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1.
Blood Adv ; 3(21): 3261-3265, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31698457

RESUMO

Most elderly patients affected with acute myeloid leukemia (AML) will relapse and die of their disease even after achieving complete remission, thus emphasizing the urgent need for new therapeutic approaches with minimum toxicity to normal hematopoietic cells. Cranberry (Vaccinium spp.) extracts have exhibited anticancer and chemopreventive properties that have been mostly attributed to A-type proanthocyanidin (A-PAC) compounds. A-PACs, isolated from a commercially available cranberry extract, were evaluated for their effects on leukemia cell lines, primary AML samples, and normal CD34+ cord blood specimens. Our results indicated potent and specific antileukemia activity in vitro. In addition, the antileukemia activity of A-PACs extended to malignant progenitor and stem cell populations, sparing their normal counterparts. The antileukemia effects of A-PACs were also observed in vivo using patient derived xenografts. Surprisingly, we found that the mechanism of cell death was driven by activation of NF-κB. Overall, our data suggest that A-PACs could be used to improve treatments for AML by targeting leukemia stem cells through a potentially novel pathway.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Proantocianidinas/farmacologia , Vaccinium macrocarpon/química , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Camundongos , Extratos Vegetais/química , Proantocianidinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nat Commun ; 7: 13817, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28004654

RESUMO

Hepatic stellate cell (HSC) activation on liver injury facilitates fibrosis. Hepatokines affecting HSCs are largely unknown. Here we show that hepcidin inhibits HSC activation and ameliorates liver fibrosis. We observe that hepcidin levels are inversely correlated with exacerbation of fibrosis in patients, and also confirm the relationship in animal models. Adenoviral delivery of hepcidin to mice attenuates liver fibrosis induced by CCl4 treatment or bile duct ligation. In cell-based assays, either hepcidin from hepatocytes or exogenous hepcidin suppresses HSC activation by inhibiting TGFß1-mediated Smad3 phosphorylation via Akt. In activated HSCs, ferroportin is upregulated, which can be prevented by hepcidin treatment. Similarly, ferroportin knockdown in HSCs prohibits TGFß1-inducible Smad3 phosphorylation and increases Akt phosphorylation, whereas ferroportin over-expression has the opposite effect. HSC-specific ferroportin deletion also ameliorates liver fibrosis. In summary, hepcidin suppresses liver fibrosis by impeding TGFß1-induced Smad3 phosphorylation in HSCs, which depends on Akt activated by a deficiency of ferroportin.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Células Estreladas do Fígado/metabolismo , Hepcidinas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Smad3/metabolismo , Animais , Proteínas de Transporte de Cátions/antagonistas & inibidores , Proteínas de Transporte de Cátions/genética , Técnicas de Silenciamento de Genes , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Hepcidinas/genética , Hepcidinas/farmacologia , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
4.
Mol Med ; 21(1): 951-958, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26736178

RESUMO

Patients surviving sepsis develop anemia, but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating tumor necrosis factor (TNF) and interleukin (IL)-6 are elevated for 5 d after the onset of sepsis, and serum high-mobility group box 1 (HMGB1) levels are increased from d 7 until at least d 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5 ± 9.0% versus 37.4 ± 6.1%, p < 0.01; hemoglobin 14.0 ± 1.7 versus 11.7 ± 1.2 g/dL, p < 0.01). Together, these results indicate that HMGB1 mediates anemia by interfering with erythropoiesis, suggesting a potential therapeutic strategy for anemia in sepsis.

5.
Blood ; 123(25): 3864-72, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24795345

RESUMO

In ß-thalassemia, unequal production of α- and ß-globin chains in erythroid precursors causes apoptosis and inhibition of late-stage erythroid differentiation, leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis. Here we used a murine model of ß-thalassemia intermedia (Hbb(th1/th1) mice) to investigate effects of a modified activin receptor type IIB (ActRIIB) ligand trap (RAP-536) that inhibits Smad2/3 signaling. In Hbb(th1/th1) mice, treatment with RAP-536 reduced overactivation of Smad2/3 in splenic erythroid precursors. In addition, treatment of Hbb(th1/th1) mice with RAP-536 reduced α-globin aggregates in peripheral red cells, decreased the elevated reactive oxygen species present in erythroid precursors and peripheral red cells, and alleviated anemia by promoting differentiation of late-stage erythroid precursors and reducing hemolysis. Notably, RAP-536 treatment mitigated disease complications of IE, including iron overload, splenomegaly, and bone pathology, while reducing erythropoietin levels, improving erythrocyte morphology, and extending erythrocyte life span. These results implicate signaling by the transforming growth factor-ß superfamily in late-stage erythropoiesis and reveal potential of a modified ActRIIB ligand trap as a novel therapeutic agent for thalassemia syndrome and other red cell disorders characterized by IE.


