Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.547
Filtrar
1.
Int J Infect Dis ; 97: 303-305, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32497811

RESUMO

The coronavirus 2 (SARS-CoV-2) pandemic is viciously spreading through the continents with rapidly increasing mortality rates. Current management of COVID-19 is based on the premise that respiratory failure is the leading cause of mortality. However, mounting evidence links accelerated pathogenesis in gravely ill COVID-19 patients to a hyper-inflammatory state involving a cytokine storm. Several components of the heightened inflammatory state were addressed as therapeutic targets. Another key component of the heightened inflammatory state is hyper-ferritinemia which reportedly identifies patients with increased mortality risk. In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic marker of disease progression, or a key modulator in disease pathogenesis. Here we address implications of a possible role for hyper-ferritinemia, and altered iron homeostasis in COVID-19 pathogenesis, and potential therapeutic targets in this regard.


Assuntos
Infecções por Coronavirus/patologia , Sobrecarga de Ferro/virologia , Pneumonia Viral/patologia , Betacoronavirus , Infecções por Coronavirus/mortalidade , Síndrome da Liberação de Citocina/virologia , Ferroptose , Hepcidinas/fisiologia , Humanos , Inflamação , Ferro/sangue , Mitocôndrias/patologia , Mitocôndrias/fisiologia , Estresse Oxidativo , Pandemias , Pneumonia Viral/mortalidade
2.
Lancet Haematol ; 7(6): e469-e478, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32470438

RESUMO

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.


Assuntos
Deferasirox/uso terapêutico , Deferiprona/uso terapêutico , Transfusão de Eritrócitos/métodos , Hemoglobinopatias/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Administração Oral , Adolescente , Agranulocitose/induzido quimicamente , Agranulocitose/epidemiologia , Albânia/epidemiologia , Anemia Falciforme/terapia , Técnicas de Imagem Cardíaca/métodos , Criança , Pré-Escolar , Chipre/epidemiologia , Deferasirox/administração & dosagem , Deferasirox/economia , Deferiprona/administração & dosagem , Deferiprona/economia , Egito/epidemiologia , Transfusão de Eritrócitos/estatística & dados numéricos , Feminino , Ferritinas/sangue , Ferritinas/efeitos dos fármacos , Grécia/epidemiologia , Hemoglobinopatias/terapia , Humanos , Lactente , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/economia , Sobrecarga de Ferro/sangue , Itália/epidemiologia , Imagem por Ressonância Magnética , Masculino , Cooperação do Paciente , Resultado do Tratamento , Tunísia/epidemiologia , Reino Unido/epidemiologia , Doenças Urológicas/induzido quimicamente , Doenças Urológicas/epidemiologia , Talassemia beta/terapia
3.
Adv Clin Exp Med ; 29(4): 475-480, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32369274

RESUMO

BACKGROUND: Splenic iron overload is the most common clinical condition in patients with thalassemia. However, few studies of the effects of splenectomy have been published. OBJECTIVES: To evaluate the relationship between splenic iron overload and liver, heart and muscle features visible in T2*-weighted magnetic resonance imaging, and to investigate the effects of splenectomy on these tissues in patients with beta-thalassemia major (TM). MATERIAL AND METHODS: We retrospectively included 131 patients (76 male and 55 female) diagnosed with TM. All radiological assessments were performed with the aid of a Philips Achieva 1.5T scanner running a multiecho gradient-echo sequence. Hepatic and splenic T2* values were assessed in the same gradient multiecho series. Muscle T2* values were assessed in the shoulder girdle muscles adjacent to the heart area. The relationships among splenic T2*, hepatic T2*, cardiac T2* and muscle T2* parameters, serum ferritin levels, age and other parameters were evaluated. RESULTS: The splenic T2* value correlated with serum ferritin level and the hepatic T2* value (p < 0.001 and p < 0.001, respectively). The splenic T2* value did not correlate with age, cardiac or muscle T2* values, or with spleen size (p = 0.27, 0.21, 0.99, and 0.39, respectively). The muscle T2* value correlated weakly with the serum ferritin level (p = 0.022). The cardiac T2* value was lower and the liver size greater in patients who had undergone splenectomy compared with those who had not (p < 0.001 and 0.001, respectively). CONCLUSIONS: Splenic iron overload correlated with hepatic overload and the serum ferritin level. Splenectomy increased cardiac iron overload and triggered liver enlargement. However, the muscle iron overload was low and the muscles were therefore unaffected by splenectomy.


