical approches"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Arezes"
                            1 => "E&#46; Nemeth"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Lab Hem"
                        "fecha" => "2015"
                        "volumen" => "37"
                        "paginaInicial" => "92"
                        "paginaFinal" => "98"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Disorders of iron metabolism&#46; Part I&#58; molecular basis of iron homeostasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46; Mu&#241;oz"
                            1 => "J&#46;A&#46; Garc&#237;a-Erce"
                            2 => "A&#46;F&#46; Remacha"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jcp.2010.079046"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Pathol"
                        "fecha" => "2011"
                        "volumen" => "64"
                        "paginaInicial" => "281"
                        "paginaFinal" => "286"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21177266"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Iron&#44; erythropoiesis&#44; and host defense&#58; A m&#233;nage &#224; trois"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "T&#46; Ganz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:2 [
                        "tituloSerie" => "Am Soc Hematol E Donnall Thomas Lecture"
                        "fecha" => "2014"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anemia of inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E&#46; Nemeth"
                            1 => "T&#46; Ganz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.hoc.2014.04.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hematol Oncol Clin North Am"
                        "fecha" => "2014"
                        "volumen" => "28"
                        "paginaInicial" => "671"
                        "paginaFinal" => "681"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25064707"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Physiology of iron metabolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Waldvogel-Abramowski"
                            1 => "G&#46; Waeber"
                            2 => "C&#46; Gassner"
                            3 => "A&#46; Buser"
                            4 => "B&#46;M&#46; Frey"
                            5 => "B&#46; Favrat"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000362888"
                      "Revista" => array:6 [
                        "tituloSerie" => "Transfus Med Hemother"
                        "fecha" => "2014"
                        "volumen" => "41"
                        "paginaInicial" => "213"
                        "paginaFinal" => "221"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25053935"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepcidina and iron homeostasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46; Ganz"
                            1 => "E&#46; Nemeth"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbamcr.2012.01.014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochim Biophys Acta"
                        "fecha" => "2012"
                        "volumen" => "1823"
                        "paginaInicial" => "1434"
                        "paginaFinal" => "1443"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22306005"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0330"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of erythroferrone as an erythroid regulator of iron metabolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "L&#46; Kautz"
                            1 => "G&#46; Jung"
                            2 => "E&#46;V&#46; Valore"
                            3 => "S&#46; Rivella"
                            4 => "E&#46; Nemeth"
                            5 => "T&#46; Ganz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ng.2996"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Genet"
                        "fecha" => "2014"
                        "volumen" => "46"
                        "paginaInicial" => "678"
                        "paginaFinal" => "684"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24880340"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0335"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetics&#44; genetic testing&#44; and management of hemochromatosis&#58; 15 years since hepcidin"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46; Pietrangelo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2015.06.045"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2015"
                        "volumen" => "149"
                        "paginaInicial" => "1240"
                        "paginaFinal" => "1251"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26164493"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0340"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The pathophisiology and pharmacology of hepcidin"
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                        0 => array:2 [
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                          "autores" => array:2 [
                            0 => "P&#46; Ruchala"
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                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.tips.2014.01.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Trends Pharmacol Sci"
                        "fecha" => "2014"
                        "volumen" => "35"
                        "paginaInicial" => "155"
                        "paginaFinal" => "161"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24552640"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0345"
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                    0 => array:2 [
                      "titulo" => "Hepcidin A promising therapeutic target for iron disorders&#46; A systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46; Liu"
                            1 => "B&#46; Sun"
                            2 => "H&#46; Yin"
                            3 => "S&#46; Liu"
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                    0 => array:2 [
                      "titulo" => "HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "X&#46;G&#46; Wu"
                            1 => "Y&#46; Wang"
                            2 => "Q&#46; Wu"
                            3 => "W&#46;H&#46; Cheng"
                            4 => "W&#46; Liu"
                            5 => "Y&#46; Zhao"
                          ]
                        ]
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                        "paginaInicial" => "1335"
                        "paginaFinal" => "1343"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24904118"
                            "web" => "Medline"
                          ]
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                ]