Assuntos
Receptores de Activinas Tipo II/genética , Eritropoese/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Transdução de Sinais/efeitos dos fármacos , Talassemia beta/tratamento farmacológico , Receptores de Activinas Tipo II/metabolismo , Anemia/sangue , Anemia/genética , Anemia/prevenção & controle , Animais , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Células Precursoras Eritroides/efeitos dos fármacos , Células Precursoras Eritroides/metabolismo , Eritropoese/genética , Hemólise/efeitos dos fármacos , Hemólise/genética , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/genética , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Globinas beta/genética , Globinas beta/metabolismo , Talassemia beta/sangue , Talassemia beta/genética
6.
Blood ; 123(8): 1137-45, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24357729

RESUMO

Anemia of inflammation (AI) is commonly observed in chronic inflammatory states and may hinder patient recovery and survival. Induction of hepcidin, mediated by interleukin 6, leads to iron-restricted erythropoiesis and anemia. Several translational studies have been directed at neutralizing hepcidin overexpression as a therapeutic strategy against AI. However, additional hepcidin-independent mechanisms contribute to AI, which are likely mediated by a direct effect of inflammatory cytokines on erythropoiesis. In this study, we used wild-type, hepcidin knockout (Hamp-KO) and interleukin 6 knockout (IL-6-KO) mice as models of AI. AI was induced with heat-killed Brucella abortus (BA). The distinct roles of iron metabolism and inflammation triggered by interleukin 6 and hepcidin were investigated. BA-treated wild-type mice showed increased expression of hepcidin and inflammatory cytokines, as well as transitory suppression of erythropoiesis and shortened red blood cell lifespan, all of which contributed to the severe anemia of these mice. In contrast, BA-treated Hamp-KO or IL-6-KO mice showed milder anemia and faster recovery compared with normal mice. Moreover, they exhibited different patterns in the development and resolution of anemia, supporting the notion that interleukin 6 and hepcidin play distinct roles in modulating erythropoiesis in AI.


Assuntos
Anemia/imunologia , Brucella abortus , Brucelose/imunologia , Hepcidinas/imunologia , Interleucina-6/imunologia , Anemia/genética , Anemia/microbiologia , Animais , Medula Óssea/imunologia , Brucelose/complicações , Modelos Animais de Doenças , Eritropoese/imunologia , Feminino , Hepcidinas/genética , Temperatura Alta , Interleucina-6/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Recuperação de Função Fisiológica/imunologia
7.
Proc Natl Acad Sci U S A ; 110(50): E4922-30, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24282296

RESUMO

Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including ß-thalassemia major, which is characterized by a defective ß-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In ß-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in ß-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2α (HIF2α) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of ß-thalassemia and are essential for excess iron accumulation in mouse models of ß-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2α. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2α/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2α signaling is critical for progressive iron overload in ß-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Mucosa Intestinal/metabolismo , Sobrecarga de Ferro/etiologia , Talassemia beta/complicações , Análise de Variância , Animais , Western Blotting , Ferrocianetos , Sobrecarga de Ferro/metabolismo , Luciferases , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/metabolismo , Talassemia beta/metabolismo
8.
J Clin Invest ; 123(8): 3614-23, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23863711

RESUMO

The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mechanistically, the erythroid iron restriction response results from inactivation of aconitase enzymes and can be suppressed by providing the aconitase product isocitrate. Recent studies have implicated the erythroid iron restriction response in anemia of chronic disease and inflammation (ACDI), offering new therapeutic avenues for a major clinical problem; however, inflammatory signals may also directly repress erythropoiesis in ACDI. Here, we show that suppression of the erythroid iron restriction response by isocitrate administration corrected anemia and erythropoietic defects in rats with ACDI. In vitro studies demonstrated that erythroid repression by inflammatory signaling is potently modulated by the erythroid iron restriction response in a kinase-dependent pathway involving induction of the erythroid-inhibitory transcription factor PU.1. These results reveal the integration of iron and inflammatory inputs in a therapeutically tractable erythropoietic regulatory circuit.