Assuntos
Ferritinas/sangue , Coração/diagnóstico por imagem , Sobrecarga de Ferro/sangue , Fígado/diagnóstico por imagem , Músculos/diagnóstico por imagem , Esplenectomia/efeitos adversos , Talassemia beta/sangue , Talassemia beta/patologia , Feminino , Humanos , Fígado/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Miocárdio/metabolismo , Estudos Retrospectivos
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 110-117, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376555

RESUMO

OBJECTIVE: To explore the effect of cyclophosphamide on hematopoietic stem cells (HSCs) in mice with iron overload. METHODS: Mouse models of iron overload were established in 30 male C57BL/6 mice by intraperitoneal injections of iron dextran at low (0.25 g/kg), moderate (0.5 g/kg), and high (1 g/kg) doses (n=10), with another 10 PBS-treated mice as the control group. The changes in body weight, liver, spleen and bone marrow of the mice were recorded, and serum level of ferritin was detected. The mice receiving a moderate dose of iron dextran were further divided into 8 groups for observation at different time points (D1, D2, D3, D4, D5, D6, D7, and D14 groups) and were given intraperitoneal injection of 50 mg/kg cyclophosphamide (Cy) for 2 consecutive days. Peripheral blood cells, bone marrow mononuclear cells (BMMNCs), and the frequencies of different HSCs (HPCs, HSCs, LT-HSCs) in the BMMNCs were monitored. The cell cycle distribution in the HSCs, level of reactive oxygen species and the microenvironment of the HSCs were analyzed using flow cytometry. RESULTS: Compared with the control mice, the mice with iron overload showed obvious weight loss with significantly increased serum ferritin level, enlargement of the liver and spleen, and iron deposition in the organs (P < 0.05). No significant changes were noted in the peripheral blood of the mice with iron overload. The cyclophosphamide-treated mice exhibited significantly decreased number of WBCs and lymphocyte ratio at days 1 to 4 (P < 0.05). The numbers of BMMNCs and HPCs in mice with iron overload did not show significant changes as compared with those in the control mice, but the numbers of HSCs and LTHSCs decreased significantly in the mice with iron overload (P < 0.05). In cyclophosphamide-treated mice, the number of HSCs increased since day 1 and reached the peak level on day 3 (P < 0.05). Compared with those in the control group, the HSCs did not exhibit significant changes in cell cycle distribution in mice with iron overload, but the proportion of G0/G1 cells decreased significantly in cyclophosphamide group since day 1 and reached the lowest level on day 3 (P < 0.05). CONCLUSIONS: Iron deposition in the bone marrow causes long- term damages of the HSCs in the bone marrow but does not induce obvious changes in the peripheral blood. In mice with iron overload, intraperitoneal injection of 50 mg/kg cyclophosphamide for two days promotes cell cycle changes of the resting HSCs to mobilize the HSCs, and this effect is the most obvious on day 4.


Assuntos
Ciclofosfamida/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Sobrecarga de Ferro , Animais , Células da Medula Óssea/efeitos dos fármacos , Ciclo Celular , Ferritinas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
BMC Med Genet ; 21(1): 75, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32268883

RESUMO

BACKGROUND: ß Thalassemia is one of the most common groups of hereditary haemoglobinopathies. Affected people with thalassemia major are dependent on regular blood transfusion which on the long term leads to iron overload. Hepcidin is a peptide hormone and an important regulator of iron homeostasis, especially in thalassemia. Expression of this hormone is influenced by polymorphisms within the hepcidin gene, HAMP. Several studies emphasized the role of single nucleotide polymorphisms (SNPs) located in the promoter region of the gene. This study aimed to analyze the association between three SNPs in promoter of HAMP, c.-582A > G, c.-443C > T, and c.-153C > T, with iron overload in ß-thalassemia major patients. METHODS: A total of 102 samples from ß thalassemia major patients were collected. Genomic DNA was extracted and segments of DNA encompassing rs10421768 and rs142126068 were sequenced. Statistical analysis was performed by SPSS Statistics 23 using independent t test and Fisher's exact test. RESULTS: A total of 102 adult ß-thalassemia major patients were genotyped for three SNPs in the promoter region of HAMP gene by PCR and direct sequencing. Most of the patients (71.3%) were iron overloaded (based on plasma ferritin > 1000 ng/ml) in spite of receiving regular iron-chelating therapy. Our analysis revealed a statistically significant difference between the level of cardiac iron accumulation and c.-582A > G variant (p = 0.02). For c.-443C > T statistical analysis was on the edge of the significant relationship between the minor allele and serum ferritin (p = 0.058). All samples were homozygous for allele C of c.-153C > T. CONCLUSIONS: Despite chelating therapy, iron overload is still one of the main complications of thalassemia. Our findings and others emphasize the role of hepcidin -582A > G polymorphism as a key component of iron homeostasis in these patients.