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              "identificador" => "bib0355"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "How mutant HFE causes hereditary hemochromatosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46;U&#46; Muckenthaler"
                          ]
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                      ]
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                  "host" => array:1 [
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                        "volumen" => "124"
                        "paginaInicial" => "1212"
                        "paginaFinal" => "1213"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25147378"
                            "web" => "Medline"
                          ]
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                ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Iron-deficiency anemia"
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "C&#46; Camaschella"
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2015"
                        "volumen" => "372"
                        "paginaInicial" => "1832"
                        "paginaFinal" => "1843"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25946282"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0365"
              "etiqueta" => "15"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Disorders of iron metabolism&#46; Part II&#58; iron deficiency and iron overlad"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46; Mu&#241;oz"
                            1 => "J&#46;A&#46; Garc&#237;a-Erce"
                            2 => "A&#46;F&#46; Remacha"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jcp.2010.086991"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Pathol"
                        "fecha" => "2011"
                        "volumen" => "64"
                        "paginaInicial" => "287"
                        "paginaFinal" => "296"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21177268"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0370"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepcidin regulation in the anemia of inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "C&#46;Y&#46; Wang"
                            1 => "J&#46;L&#46; Babitt"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MOH.0000000000000236"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Hematol"
                        "fecha" => "2016"
                        "volumen" => "23"
                        "paginaInicial" => "189"
                        "paginaFinal" => "197"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26886082"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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                    0 => array:2 [
                      "titulo" => "Nuevas expectativas en el tratamiento de la anemia en la enfermedad renal cr&#243;nica"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;M&#46; L&#243;pez-G&#243;mez"
                            1 => "S&#46; Abad"
                            2 => "A&#46; Vega"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.nefro.2016.03.006"
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                        "tituloSerie" => "Nefrologia"
                        "fecha" => "2016"
                        "volumen" => "36"
                        "paginaInicial" => "232"
                        "paginaFinal" => "236"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27137103"
                            "web" => "Medline"
                          ]
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                ]
              ]
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              "identificador" => "bib0380"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Haemochromatosis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46;W&#46; Powell"
                            1 => "R&#46;C&#46; Seckington"
                            2 => "Y&#46; Deugnier"
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(15)01315-X"
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                        "tituloSerie" => "Lancet"
                        "fecha" => "2016"
                        "volumen" => "388"
                        "paginaInicial" => "706"
                        "paginaFinal" => "716"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26975792"
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                        "itemHostRev" => array:3 [
                          "pii" => "S0140673605177411"
                          "estado" => "S300"
                          "issn" => "01406736"
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                  ]
                ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Hemocromatosis hereditaria&#46; Problemas en el diagn&#243;stico y tratamiento"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                            2 => "M&#46; Bruguera"
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                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Med Clin &#40;Barc&#41;"
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                        "volumen" => "144"
                        "paginaInicial" => "424"
                        "paginaFinal" => "428"
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              "identificador" => "bib0390"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The molecular basis of hepcidin-resistant hereditary hemochromatosis"
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                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Fernandes"
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                            2 => "Y&#46; Phung"
                            3 => "J&#46; Kaplan"
                            4 => "T&#46; Ganz"
                            5 => "E&#46; Nemeth"
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                    0 => array:2 [
                      "doi" => "10.1182/blood-2008-03-146134"
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                        "tituloSerie" => "Blood"
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                        "volumen" => "114"
                        "paginaInicial" => "437"
                        "paginaFinal" => "443"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19383972"
                            "web" => "Medline"
                          ]
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                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of ineffective erythropoiesis in non-transfusion-dependent thalassemia"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
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                    0 => array:2 [
                      "doi" => "10.1016/S0268-960X(12)70005-X"
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                        "tituloSerie" => "Blood Rev"
                        "fecha" => "2012"