Assuntos
Anemia/tratamento farmacológico , Células Eritroides/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Deficiências de Ferro , Isocitratos/farmacologia , Aconitato Hidratase/metabolismo , Anemia/metabolismo , Anemia/patologia , Animais , Células Cultivadas , Células Eritroides/enzimologia , Feminino , Humanos , Interferon gama/fisiologia , Isocitratos/uso terapêutico , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais , Transativadores/metabolismo , Ativação Transcricional
9.
Nat Med ; 19(4): 437-45, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23502961

RESUMO

Regulation of erythropoiesis is achieved by the integration of distinct signals. Among them, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages to physiological and pathological conditions of enhanced erythropoiesis. We used mouse models of induced anemia, polycythemia vera and ß-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively to recovery from induced anemia, as well as the pathological progression of polycythemia vera and ß-thalassemia, by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a direct impact of macrophages on the proliferation and enucleation of erythroblasts from healthy individuals and patients with polycythemia vera or ß-thalassemia. The contribution of macrophages to stress and pathological erythropoiesis, which we have termed stress erythropoiesis macrophage-supporting activity, may have therapeutic implications.


Assuntos
Eritropoese/fisiologia , Macrófagos/fisiologia , Policitemia Vera/fisiopatologia , Talassemia beta/fisiopatologia , Animais , Ácido Clodrônico/farmacologia , Modelos Animais de Doenças , Contagem de Eritrócitos , Eritropoese/efeitos dos fármacos , Feminino , Hematócrito , Hemoglobinas/análise , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reticulócitos/fisiologia , Estresse Fisiológico/fisiologia
10.
J Clin Invest ; 123(4): 1531-41, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23524968

RESUMO

ß-Thalassemia and HFE-related hemochromatosis are 2 of the most frequently inherited disorders worldwide. Both disorders are characterized by low levels of hepcidin (HAMP), the hormone that regulates iron absorption. As a consequence, patients affected by these disorders exhibit iron overload, which is the main cause of morbidity and mortality. HAMP expression is controlled by activation of the SMAD1,5,8/SMAD4 complex. TMPRSS6 is a serine protease that reduces SMAD activation and blocks HAMP expression. We identified second generation antisense oligonucleotides (ASOs) targeting mouse Tmprss6. ASO treatment in mice affected by hemochromatosis (Hfe(-/-)) significantly decreased serum iron, transferrin saturation and liver iron accumulation. Furthermore, ASO treatment of mice affected by ß-thalassemia (HBB(th3/+) mice, referred to hereafter as th3/+ mice) decreased the formation of insoluble membrane-bound globins, ROS, and apoptosis, and improved anemia. These animals also exhibited lower erythropoietin levels, a significant amelioration of ineffective erythropoiesis (IE) and splenomegaly, and an increase in total hemoglobin levels. These data suggest that ASOs targeting Tmprss6 could be beneficial in individuals with hemochromatosis, ß-thalassemia, and related disorders.


Assuntos
Hemocromatose/terapia , Proteínas de Membrana/genética , Serina Endopeptidases/genética , Talassemia beta/terapia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Células Cultivadas , Feminino , Técnicas de Silenciamento de Genes , Hemocromatose/sangue , Hemocromatose/genética , Proteína da Hemocromatose , Hepatócitos/metabolismo , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Ferro/sangue , Ferro/metabolismo , Fígado/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oligonucleotídeos Antissenso/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serina Endopeptidases/metabolismo , Baço/metabolismo , Baço/patologia , Transferrina/metabolismo , Talassemia beta/sangue , Talassemia beta/genética
11.
PLoS One ; 7(3): e32345, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22479321

RESUMO

Preclinical and clinical studies demonstrate the feasibility of treating ß-thalassemia and Sickle Cell Disease (SCD) by lentiviral-mediated transfer of the human ß-globin gene. However, previous studies have not addressed whether the ability of lentiviral vectors to increase hemoglobin synthesis might vary in different patients.We generated lentiviral vectors carrying the human ß-globin gene with and without an ankyrin insulator and compared their ability to induce hemoglobin synthesis in vitro and in thalassemic mice. We found that insertion of an ankyrin insulator leads to higher, potentially therapeutic levels of human ß-globin through a novel mechanism that links the rate of transcription of the transgenic ß-globin mRNA during erythroid differentiation with polysomal binding and efficient translation, as reported here for the first time. We also established a preclinical assay to test the ability of this novel vector to synthesize adult hemoglobin in erythroid precursors and in CD34(+) cells isolated from patients affected by ß-thalassemia and SCD. Among the thalassemic patients, we identified a subset of specimens in which hemoglobin production can be achieved using fewer copies of the vector integrated than in others. In SCD specimens the treatment with AnkT9W ameliorates erythropoiesis by increasing adult hemoglobin (Hb A) and concurrently reducing the sickling tetramer (Hb S).Our results suggest two major findings. First, we discovered that for the purpose of expressing the ß-globin gene the ankyrin element is particularly suitable. Second, our analysis of a large group of specimens from ß-thalassemic and SCD patients indicates that clinical trials could benefit from a simple test to predict the relationship between the number of vector copies integrated and the total amount of hemoglobin produced in the erythroid cells of prospective patients. This approach would provide vital information to select the best candidates for these clinical trials, before patients undergo myeloablation and bone marrow transplant.