Assuntos
Hepcidinas/genética , Quelantes de Ferro/uso terapêutico , Polimorfismo de Nucleotídeo Único , Talassemia beta/tratamento farmacológico , Talassemia beta/genética , Adulto , Estudos de Coortes , Feminino , Homeostase/genética , Humanos , Irã (Geográfico) , Ferro/metabolismo , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/genética , Masculino , Regiões Promotoras Genéticas/genética , Falha de Tratamento , Talassemia beta/sangue
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 686-689, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319417

RESUMO

Abstract  Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders derived from haematopoietic stem and progenitor cells, also is a common malignant hematological diseases. It is characterized by ineffective bone marrow (BM) haematopoiesis, peripheral blood cytopaenias and a risk of progression to acute myeloid leukaemia. Iron overload is caused from transfusion dependence and ineffective hematopoiesis, which seriously affects the survival and prognosis of MDS patients. The role of immune inflammation in the development of MDS has been widely concerned. Oxidative stress and metabolic disorder caused from iron overload enhance the immune inflammatory response and accelerate the disease progression. Iron overload and immune inflammation are risk factors for the progression of MDS.


Assuntos
Sobrecarga de Ferro , Síndromes Mielodisplásicas , Progressão da Doença , Humanos , Leucemia Mieloide Aguda , Fatores de Risco
7.
Life Sci ; 250: 117573, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32209423

RESUMO

Chronic intermittent hypoxia (CIH) is a consequence of obstructive sleep apnea (OSA), which increases reactive oxygen species (ROS) generation, resulting in oxidative damage and neurocognitive impairment. This study was designed to determine whether abnormal iron metabolism occurs in the brain under conditions of CIH and whether Huperzine A (HuA) could improve abnormal iron metabolism and neurological damage. The mouse model of CIH was established by reducing the percentage of inspired O2 (FiO2) from 21% to 9% 20 times/h for 8 h/day, and Huperzine A (HuA, 0.1 mg/kg, i.p.) was administered during CIH exposure for 21 days. HuA significantly improved cognitive impairment and neuronal damage in the hippocampus of CIH mice via increasing the ratio of Bcl-2/Bax and inhibiting caspase-3 cleavage. HuA considerably decreased ROS levels by downregulating the high levels of NADPH oxidase (NOX 2, NOX 4) mediated by CIH. There was an overload of iron, which was characterized by high levels of ferritin (FTL and FTH) and transferrin receptor 1 (TfR1) and low levels of ferroportin 1 (FPN1) in the hippocampus of CIH mice. Decreased levels of TfR1 and FTL proteins observed in HuA treated CIH group, could reduce iron overload in hippocampus. HuA increased PSD 95 protein expression, CREB activation and BDNF protein expression to protect against synaptic plasticity impairment induced by CIH. HuA acts as an effective iron chelator to attenuate apoptosis, oxidative stress and synaptic plasticity mediated by CIH.


Assuntos
Alcaloides/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipóxia/patologia , Sobrecarga de Ferro/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Apoptose , Comportamento Animal , Caspase 3/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Modelos Animais de Doenças , Ferritinas/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Oxigênio/metabolismo , Espécies Reativas de Oxigênio , Receptores da Transferrina/metabolismo
8.
Lab Med ; 51(2): 143-150, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32155272