                        "volumen" => "26"
                        "paginaInicial" => "S12"
                        "paginaFinal" => "S15"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22631035"
                            "web" => "Medline"
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              ]
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              "identificador" => "bib0400"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ineffective erythropoiesis and regulation of iron status in iron loading anaemias"
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2016"
                        "volumen" => "172"
                        "paginaInicial" => "512"
                        "paginaFinal" => "523"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26491866"
                            "web" => "Medline"
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                    0 => array:2 [
                      "titulo" => "Morbidities in non-transfusion-dependent thalassemia"
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                            0 => "A&#46;N&#46; Saliba"
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                        "tituloSerie" => "Ann N Y Acad Sci"
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                        "volumen" => "1368"
                        "paginaInicial" => "82"
                        "paginaFinal" => "94"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27186941"
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                ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Swinkels hepcidin in the diagnosis of iron disorders"
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                            0 => "D&#46; Girelli"
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                        "volumen" => "127"
                        "paginaInicial" => "2809"
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                    0 => array:2 [
                      "titulo" => "Manipulation of the hepcidin pathway for therapeutics purpose"
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                        "tituloSerie" => "Haematologica"
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                        "volumen" => "98"
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                      "titulo" => "Pharmacological targeting of the hepcidin&#47;ferroportin axis"
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                        "tituloSerie" => "Front Pharmacol"
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                        "volumen" => "7"
                        "paginaInicial" => "160"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27445804"
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                      "titulo" => "Hepcidin&#46; Minireview"
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                        "tituloSerie" => "J Clin Diagn Res"
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                        "link" => array:1 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia"
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                      "titulo" => "An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe&#40;&#8722;&#47;&#8722;&#41; mice and ameliorates anemia and iron overload in murine &#946;-thalassemia intermedia"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23223430"
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                    0 => array:2 [
                      "titulo" => "Inhibiting the hepcidin inhibitor for treatment of iron overload"
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                    0 => array:2 [
                      "titulo" => "The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders"
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                      "titulo" => "Modulation of hepcidin to treat iron deregulation&#58; potential clinical applications"
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                          "autores" => array:4 [
                            0 => "N&#46;L&#46; Blanchette"
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                            3 => "S&#46;V&#46; Torti"
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                        "tituloSerie" => "Expert Rev Hematol"
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                        "paginaFinal" => "186"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26669208"
                            "web" => "Medline"
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                      "titulo" => "Anti-repulsive guidance molecule C &#40;RGMc&#41; antibodies increases serum iron in rats and cynomolgus monkeys by hepcidin downregulation"
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                            4 => "L&#46; Huang"
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                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "Anti-hemojuvelin antibody corrects anemia caused by inappropriately high hepcidin levels"
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                        "volumen" => "101"
                        "paginaInicial" => "e173"
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                      "titulo" => "Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats"
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                            3 => "M&#46; Nairz"
                            4 => "M&#46; Theurl"
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                          0 => array:2 [
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                            "web" => "Medline"
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                    0 => array:2 [
                      "titulo" => "Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation"
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                          "autores" => array:6 [
                            0 => "A&#46;U&#46; Steinbicker"
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                            2 => "A&#46;J&#46; Vonner"
                            3 => "R&#46;Z&#46; Yusuf"
                            4 => "D&#46;Y&#46; Deng"
                            5 => "C&#46;S&#46; Lai"
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                        "paginaInicial" => "4915"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21393479"
                            "web" => "Medline"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice"
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                            4 => "G&#46; Montosi"
                            5 => "S&#46; Chen"
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                        "tituloSerie" => "Gastroenterology"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20682319"
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              "identificador" => "bib0480"