Assuntos
Anemia Falciforme/terapia , Terapia Genética/métodos , Hemoglobinas/metabolismo , Talassemia beta/terapia , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/genética , Animais , Anquirinas/genética , Antígenos CD34/metabolismo , Sequência de Bases , Diferenciação Celular/genética , Linhagem Celular Tumoral , Células Cultivadas , Células Precursoras Eritroides/metabolismo , Expressão Gênica , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Hemoglobinas/genética , Humanos , Elementos Isolantes/genética , Lentivirus/genética , Camundongos , Dados de Sequência Molecular , Mutação , Células NIH 3T3 , Globinas beta/genética , Talassemia beta/sangue , Talassemia beta/genética
12.
Ann Hematol ; 91(8): 1201-13, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22460946

RESUMO

Gene therapy might fall short in achieving a complete reversion of the ß-thalassemic phenotype due to current limitations in vector design and myeloablative regimen. Following gene transfer, all or a large proportion of erythroid cells might express suboptimal levels of ß-globin, impairing the therapeutic potential of the treatment. Our aim was to evaluate whether, in absence of complete reversion of the ß-globin phenotype upon gene transfer, it is possible to use fetal hemoglobin induction to eliminate the residual α-globin aggregates and achieve normal levels of hemoglobin. Transgenic K562 cell lines and erythroid precursor cells from ß(0)39-thalassemia patients were employed. Gene therapy was performed with the lentiviral vector T9W. Induction of fetal hemoglobin was obtained using mithramycin. Levels of mRNA and hemoglobins were determined by qRT-PCR and HPLC. First, we analyzed the effect of mithramycin on K562 transgenic cell lines harboring different copies of a lentiviral vector carrying the human ß-globin gene, showing that γ-globin mRNA expression and HbF production can be induced in the presence of high levels of ß-globin gene expression and HbA accumulation. We then treated erythroid progenitor cells from ß-thalassemic patients with T9W, which expresses the human ß-globin gene and mithramycin separately or in combination. When transduction with our lentiviral vector is insufficient to completely eliminate the unpaired α-globin chains, combination of ß-globin gene transfer therapy together with fetal hemoglobin induction might be very efficacious to remove the excess of α-globin proteins in thalassemic erythroid progenitor cells.


Assuntos
Células Precursoras Eritroides/efeitos dos fármacos , Hemoglobina Fetal/metabolismo , Terapia Genética , Hemoglobina A/genética , Plicamicina/uso terapêutico , Talassemia beta/terapia , Adulto , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Células Cultivadas , Terapia Combinada/métodos , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/fisiologia , Técnicas de Transferência de Genes , Terapia Genética/métodos , Células HEK293 , Hemoglobina A/metabolismo , Humanos , Células K562 , Plicamicina/farmacologia , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/metabolismo
15.
Blood ; 117(4): 1379-89, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21059897

RESUMO

In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and ß-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis.


Assuntos
Células Eritroides/metabolismo , Eritropoese/genética , Antígenos de Histocompatibilidade Classe I/genética , Ferro/metabolismo , Proteínas de Membrana/genética , Envelhecimento/sangue , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/fisiologia , Homeostase/genética , Homeostase/fisiologia , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Transferrina/metabolismo , Regulação para Cima/genética , Regulação para Cima/fisiologia
16.
Hematol Oncol Clin North Am ; 24(6): 1089-107, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21075282

RESUMO

ß-Thalassemia is a genetic disorder caused by mutations in the ß-globin gene and characterized by chronic anemia caused by ineffective erythropoiesis, and accompanied by a variety of serious secondary complications such as extramedullary hematopoiesis, splenomegaly, and iron overload. In the past few years, numerous studies have shown that such secondary disease conditions have a genetic basis caused by the abnormal expression of genes with a role in controlling erythropoiesis and iron metabolism. In this article, the most recent discoveries related to the mechanism(s) responsible for anemia/ineffective erythropoiesis and iron overload are discussed in detail. Particular attention is paid to the pathway(s) controlling the expression of hepcidin, which is the main regulator of iron metabolism, and the Epo/EpoR/Jak2/Stat5 signaling pathway, which regulates erythropoiesis. Better understanding of how these pathways function and are altered in ß-thalassemia has revealed several possibilities for development of new therapeutic approaches to treat of the complications of this disease.


Assuntos
Anemia/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Eritropoese , Talassemia beta/metabolismo , Animais , Eritropoetina/metabolismo , Hepcidinas , Humanos , Ferro/metabolismo , Sobrecarga de Ferro , Receptores da Eritropoetina/metabolismo
17.
J Clin Invest ; 120(12): 4466-77, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21099112

RESUMO

Excessive iron absorption is one of the main features of ß-thalassemia and can lead to severe morbidity and mortality. Serial analyses of ß-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with ß-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in ß-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in ß-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with ß-thalassemia and related disorders.


Assuntos
Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Talassemia beta/tratamento farmacológico , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Sequência de Bases , Primers do DNA/genética , Modelos Animais de Doenças , Eritropoese/efeitos dos fármacos , Expressão Gênica , Hepcidinas , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/metabolismo , Ferro da Dieta/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Talassemia beta/sangue , Talassemia beta/metabolismo
18.
Ann N Y Acad Sci ; 1202: 24-30, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20712768

RESUMO

beta-thalassemia is a disease associated with decreased beta-globin production leading to anemia, ineffective erythropoiesis, and iron overload. New mechanisms associated with modulation of erythropoiesis and iron metabolism have recently been discovered in thalassemic mice, improving our understanding of the pathophysiology of this disease. These discoveries have the potential to be translated into clinically-relevant therapeutic options to reduce ineffective erythropoiesis and iron overload. A new generation of therapies based on limiting ineffective erythropoiesis, iron absorption, and the correction of iron maldistribution could be on the way, possibly complementing and improving the current standard of patient care.


Assuntos
Modelos Animais de Doenças , Eritropoese/fisiologia , Ferro/metabolismo , Talassemia beta/metabolismo , Talassemia beta/fisiopatologia , Animais , Antibacterianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Hepcidinas , Humanos , Sobrecarga de Ferro/metabolismo , Camundongos
19.
Ann N Y Acad Sci ; 1202: 221-5, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20712796

RESUMO

Hepcidin (HAMP) negatively regulates iron absorption, degrading the iron exporter ferroportin at the level of enterocytes and macrophages. We showed that mice with beta-thalassemia intermedia (th3/+) have increased anemia and iron overload. However, their hepcidin expression is relatively low compared to their iron burden. We also showed that the iron metabolism gene Hfe is down-regulated in concert with hepcidin in th3/+ mice. These observations suggest that low hepcidin levels are responsible for abnormal iron absorption in thalassemic mice and that down-regulation of Hfe might be involved in the pathway that controls hepcidin synthesis in beta-thalassemia. Therefore, these studies suggest that increasing hepcidin and/or Hfe expression could be a strategy to reduces iron overload in these animals. The goal of this paper is to review recent findings that correlate hepcidin, Hfe, and iron metabolism in beta-thalassemia and to discuss potential novel therapeutic approaches based on these recent discoveries.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Sobrecarga de Ferro/metabolismo , Proteínas de Membrana/metabolismo , Talassemia beta/metabolismo , Anemia/etiologia , Anemia/metabolismo , Animais , Antibacterianos/metabolismo , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Terapia Genética , Vetores Genéticos/genética , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/uso terapêutico , Humanos , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/terapia , Proteínas de Membrana/genética , Proteínas de Membrana/uso terapêutico , Talassemia beta/complicações , Talassemia beta/genética , Talassemia beta/terapia
20.
Adv Hematol ; 2010: 938640, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20508726

RESUMO

beta-thalassemia encompasses a group of monogenic diseases that have in common defective synthesis of beta-globin. The defects involved are extremely heterogeneous and give rise to a large phenotypic spectrum, with patients that are almost asymptomatic to cases in which regular blood transfusions are required to sustain life. As a result of the inefficient synthesis of beta-globin, the patients suffer from chronic anemia due to a process called ineffective erythropoiesis (IE). The sequelae of IE lead to extramedullary hematopoiesis (EMH) with massive splenomegaly and dramatic iron overload, which in turn is responsible for many of the secondary pathologies observed in thalassemic patients. The processes are intimately linked such that an ideal therapeutic approach should address all of the complications. Although beta-thalassemia is one of the first monogenic diseases to be described and represents a global health problem, only recently has the scientific community started to focus on the real molecular mechanisms that underlie this disease, opening new and exciting therapeutic perspectives for thalassemic patients worldwide.

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