RESUMO

BACKGROUND: Cardiomyopathic manifestations induced by continuous blood transfusion are the leading cause of death among patients with thalassemia major (TM). Despite introduction of chelation therapy, heart failure after cardiomyopathic manifestations is still a major threat to patients. METHODS: We performed a search of relevant English-language literature, retrieving publications from the PubMed database and the Google Scholar search engine (2005-2018). We used "thalassemia major", "cardiomyopathy", "iron overload", "cardiac magnetic resonance T2" "chelation therapy", and "iron burden" as keywords. RESULTS: The results of the studies we found suggest that cardiac hepcidin is a major regulator of iron homeostasis in cardiac tissue. Unlike previous assumptions, the heart appears to have a limited regeneration capability, originating from a small population of hypoxic cardiomyocytes. CONCLUSIONS: Oxygen levels determine cardiomyocyte gene-expression patterns. Upregulation of cardiac hepcidin in hypoxia preserves cardiomyocytes from forming out of reactive oxygen species catalyzed by free cellular iron in cardiomyocytes. Using the limited regeneration capacity of cardiac cells and gaining further understanding of the cellular aspects of cardiomyopathic manifestations may help health care professionals to develop new therapeutic strategies.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Terapia por Quelação/métodos , Testes Diagnósticos de Rotina/métodos , Gerenciamento Clínico , Sobrecarga de Ferro/complicações , Talassemia/complicações , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Humanos , Talassemia/terapia
9.
Ann Hematol ; 99(4): 715-727, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112123

RESUMO

Hereditary xerocytosis (HX), also known as dehydrated stomatocytosis (DHSt) is a dominantly inherited genetic disorder exhibiting red cell membrane dehydration caused by the loss of the monovalent cation K+ and water. Variants in mechanosensitive Piezo ionic channels of the PIEZO1 gene are the primary cause of HX. We have utilized high throughput and highly precise next-generation sequencing (NGS) to make a diagnosis and examine the genotype-phenotype relationship in inflexible HX cases. Seven unrelated patients with unexplained hemolytic anemia were scrutinized with a panel probing 8000 genes related to congenital anemia. Targeted next-generation sequencing identified 8 missense variants in the PIEZO1 gene in 7 unrelated Indian patients. Three of the 8 variants are novel (c.1795G > C, c.2915G > A, c.7372 T > C) and the remaining five (c.4082A > G, c.6829C > A, c.7374C > G, c.7381G > A, c.7483_7488dup) are previously reported. The variants have been validated by Sanger sequencing. One patient with autosomal dominant mutation (c.7372 T > C) is associated with iron refractory iron deficiency anemia. Of the 7 patients, one has HX in combination with a novel homozygous variant (c.994G > A) in the PKLR gene causing PK deficiency resulting in severe clinical manifestations with phenotypic variability. In silico prediction using bioinformatics tools were used to study the possible damaging effects of the novel variants. Structural-functional analysis of the novel variants was investigated by molecular modeling software (PyMOL and Swiss PDB). These results encompass the heterogeneous behavior of mechano-sensitive Piezo1 protein observed in HX patients in India. Moreover, NGS imparted a subtle, economical, and quick tool for understanding the genetic cause of undiagnosed cases of congenital hemolytic anemia. NGS grants a potential technology integrating clinical history together with molecular report profiting in such patients and their families.


Assuntos
Anemia Hemolítica Congênita/genética , Hidropisia Fetal/genética , Canais Iônicos/genética , Mutação de Sentido Incorreto , Adolescente , Sequência de Aminoácidos , Anemia Hemolítica Congênita/sangue , Anemia Hemolítica Congênita/complicações , Anemia Hemolítica Congênita/etnologia , Anemia Ferropriva/genética , Animais , Criança , Pré-Escolar , Simulação por Computador , Feminino , Genes Dominantes , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hidropisia Fetal/sangue , Hidropisia Fetal/etnologia , Índia , Canais Iônicos/química , Canais Iônicos/fisiologia , Sobrecarga de Ferro/etiologia , Masculino , Camundongos , Modelos Moleculares , Conformação Proteica , Piruvato Quinase/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade
10.
Environ Sci Technol ; 54(6): 3181-3190, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32083855

RESUMO

The mechanism of graphene-based nanomaterial (GBM)-induced phytotoxicity and its association with the GBM physicochemical properties are not yet fully understood. The present study compared the effects of graphene oxide (GO) and reduced GO (rGO) on rice seedling growth under hydroponic conditions for 3 weeks. GO at 100 and 250 mg/L reduced shoot biomass (by 25 and 34%, respectively) and shoot elongation (by 17 and 43%, respectively) and caused oxidative damage, while rGO exhibited no overt effect except for the enhancement of the antioxidant enzyme activities, suggesting that the surface oxygen content is a critical factor affecting the biological impacts of GBMs. GO treatments (100 and 250 mg/L) enhanced the iron (Fe) translocation and caused excessive Fe accumulation in shoots (2.2 and 3.6 times higher than control), which was found to be the main reason for the oxidative damage in shoots. GO-induced acidification of the nutrient solution was the main driver for the Fe overload in plants. In addition to the antioxidant regulators, the plants triggered other pathways to defend against the Fe toxicity via downregulation of the Fe transport associated metabolites (mainly coumarins and flavonoids). Plant root exudates facilitated the reduction of toxic GO to nontoxic rGO, acting as another route for plant adaption to GO-induced phytotoxicity. This study provides new insights into the mechanism of the phytotoxicity of GBMs. It also provides implications for the agricultural application of GBM that the impacts of GBMs on the uptake of multiple nutrients in plants should be assessed simultaneously and reduced forms of GBMs are preferential to avoid toxicity.