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                          0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Identification of siRNA delivery enhancers by a chemical library screen"
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                        "tituloSerie" => "Nucleic Acids Res"
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                          0 => array:2 [
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              "identificador" => "bib0495"
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                    0 => array:2 [
                      "titulo" => "Oversulfated heparins with low anticoagulant activity are strong and fast inhibitors of hepcidin expression <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>"
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                0 => array:2 [
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                            2 => "N&#46; Munshi"
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                            4 => "M&#46; Qi"
                            5 => "M&#46; Schaffer"
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                        "tituloSerie" => "Clin Cancer Res"
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                          0 => array:2 [
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                      "titulo" => "Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody &#40;tocilizumab&#41; improves anemia of inflammation in multicentric Castleman disease"
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                            4 => "T&#46; Nishikawa"
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                  "host" => array:1 [
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                        "paginaInicial" => "3627"
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              "identificador" => "bib0510"
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                    0 => array:2 [
                      "titulo" => "AG490&#58; an inhibitor of hepcidin expression in vivo"
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                          "etal" => false
                          "autores" => array:4 [
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                    0 => array:2 [
                      "doi" => "10.3748/wjg.v17.i45.5032"
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                        "tituloSerie" => "World J Gastroenterol"
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                        "paginaFinal" => "5034"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22174555"
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                    0 => array:2 [
                      "titulo" => "Hyporesponsiveness to erythropoietin&#58; causes and management"
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                          "etal" => false
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                        "tituloSerie" => "Adv Chronic Kidney Dis"
                        "fecha" => "2009"
                        "volumen" => "16"
                        "paginaInicial" => "94"
                        "paginaFinal" => "100"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19233068"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0520"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat &#40;FG-4592&#41; for the treatment of anemia in patients with CKD"
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                        "tituloSerie" => "Clin J Am Soc Nephrol"
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                        "volumen" => "11"
                        "paginaInicial" => "982"
                        "paginaFinal" => "991"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27094610"
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                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Improved mass spectrometry assay for plasma hepcidin&#58; detection and characterization of a novel hepcidin isoform"
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                          "etal" => true
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                            1 => "E&#46;T&#46; Wiegerinck"
                            2 => "S&#46; Klaver"
                            3 => "M&#46; Kolodziejczyk"
                            4 => "H&#46; Gille"
                            5 => "A&#46;M&#46; Hohlbaum"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0075518"
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                        "tituloSerie" => "PLoS One"
                        "fecha" => "2013"
                        "volumen" => "8"
                        "paginaInicial" => "e75518"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24124495"
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                          ]
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                ]
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              "identificador" => "bib0530"
              "etiqueta" => "48"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;S&#46; Cooke"
                            1 => "B&#46; Hinkle"
                            2 => "H&#46; Salimi-Moosavi"
                            3 => "I&#46; Foltz"
                            4 => "C&#46; King"
                            5 => "P&#46; Rathanaswami"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2013-06-505792"
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                        "tituloSerie" => "Blood"
                        "fecha" => "2013"
                        "volumen" => "122"
                        "paginaInicial" => "3054"
                        "paginaFinal" => "3061"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23945155"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0535"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Iron mobilization and pharmacodynamic marker measurements in non-human primates following administration of PRS-080&#44; a novel and highly specific anti-hepcidin therapeutic &#91;abstract&#93;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Hohlbaum"
                            1 => "H&#46; Gille"
                            2 => "J&#46; Christian"
                            3 => "A&#46; Allersdorfer"
                            4 => "J&#46; Jaworski"
                            5 => "J&#46; Burrows"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Am J Hematol"
                        "fecha" => "2013"
                        "volumen" => "5"
                        "paginaInicial" => "E41"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0540"
              "etiqueta" => "50"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Schwoebel"
                            1 => "L&#46;T&#46; van Eijk"
                            2 => "D&#46; Zboralski"
                            3 => "S&#46; Sell"
                            4 => "K&#46; Buchner"
                            5 => "C&#46; Maasch"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2012-09-456756"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2013"
                        "volumen" => "121"
                        "paginaInicial" => "2311"
                        "paginaFinal" => "2315"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23349391"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0545"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "LY2928057&#44; an antibody targeting ferroportin&#44; is a potent inhibitor of hepcidin activity and increases iron mobilization in normal cynomolgus monkeys"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;R&#46; Witcher"
                            1 => "D&#46; Leung"
                            2 => "K&#46;A&#46; Hill"
                            3 => "D&#46;C&#46; de Rosa"
                            4 => "J&#46; Xu"
                            5 => "J&#46; Manetta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2013"
                        "volumen" => "122"
                        "paginaInicial" => "3433"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0550"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High-throughput screening of small molecules identifies hepcidin antagonists"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46; Fung"
                            1 => "P&#46; Sugianto"
                            2 => "J&#46; Hsu"
                            3 => "R&#46; Damoiseaux"
                            4 => "T&#46; Ganz"
                            5 => "E&#46; Nemeth"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1124/mol.112.083428"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Pharmacol"
                        "fecha" => "2013"
                        "volumen" => "83"
                        "paginaInicial" => "681"
                        "paginaFinal" => "690"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23292796"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of subcutaneous and intravenous golimumab on inflammatory biomarkers in patients with rheumatoid arthritis&#58; results of a phase 1&#44; randomized&#44; open-label trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;K&#46; Doyle"
                            1 => "M&#46;U&#46; Rahman"
                            2 => "B&#46; Frederick"
                            3 => "C&#46;A&#46; Birbara"
                            4 => "D&#46; de Vries"
                            5 => "G&#46; Teodter"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/kes381"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheumatology"
                        "fecha" => "2013"
                        "volumen" => "52"
                        "paginaInicial" => "1214"
                        "paginaFinal" => "1219"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23418046"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tumour necrosis factor alpha downregulates human hemojuvelin expression via a novel response element within its promoter"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;F&#46; Salama"
                            1 => "H&#46;K&#46; Bayele"
                            2 => "S&#46;S&#46; Srai"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1423-0127-19-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biomed Sci"
                        "fecha" => "2012"
                        "volumen" => "19"
                        "paginaInicial" => "1"
                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22212150"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Suppression of iron-regulatory hepcidin by vitamin D"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Bacchetta"
                            1 => "J&#46;J&#46; Zaritsky"
                            2 => "J&#46;L&#46; Sea"
                            3 => "R&#46;F&#46; Chun"
                            4 => "T&#46;S&#46; Lisse"
                            5 => "K&#46; Zavala"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2013040355"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Soc Nephrol"
                        "fecha" => "2014"
                        "volumen" => "25"
                        "paginaInicial" => "564"
                        "paginaFinal" => "572"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24204002"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0570"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "17&#946;-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Q&#46; Yang"
                            1 => "J&#46; Jian"
                            2 => "S&#46; Katz"
                            3 => "S&#46;B&#46; Abramson"
                            4 => "X&#46; Huang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/en.2011-2045"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrinology"
                        "fecha" => "2012"
                        "volumen" => "153"
                        "paginaInicial" => "3170"
                        "paginaFinal" => "3178"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22535765"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0575"
              "etiqueta" => "57"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46; Guo"
                            1 => "E&#46; Bachman"
                            2 => "M&#46; Li"
                            3 => "C&#46;N&#46; Roy"
                            4 => "J&#46; Blusztajn"
                            5 => "S&#46; Wong"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/acel.12052"
                      "Revista" => array:6 [
                        "tituloSerie" => "Aging Cell"
                        "fecha" => "2013"
                        "volumen" => "12"
                        "paginaInicial" => "280"
                        "paginaFinal" => "291"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23399021"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0580"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Screening identifies the Chinese medicinal plant caulis spatholobi as an effective HAMP expression inhibitor"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Guan"
                            1 => "P&#46; An"
                            2 => "Z&#46; Zhang"
                            3 => "F&#46; Zhang"
                            4 => "Y&#46; Tu"
                            5 => "Q&#46; Wu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3945/jn.113.174201"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Nutr"
                        "fecha" => "2013"
                        "volumen" => "143"
                        "paginaInicial" => "1061"
                        "paginaFinal" => "1066"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23700338"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
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