Assuntos
Grafite , Sobrecarga de Ferro , Nanoestruturas , Oryza , Poluentes do Solo , Humanos , Concentração de Íons de Hidrogênio , Estresse Oxidativo , Raízes de Plantas , Plântula
12.
Zoolog Sci ; 37(1): 61-69, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32068375

RESUMO

Iron is an essential element for hemoglobin synthesis during erythropoiesis. Iron overload, in contrast, adversely affects erythropoiesis and causes organ dysfunction. Research using various animal models may help to elucidate pathophysiological mechanisms induced by excess iron. In the present study, we evaluated the relationship between iron metabolism and erythropoietic activity in the African clawed frog, Xenopus laevis. In X. laevis, both erythropoiesis and iron metabolism occur in the liver. First, we developed a method to quantify iron levels in the liver and plasma using 2-nitroso-5-[N-n-propyl-N-(3-sulfopropyl) amino] phenol (Nitroso-PSAP). We then measured iron levels and analyzed hematopoietic parameters in frogs that were orally administered sodium ferrous citrate (SFC). The hepatic iron level increased in the SFC group, but the number of erythrocytes, hematocrit, and hemoglobin concentration did not change, suggesting that the regulation of the production and release of mature erythrocytes in the liver was not directly affected by dietary iron. At four days after administration of 2 mg/kg SFC, the number of immature erythrocytes decreased in the liver. Interestingly, atypical blood cells with hyper-segmented nuclei were observed, identified by acridine orange cell staining; these atypical blood cells were hardly detectable under the steady state. Compared with previously reported results in mice, the increase in the hepatic iron levels was small, but our results indicate that SFC affects hematopoietic activity. These results establish a novel model for iron metabolism and provide new insights into the relationship between iron metabolism and erythropoiesis in vertebrates.


Assuntos
Eritropoese/fisiologia , Sobrecarga de Ferro/fisiopatologia , Fígado/fisiopatologia , Xenopus laevis/fisiologia , Animais , Eritropoese/efeitos dos fármacos , Compostos Ferrosos/farmacologia , Ferro/análise , Ferro/sangue , Ferro/metabolismo , Fígado/citologia , Fígado/metabolismo , Masculino , Modelos Animais , Xenopus laevis/metabolismo
13.
Ann Hematol ; 99(3): 431-441, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006153

RESUMO

Macrophages are characterized by phenotypical and functional heterogeneity. In different microenvironments, macrophages can polarize into two types: classically activated macrophages (M1) or alternatively activated macrophages (M2). M1 macrophages are a well-known bacteriostatic macrophage, and conversely, M2 macrophages may play an important role in tumor growth and tissue remodeling. M1 macrophages have been reported to have high intracellular iron stores, while M2 macrophages contain lower intracellular iron. It has been well-described that disturbances of iron homeostasis are associated with altered immune function. Thus, it is important to investigate if chronic iron overload is capable of polarizing macrophages. Human monocytic leukemia THP-1 cells were maintained in culture medium that contained 100 µM ferrous sulfate heptahydrate (FeSO4) (I-THP-1) and differentiated into THP-1-derived macrophages (I-TDMs) by induction with phorbol 12-myristate 13-acetate (PMA). We characterized that I-TDMs not only enhanced the surface expression of CD163 and CD206 but also increased arginase and decreased iNOS protein expression. I-TDMs enhanced pSTAT6 expression and decreased pSTAT1 and NF-κB expressions. Furthermore, the gene expression profile of I-TDMs was comparable with M2 macrophages by performing human oligonucleotide DNA microarray analysis. Finally, functional assays demonstrated I-TDMs secreted higher levels of IL-10 but not M1 cytokines. Additionally, the conditional medium of I-TDMs had enhanced migration and increased invasion of A375 melanoma cells which was similar to the characteristics of tumor-associated macrophages. Taken together, we demonstrated that THP-1-derived macrophages polarized to a phenotype of M2-like characteristics when subjected to chronic iron overload.


Assuntos
Movimento Celular/imunologia , Sobrecarga de Ferro/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Movimento Celular/efeitos dos fármacos , Compostos Ferrosos/efeitos adversos , Compostos Ferrosos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/patologia , Macrófagos/patologia , Monócitos/patologia , Células THP-1 , Acetato de Tetradecanoilforbol/farmacologia
14.
Ann Hematol ; 99(4): 677-692, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078008

RESUMO

The development in the therapeutic landscape of myelodysplastic syndromes (MDS) has substantially lagged behind other hematologic malignancies with no new drug approvals for MDS for 13 years since the approval of decitabine in the United States in 2006. While therapeutic concepts for MDS patients continue to be primarily defined by clinical-pathologic risk stratification tools such as the International Prognostic Scoring System (IPSS) and its revised version IPSS-R, our understanding of the genetic landscape and the molecular pathogenesis of MDS has greatly evolved over the last decade. It is expected that the therapeutic approach to MDS patients will become increasingly individualized based on prognostic and predictive genetic features and other biomarkers. Herein, we review the current treatment of lower-risk MDS patients and discuss promising agents in advanced clinical testing for the treatment of symptomatic anemia in lower-risk MDS patients such as luspatercept and imetelstat. Lastly, we review the clinical development of new agents and the implications of the wider availability of mutational analysis for the management of individual MDS patients.


Assuntos
Síndromes Mielodisplásicas/terapia , Anemia/tratamento farmacológico , Anemia/etiologia , Anemia/terapia , Transfusão de Sangue , Terapia por Quelação , Ensaios Clínicos como Assunto , Síndrome do Miado do Gato , Drogas em Investigação/uso terapêutico , Previsões , Hematínicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Lenalidomida/uso terapêutico , Terapia de Alvo Molecular , Estudos Multicêntricos como Assunto , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Medicina de Precisão , Prognóstico , Medição de Risco , Índice de Gravidade de Doença
15.
Water Res ; 173: 115602, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070833

RESUMO

Eutrophication of water bodies markedly reduces their recreational and economic use, which in turn compels those interested to pursuing prompt and effective restoration. This also applies to waters with a moderate pool of biogenic resources which, following temporarily increased nutrient alimentation from the catchment area may become eutrophic. The in-situ experiment tested the impact of chemical restoration on benthic macroalgae (Chara hispida L.) found in meso-eutrophic waters. Commonly used doses of iron sulphate were applied, defined as Low - 10.8 g Fe m-2 and High - 21.6 g Fe m-2. It was presumed that the sudden shift of abiotic conditions of the environment will disturb growth and stoichiometry of the species. Analyses encompassed physicochemical water parameters (e.g. nutrient concentration, light availability), morphological features and elemental composition of the charophytes. Application of the coagulant caused shading of the plants and elimination of bioavailable phosphates from the water. This induced changes of behavioural ecology of the species, manifesting in elongation of the main axis and increase of the assimilation area (growth of branchlets and side-axes) as well as stoichiometric changes. It was found that shortage of phosphates in the water resulted in decreased phosphorus concentration in the thalli due to biological dilution. The increase of assimilation area and phosphorus dilution in the thalli have not been previously reported for charophytes. In this study, the qualitative transformation of the environment following application of iron as part of chemical lake restoration was evinced in significant ecological changes that adversely affected macrophytobenthos. The findings of the experiment can therefore be taken into account while planning restoration procedures, so as to preclude the risk of a negative trend of ecological changes.


Assuntos
Caráceas , Carofíceas , Sobrecarga de Ferro , Alga Marinha , Eutrofização , Humanos , Lagos , Fósforo
16.
Blood Adv ; 4(2): 327-355, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31985807

RESUMO

BACKGROUND: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. OBJECTIVE: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. METHODS: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. RESULTS: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. CONCLUSIONS: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.


Assuntos
Anemia Falciforme/terapia , Transfusão de Eritrócitos/métodos , Tipagem e Reações Cruzadas Sanguíneas , Medicina Baseada em Evidências , Humanos , Sobrecarga de Ferro/prevenção & controle , Sobrecarga de Ferro/terapia , Reação Transfusional/prevenção & controle , Reação Transfusional/terapia
17.
Transplant Proc ; 52(1): 169-174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31955851

RESUMO

Renal transplant patients may present important serum iron overload (IO), which can persist for long periods after transplantation, but its mechanisms are not fully understood. We raised the hypothesis that post-transplant hypererythropoietinemia might induce reduction in serum hepcidin, favoring iron absorption. The aims of this study were to determine the prevalence of IO and associated factors in transplant patients and to evaluate erythropoietin and hepcidin levels in patients with and without IO. A total of 168 patients were included, with a median time of dialysis and transplantation of 28 and 65 months, respectively. Most patients (85%) received large amounts of parenteral iron (3600 mg iron) during the dialysis period. Median ferritin was 427 ng/mL, and transferrin saturation was 33%. IO was present in 26 patients (15%). A comparison of patients with and without IO showed a predominance of male and nonwhite patients in the former group (P < .001 and .002, respectively). The total amount of iron used before transplantation and hemoglobin levels were higher in the group with IO (P = .023 and .046, respectively). Hepcidin was higher in the group with IO (P < .0001), whereas erythropoietin did not differ between groups. There was no correlation between serum levels of hepcidin and erythropoietin (r = -0.001). In conclusion, factors associated with IO were male sex, higher hemoglobin levels, and the amount of iron received before transplantation. IO was not the result of reduction in hepcidin secondary to hypererythropoietinemia. The elevated levels of serum hepcidin were possibly secondary to IO, mediated by mechanisms that are independent of the hepcidin-erythropoietin axis.


Assuntos
Eritropoetina/sangue , Hepcidinas/sangue , Sobrecarga de Ferro/epidemiologia , Transplante de Rim , Adulto , Feminino , Ferritinas/sangue , Humanos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , Diálise Renal , Fatores de Risco
18.
Pediatr Blood Cancer ; 67(4): e28137, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31889398

RESUMO

BACKGROUND: The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS: We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS: Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 ± 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS: We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.


Assuntos
Hiperplasia Nodular Focal do Fígado/diagnóstico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversos , Sobrecarga de Ferro/fisiopatologia , Criança , Feminino , Hiperplasia Nodular Focal do Fígado/etiologia , Seguimentos , Neoplasias Hematológicas/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Prognóstico , Estudos Retrospectivos
19.
Arch Biochem Biophys ; 680: 108241, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31891670

RESUMO

Excessive iron accumulation in the heart can lead to iron overload cardiomyopathy (IOC), the leading cause of death in hemochromatosis patients. Current understanding regarding the mechanism by which iron overload causes a deterioration in cardiac performance, mitochondrial dysfunction, and impaired mitochondrial dynamics remains limited. Ferroptosis, a newly identified form of regulated cell death, has recently been revealed influencing the pathophysiological process of IOC. Nevertheless, the direct effect of cardiac iron overload on ferroptotic cell death is incompletely characterized. This review article comprehensively summarizes and discusses the effects of iron overload on cardiac mitochondrial function, cardiac mitochondrial dynamics, ferroptosis of cardiomyocytes, and left ventricular function in in vitro and in vivo reports. This review also provides relevant consistent and controversial information which can facilitate further mechanistic investigation into iron-induced cardiac dysfunction in the clinical setting in the near future.


Assuntos
Ferroptose , Sobrecarga de Ferro/metabolismo , Dinâmica Mitocondrial , Miócitos Cardíacos/metabolismo , Animais , Morte Celular , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Estresse Oxidativo
20.
Bull Cancer ; 107(1S): S18-S27, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-30952358

RESUMO

Hepatobiliary complications are frequent in the context of allogeneic hematopoietic cell transplantation (allo-HCT) and contribute largely to the morbidity and mortality after transplantation. Within the framework of the ninth workshops of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2018, diagnostic approaches and treatments of hepatobiliary dysfunctions prior to and following transplantation were reviewed according to the analysis of published studies.


Assuntos
Doenças Biliares/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatias/etiologia , Aloenxertos , Doenças Biliares/diagnóstico , Doenças Biliares/terapia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Gerenciamento Clínico , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Hepatite Viral Humana/diagnóstico , Hepatite Viral Humana/terapia , Hepatite Viral Humana/transmissão , Humanos , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/terapia , Hepatopatias/diagnóstico , Hepatopatias/terapia , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA