RESUMEN
BACKGROUND: Iron (Fe) supplementation is a critical component of anemia therapy for patients with chronic kidney disease (CKD). However, serum Fe, ferritin, and transferrin saturation, used to guide Fe replacement, are far from optimal, as they can be influenced by malnutrition and inflammation. Currently, there is a trend of increasing Fe supplementation to target high ferritin levels, although the long-term risk has been overlooked. METHODS: We prospectively enrolled 28 patients with CKD on hemodialysis with high serum ferritin (> 1000 ng/ml) and tested the effects of 1-year deferoxamine treatment, accompanied by withdrawal of Fe administration, on laboratory parameters (Fe status, inflammatory and CKD-MBD markers), heart, liver, and iliac crest Fe deposition (quantitative magnetic resonance imaging [MRI]), and bone biopsy (histomorphometry and counting of the number of Fe positive cells in the bone marrow). RESULTS: MRI parameters showed that none of the patients had heart iron overload, but they all presented iron overload in the liver and bone marrow, which was confirmed by bone histology. After therapy, ferritin levels decreased, although neither hemoglobin levels nor erythropoietin dose was changed. A significant decrease in hepcidin and FGF-23 levels was observed. Fe accumulation was improved in the liver and bone marrow, reaching normal values only in the bone marrow. No significant changes in turnover, mineralization or volume were observed. CONCLUSIONS: Our data suggest that treatment with deferoxamine was safe and could improve Fe accumulation, as measured by MRI and histomorphometry. Whether MRI is considered a standard tool for investigating bone marrow Fe accumulation requires further investigation. Registry and the registration number of clinical trial: ReBEC (Registro Brasileiro de Ensaios Clinicos) under the identification RBR-3rnskcj available at: https://ensaiosclinicos.gov.br/pesquisador.
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Médula Ósea , Deferoxamina , Ferritinas , Sobrecarga de Hierro , Hierro , Hígado , Diálisis Renal , Humanos , Masculino , Femenino , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/metabolismo , Médula Ósea/metabolismo , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Ferritinas/sangre , Ferritinas/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/diagnóstico por imagen , Persona de Mediana Edad , Deferoxamina/uso terapéutico , Deferoxamina/administración & dosificación , Hierro/metabolismo , Anciano , Imagen por Resonancia Magnética , Estudios Prospectivos , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/sangre , Factor-23 de Crecimiento de Fibroblastos , Hepcidinas/metabolismoRESUMEN
Obesity is associated with dysfunctions in hypothalamic neurons that regulate metabolism, including agouti-related protein (AgRP)-expressing neurons. In a recent article, Zhang et al. demonstrated that either diet- or genetically induced obesity promoted iron accumulation specifically in AgRP neurons. Preventing iron overload in AgRP neurons mitigated diet-induced obesity and related comorbidities in male mice.
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Proteína Relacionada con Agouti , Hierro , Obesidad , Obesidad/metabolismo , Animales , Humanos , Hierro/metabolismo , Proteína Relacionada con Agouti/metabolismo , Ratones , Neuronas/metabolismo , Masculino , Hipotálamo/metabolismo , Sobrecarga de Hierro/metabolismoRESUMEN
PURPOSE: The present study aimed at evaluating possible synergistic effects between two risk factors for cognitive decline and neurodegenerative disorders, i.e. iron overload and exposure to a hypercaloric/hyperlipidic diet, on cognition, insulin resistance, and hippocampal GLUT1, GLUT3, Insr mRNA expression, and AKT phosporylation. METHODS: Male Wistar rats were treated with iron (30 mg/kg carbonyl iron) or vehicle (5% sorbitol in water) from 12 to 14th post-natal days. Iron-treated rats received a standard laboratory diet or a high fat diet from weaning to adulthood (9 months of age). Recognition and emotional memory, peripheral blood glucose and insulin levels were evaluated. Glucose transporters (GLUT 1 and GLUT3) and insulin signaling were analyzed in the hippocampus of rats. RESULTS: Both iron overload and exposure to a high fat diet induced memory deficits. Remarkably, the association of iron with the high fat diet induced more severe cognitive deficits. Iron overload in the neonatal period induced higher insulin levels associated with significantly higher HOMA-IR, an index of insulin resistance. Long-term exposure to a high fat diet resulted in higher fasting glucose levels. Iron treatment induced changes in Insr and GLUT1 expression in the hippocampus. At the level of intracellular signaling, both iron treatment and the high fat diet decreased AKT phosphorylation. CONCLUSION: The combination of iron overload with exposure to a high fat diet only led to synergistic deleterious effect on emotional memory, while the effects induced by iron and by the high fat diet on AKT phosphorylation were comparable. These findings indicate that there is, at least to some extent, an additive effect of iron combined with the diet. Further studies investigating the mechanisms associated to deleterious effects on cognition and susceptibility for the development of age-associated neurodegenerative disorders are warranted.
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Animales Recién Nacidos , Dieta Alta en Grasa , Transportador de Glucosa de Tipo 1 , Hipocampo , Resistencia a la Insulina , Sobrecarga de Hierro , Trastornos de la Memoria , Ratas Wistar , Animales , Masculino , Dieta Alta en Grasa/efectos adversos , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/metabolismo , Trastornos de la Memoria/etiología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratas , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 3/metabolismo , Transportador de Glucosa de Tipo 3/genética , Receptor de Insulina/metabolismo , Receptor de Insulina/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucemia/metabolismo , Insulina/sangre , Transducción de SeñalRESUMEN
Iron overload (IOL) increases the risk of diabetes mellitus (DM). Capsaicin (CAP), an agonist of transient receptor potential vanilloid-1 (TRPV1), reduces the effects of IOL. We evaluated the effects of chronic CAP administration on hepcidin expression, kidney iron deposits, and urinary biomarkers in a male Wistar rat model with IOL and DM (DM-IOL). IOL was induced with oral administration of iron for 12 weeks and DM was induced with streptozotocin. Four groups were studied: Healthy, DM, DM-IOL, and DM-IOL + CAP (1 mg·kg-1·day-1 for 12 weeks). Iron deposits were visualized with Perls tissue staining and a colorimetric assay. Serum hepcidin levels were measured with an enzyme-linked immunosorbent assay. Kidney biomarkers were assayed in 24 h urine samples. In the DM-IOL + CAP group, the total area of iron deposits and the total iron content in kidneys were smaller than those observed in both untreated DM groups. CAP administration significantly increased hepcidin levels in the DM-IOL group. Urinary levels of albumin, cystatin C, and beta-2-microglobulin were similar in all three experimental groups. In conclusion, we showed that in a DM-IOL animal model, CAP reduced renal iron deposits and increased the level of circulating hepcidin.
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Diabetes Mellitus Experimental , Sobrecarga de Hierro , Ratas , Masculino , Animales , Hepcidinas/metabolismo , Hierro/metabolismo , Capsaicina/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Ratas Wistar , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/metabolismo , Riñón/metabolismo , BiomarcadoresRESUMEN
Oxidative stress is an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control, and/or molecular damage altering cellular functions. This redox imbalance may trigger different responses depending on the antioxidant potential of a given cell, the level of reactive oxygen/nitrogen species (ROS/RNS) attained and the time of exposure, with protective effects being induced at low ROS/RNS levels in acute or short-term conditions, and harmful effects after high ROS/RNS exposure in prolonged situations. Relevant conditions underlying liver redox imbalance include iron overload associated with ROS production via Fenton chemistry and the magnitude of the iron labile pool achieved, with low iron exposure inducing protective effects related to nuclear factor-κB, signal transducer and activation of transcription 3, and nuclear factor erythroid-related factor 2 (Nrf2) activation and upregulation of ferritin, hepcidin, acute-phase response and antioxidant components, whereas high iron exposure causes drastic oxidation of biomolecules, mitochondrial dysfunction, and cell death due to necrosis, apoptosis and/or ferroptosis. Redox imbalance in nonalcoholic fatty liver disease (NAFLD) is related to polyunsaturated fatty acid depletion, lipogenic factor sterol regulatory element-binding protein-1c upregulation, fatty acid oxidation-dependent peroxisome proliferator-activated receptor-α downregulation, low antioxidant factor Nrf2 and insulin resistance, a phenomenon that is exacerbated in nonalcoholic steatohepatitis triggering an inflammatory response. Thyroid hormone (T3 ) administration determines liver preconditioning against ischemia-reperfusion injury due to the redox activation of several transcription factors, AMP-activated protein kinase, unfolded protein response and autophagy. High grade liver redox imbalance occurring in severe iron overload is adequately handled by iron chelation, however, that underlying NAFLD/NASH is currently under study in several Phase II and Phase III trials.
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Sobrecarga de Hierro , Enfermedad del Hígado Graso no Alcohólico , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/metabolismo , Hígado , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Hormonas Tiroideas/farmacologíaRESUMEN
Iron (Fe) overload triggers free radical production and lipid peroxidation processes that may lead to cell death (ferroptosis). The hypothesis of this work was that acute Fe-dextran treatment triggers Nrf2-mediated antioxidant regulation in rat brain involving glutathione (GSH) metabolism. Over the initial 8 h after Fe-dextran administration (single dose of 500 mg Fe-dextran/kg), total Fe, malondialdehyde (MDA) content, glutathione peroxidase (GPx), GPx-Se dependent (GPx-Se) and glutathione S-transferases (GST) activities were increased in rat whole brain. The content of GSH and the activity of glutathione reductase (GR) showed decreases (p < 0.05) after 6 and 8 h post injection in cortex. A significant increase in nuclear Nrf2 protein levels over control values was achieved after 6 h of Fe-dextran administration, while no significant differences were observed in the cytosolic fraction. Nuclear Nrf2/cytosolic Nrf2 ratios showed enhancement (p < 0.05) after 6 h of Fe overload, suggesting a greater translocation of the factor to the nucleus. No significant differences were observed in the expression of Keap1 in nuclear or cytosolic extracts. It is concluded that acute Fe overload induces oxidative stress in rat brain with the concomitant lipid peroxidation increase and GSH depletion, leading to the elevation of Nrf2-controlled GPx, GPx-Se and GST protein expression as a protective adaptive response. Further studies are required to fully comprehend the complex network of interrelated processes keeping the balance of GSH functions as chelator, antioxidant and redox buffer in the understanding of the ferroptotic and hormetic mechanisms triggered by Fe overload in brain.
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Sobrecarga de Hierro , Factor 2 Relacionado con NF-E2 , Animales , Antioxidantes/farmacología , Encéfalo/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Sobrecarga de Hierro/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Peroxidación de Lípido , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , RatasRESUMEN
NEW FINDINGS: What is the central question of this study? The current literature indicates that oxidative stress plays a major role in iron overload. Although exercise is a well-established approach to treat/prevent cardiovascular diseases, its effects on iron overload are not known. What is the main finding and its importance? Moderate-intensity aerobic training had benefits in a rodent model of iron-overload cardiomyopathy by improving the antioxidant capacity of the heart. After further confirmation by translational and clinical studies, we should consider using this non-pharmacological, highly accessible and easily executable adjuvant approach allied to other therapies to improve the quality of life of iron-overloaded patients. ABSTRACT: Iron is an essential micronutrient for several life processes, but its excess can damage organs owing to oxidative stress, with cardiomyopathy being the leading cause of death in iron-overloaded patients. Although exercise has long been considered as a cardioprotective tool, its effects on iron overload are not known. This study was designed to investigate the effects of moderate-intensity aerobic training in rats previously submitted to chronic iron overload. Wistar rats received i.p. injections of iron dextran (100 mg/kg, 5 days/week for 4 weeks); thereafter, the rats were kept sedentary or exercised (60 min/day, progressive aerobic training, 60-70% of maximal speed, 5 days/week on a treadmill) for 8 weeks. At the end of the experimental period, haemodynamics were recorded and blood samples, livers and hearts harvested. Myocardial mechanics of papillary muscles were assessed in vitro, and cardiac remodelling was evaluated by histology and immunoblotting. Iron overload led to liver iron deposition, liver fibrosis and increased serum alanine aminotransferase and aspartate aminotransferase. Moreover, cardiac iron accumulation was accompanied by impaired myocardial mechanics, increased cardiac collagen type I and lipid peroxidation (TBARS), and release of creatine phosphokinase-MB to the serum. Although exercise did not influence iron levels, tissue injury markers were significantly reduced. Likewise, myocardial contractility and inotropic responsiveness were improved in exercised rats, in association with an increase in the endogenous antioxidant enzyme catalase. In conclusion, moderate-intensity aerobic exercise was associated with attenuated oxidative stress and cardiac damage in a rodent model of iron overload, thereby suggesting its potential role as a non-pharmacological adjuvant therapy for iron-overload cardiomyopathy.
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Sobrecarga de Hierro , Calidad de Vida , Animales , Corazón , Humanos , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Miocardio/metabolismo , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
Iron (Fe) is used in various cellular functions, and a constant balance between its uptake, transport, storage, and use is necessary to maintain its homeostasis in the body. Changes in Fe metabolism with a consequent overload of this metal are related to neurological changes and cover a broad spectrum of diseases, mainly when these changes occur during the embryonic period. This work aimed to evaluate the effect of exposure to Fe overload during the embryonic period of Drosophila melanogaster. Progenitor flies (male and female) were exposed to ferrous sulfate (FeSO4) for ten days in concentrations of 0.5, 1, and 5 âmM. After mating and oviposition, the progenitors were removed and the treatment bottles preserved, and the number of daily hatches and cumulative hatching of the first filial generation (F1) were counted. Subsequently, F1 flies (separated by sex) were subjected to behavioral tests such as negative geotaxis test, open field test, grooming, and aggression test. They have evaluated the levels of dopamine (DA), serotonin (5-HT), octopamine (OA), tryptophan and tyrosine hydroxylase (TH), acetylcholinesterase, reactive species, and the levels of Fe in the progenitor flies and F1. The Fe levels of F1 flies are directly proportional to what is incorporated during the period of embryonic development; we also observed a delay in hatching and a reduction in the number of the hatch of F1 flies exposed during the embryonic period to the 5mM Fe diet, a fact that may be related to the reduction of the cell viability of the ovarian tissue of progenitor flies. The flies exposed to Fe (1 and 5 âmM) showed an increase in locomotor activity (hyperactivity) and a significantly higher number of repetitive movements. In addition to a high number of aggressive encounters when compared to control flies. We can also observe an increase in the levels of biogenic amines DA and 5-HT and an increase in TH activity in flies exposed to Fe (1 and 5 âmM) compared to the control group. We conclude that the hyperactive-like behavior demonstrated in both sexes by F1 flies exposed to Fe may be associated with a dysregulation in the levels of DA and 5-HT since Fe is a cofactor of TH, which had its activity increased in this study. Therefore, more attention is needed during the embryonic development period for exposure to Fe overload.
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Drosophila melanogaster/embriología , Hipercinesia/fisiopatología , Sobrecarga de Hierro/embriología , Animales , Conducta Animal/fisiología , Aminas Biogénicas/metabolismo , Aminas Biogénicas/fisiología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Femenino , Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/genética , Hipercinesia/etiología , Hierro/metabolismo , Hierro/fisiología , Hierro/toxicidad , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/fisiopatología , Locomoción/efectos de los fármacos , Masculino , Exposición Materna , Actividad Motora/efectos de los fármacos , Oxidación-Reducción , Exposición PaternaRESUMEN
Over the years, iron accumulation in specific brain regions has been observed in normal aging and related to the pathogenesis of neurodegenerative disorders. Many neurodegenerative diseases may involve cognitive dysfunction, and we have previously shown that neonatal iron overload induces permanent cognitive deficits in adult rats and exacerbates age-associated memory decline. Autophagy is a catabolic pathway involved in the removal of toxic protein aggregates, which are a hallmark of neurodegenerative events. In the present study, we investigated whether iron accumulation would interfere with autophagy and also sought to determine the effects of rapamycin-induced stimulation of autophagy in attenuating iron-related cognitive deficits. Male Wistar rats received a single daily oral dose of vehicle or iron carbonyl (30 mg/kg) at postnatal days 12-14. In adulthood, they received daily intraperitoneal injections of vehicle or rapamycin (0.25 mg/kg) for 14 days. Results showed that iron given in the neonatal period impaired inhibitory avoidance memory and induced a decrease in proteins critically involved in the autophagy pathway, Beclin-1 and LC3, in the hippocampus. Rapamycin in the adulthood reversed iron-induced memory deficits, decreased the ratio phospho-mTOR/total mTOR, and recovered LC3 II levels in iron-treated rats. Our results suggest that iron accumulation, as observed in neurodegenerative disorders, hinders autophagy, which might play a role in iron-induced neurotoxicity. Rapamycin, by inducing authophagy, was able to ameliorate iron-induced cognitive impairments. These findings support the use of rapamycin as a potential neuroprotective treatment against the cognitive decline associated to neurodegenerative disorders.
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Autofagia/efectos de los fármacos , Disfunción Cognitiva , Sobrecarga de Hierro/tratamiento farmacológico , Hierro/efectos adversos , Trastornos de la Memoria/tratamiento farmacológico , Sirolimus/farmacología , Animales , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hierro/metabolismo , Sobrecarga de Hierro/metabolismo , Trastornos de la Memoria/inducido químicamente , Enfermedades Neurodegenerativas/metabolismo , Ratas WistarRESUMEN
INTRODUCTION AND OBJECTIVES: We aimed to study the liver iron concentration in patients referred for hyperferritinemia to six hospitals in the Basque Country and to determine if there were differences between patients with or without metabolic syndrome. PATIENTS AND METHODS: Metabolic syndrome was defined by accepted criteria. Liver iron concentration was determined by magnetic resonance imaging. RESULTS: We obtained the data needed to diagnose metabolic syndrome in 276 patients; a total of 135 patients (49%), 115/240 men (48%), and 20/36 women (55.6%) presented metabolic syndrome. In all 276 patients, an MRI for the determination of liver iron concentration (mean±SD) was performed. The mean liver iron concentration was 30.83±19.38 for women with metabolic syndrome, 38.84±25.50 for men with metabolic syndrome, and 37.66±24.79 (CI 95%; 33.44-41.88) for the whole metabolic syndrome group. In 141 patients (51%), metabolic syndrome was not diagnosed: 125/240 were men (52%) and 16/36 were women (44.4%). The mean liver iron concentration was 34.88±16.18 for women without metabolic syndrome, 44.48±38.16 for men without metabolic syndrome, and 43.39±36.43 (CI 95%, 37.32-49.46) for the whole non-metabolic syndrome group. Comparison of the mean liver iron concentration from both groups (metabolic syndrome vs non-metabolic syndrome) revealed no significant differences (p=0.12). CONCLUSIONS: Patients with hyperferritinemia and metabolic syndrome presented a mildly increased mean liver iron concentration that was not significantly different to that of patients with hyperferritinemia and non-metabolic syndrome.
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Hiperferritinemia/diagnóstico por imagen , Sobrecarga de Hierro/diagnóstico por imagen , Hierro/metabolismo , Hígado/diagnóstico por imagen , Síndrome Metabólico/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Hiperferritinemia/complicaciones , Hiperferritinemia/metabolismo , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Imagen por Resonancia Magnética , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
The hydroxamate class of compounds is well known for its pharmacological applications, especially in the context of chelation therapy. In this work we investigate the performance of the fungal hydroxamates pyridoxatin (PYR), desferriastechrome (DAC) and desferricoprogen (DCO) as mitigators of stress caused by iron overload (IO) both in buffered medium and in cells. Desferrioxamine (DFO), the gold standard for IO treatment, was used as comparison. It was observed that all the fungal chelators (in aqueous medium) or PYR and DAC (in cells) are powerful iron scavengers. However only PYR and DCO (in aqueous medium) or PYR (in cells) were also antioxidant against two forms of iron-dependent oxidative stress (ascorbate or peroxide oxidation). These findings reveal that PYR is an interesting alternative to DFO for iron chelation therapy, since it has the advantage of being cell permeable and thus potentially orally active.
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Antioxidantes/química , Dicetopiperazinas/química , Ácidos Hidroxámicos/química , Ciclohexanos/química , Quelantes del Hierro/química , Sobrecarga de Hierro/metabolismoRESUMEN
Male rats of 80-90â¯g were overloaded with either Fe(II) or Cu(II) for 42â¯days by high concentrations of FeCl2 or CuSO4 in the drinking water. The animals were fed with a commercial rodent diet of 2780â¯kcal/100â¯g. Both metal treatments led to a liver redox imbalance and dyshomeostasis with oxidative stress and damage and the concomitant enhancement of oxidative processes as indicated by in vivo surface liver chemiluminescence, the sensitive and organ non-invasive assay for oxidative free radical reactions, and by ex vivo determined processes of phospholipid peroxidation and protein oxidation. In parallel, marked decreases in the antioxidant defense were observed. Liver reduced glutathione (GSH) content and the reduced/oxidized glutathione ratio (GSH/GSSG) were early indicators of oxidative metabolic disturbance upon the metal overloads. Thus, GSH plays a central role in the defense reactions involved in the chronic toxicity of Fe and Cu. Chronic overloads of Fe or Cu in rats afford an experimental animal model of hemochromatosis and of Wilson's disease, respectively. These two animal models could be useful in the study and development of the beneficial effects of pharmacological interventions in the two human diseases.
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Cobre/metabolismo , Homeostasis , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Hígado/metabolismo , Animales , Enfermedad Crónica , Humanos , Hígado/patología , Masculino , Oxidación-Reducción , Ratas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: Transfusion-dependent anemia and iron overload are associatedwith reduced survival in myelodysplastic syndrome (MDS). This cross-sectional study aimed to evaluate the prevalence of hepatic and cardiac overload in patients with MDS as measured by T2* magnetic resonance imaging (MRI), and its correlation with survival. METHODS: MDS or chronic myelomonocytic leukemia patients had iron overload evaluated by T2* MRI. HIO was considered when hepatic iron concentration ≥ 2 g/mg. Cardiac iron overload was considered with a T2*-value < 20 ms. RESULTS: Among 71 patients analyzed, median hepatic iron concentration was 3.9 g/mg (range 0.9-16 g/mg), and 68%of patients had hepatic iron overload. Patients with hepatic iron overload had higher mean ferritin levels (1182 ng/mL versus 185 ng/mL, p < 0.0001), transferrin saturation (76% versus 34%, p < 0.0001) and lower survival rates. Median cardiac T2*value was 42 ms (range 19.7-70.1 ms), and only one patienthad a T2* value indicative of cardiac iron overload. CONCLUSIONS: Hepatic iron overload is found in two thirds of patients, even in cases without laboratory signs of iron overload. Hepatic iron overload by T2* MRI is associated with a decreased risk of survival in patients with MDS.
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Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/etiología , Hígado/diagnóstico por imagen , Hígado/patología , Imagen por Resonancia Magnética , Síndromes Mielodisplásicos/complicaciones , Miocardio/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Transformación Celular Neoplásica , Estudios Transversales , Femenino , Humanos , Incidencia , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Miocardio/metabolismo , Prevalencia , Evaluación de Síntomas , Adulto JovenRESUMEN
PURPOSE: Bone biopsy defines classical diseases that constitute the renal osteodystrophy. There is a recent concern regarding other histological findings that are not appreciated by using the turnover, mineralization, and volume (TMV) classification. Iron (Fe) overload has been considered a new challenge and the real significance of the presence of this metal in bones is not completely elucidated. Therefore, the main goal of the current study was to not only to identify bone Fe, but also correlate its presence with demographic, and biochemical characteristics. METHODS: This is a cross-sectional analysis of bone biopsies performed in 604 patients on dialysis from 2010 to 2014 in a tertiary academic Hospital. RESULTS: Histomorphometric findings revealed the presence of Fe in 29.1%. Fe was associated with higher levels of serum ferritin and serum calcium. No TMV status was related to Fe bone overload. CONCLUSION: Our study has highlighted that the presence of Fe in one-third of bone samples has unknown clinical significance. The lack of other contemporary bone biopsy study reporting Fe prevents us from comparison. The findings presented here should be specifically addressed in a future research and will require attention prior to implementation of any clinical guideline. If any proposed treatment, however, would change the bone Fe-related morbidity is undetermined.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Ilion/metabolismo , Ilion/patología , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Insuficiencia Renal Crónica/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Remodelación Ósea , Calcificación Fisiológica , Calcio/sangre , Estudios Transversales , Femenino , Ferritinas/sangre , Humanos , Sobrecarga de Hierro/sangre , Masculino , Persona de Mediana Edad , Diálisis Renal , Estudios Retrospectivos , Adulto JovenRESUMEN
Enhanced iron levels in liver are associated with oxidative stress development and damage with increased fat accumulation. The aim of this work was to assess the hypothesis that antioxidant-rich extra virgin olive oil (AR-EVOO) counteracts iron-rich diet (IRD)-induced oxidative stress hindering hepatic steatosis. Male Wistar rats were fed and IRD (200â¯mg iron/kg diet) versus a control diet (CD; 50â¯mg iron/kg diet) with alternate AR-EVOO supplementation (100â¯mg/day) for 21 days. IRD induced liver steatosis and oxidative stress (higher levels of protein oxidation and lipid peroxidation with glutathione depletion), mitochondrial dysfunction (decreased citrate synthase and complex I and II activities) and loss of polyunsaturated fatty acids (PUFAs), with a drastic enhancement in the sterol regulatory element-binding protein-1c (SREBP-1c)/peroxisome proliferator-activated receptor-α (PPAR-α) ratio upregulating the expression of lipogenic enzymes (acetyl-CoA carboxylase, fatty acid (FA) synthase and stearoyl desaturase 2) and downregulating those involved in FA oxidation (carnitine palmitoyl transferase and acyl-CoA oxidase) over values in the CD group. IRD also upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes. AR-EVOO supplementation alone did not modify the studied parameters, however, IRD combined with AR-EVOO administration returned IRD-induced changes to baseline levels of the CD group. It is concluded that IRD-induced non-alcoholic fatty liver disease (NAFLD) is prevented by AR-EVOO supplementation, which might be related to the protective effects of its components such as hydroxytyrosol, oleic acid, tocopherols and/or PUFAs, thus representing a suitable anti-steatotic strategy to avoid progression into more severe stages of the disease, underlying NAFLD associated with iron overloading pathologies or obesity.
Asunto(s)
Antioxidantes/administración & dosificación , Suplementos Dietéticos , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Aceite de Oliva/administración & dosificación , Animales , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos Omega-3/metabolismo , Humanos , Hierro/administración & dosificación , Hierro/metabolismo , Sobrecarga de Hierro/dietoterapia , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
Although iron excess is toxic to the vasculature and even that pulmonary hypertension has been reported in this scenario, the role of iron overload per se remains to be clarified. This study aimed to test the effects of chronic iron-overload in rats on the morphophysiology of resistance pulmonary arteries (RPA) and right ventricle (RV) remodeling. Rats were injected with saline or iron-dextran (10, 100 and 200â¯mg/kg/day i.p.) for 28 days. Our results indicated increased circulating iron with significant lung deposits. Moreover, rats treated with the highest dose exhibited RV dysfunction and hypertrophy; inward remodeling and increased vasoconstriction of the RPA. Vascular hyperreactivity was accompanied by reduced nitric oxide (NO), and was reversed by incubation with Dimethylsulfoxide, Catalase and Tempol. The NADPH oxidase subunit gp91phox was increased due to iron-overload, and incubation with angiotensin II type-1 receptor (AT1) antagonist losartan not only reduced oxidative stress but also restored vascular function. Thus, we concluded that AT1 pathway plays a role in pulmonary vascular dysfunction by increasing oxidative stress and reducing NO bioavailability, thereby contributing to vascular remodeling and pulmonary hypertension of iron-overload. This finding should instigate future studies on the beneficial impacts of in vivo blockade of AT1 receptor under iron overload.
Asunto(s)
Hemodinámica , Hipertensión Pulmonar/etiología , Hipertrofia Ventricular Derecha/etiología , Sobrecarga de Hierro/complicaciones , Arteria Pulmonar/fisiopatología , Remodelación Vascular , Disfunción Ventricular Derecha/etiología , Función Ventricular Derecha , Remodelación Ventricular , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Sobrecarga de Hierro/inducido químicamente , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/fisiopatología , Complejo Hierro-Dextran , Masculino , NADPH Oxidasa 2/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo , Arteria Pulmonar/metabolismo , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal/efectos de los fármacos , Resistencia Vascular , Vasoconstricción , Vasodilatación , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Iron is a trace element, essential to support life due to its inherent ability to exchange electrons with a variety of molecules. The use of iron as a cofactor in basic metabolic pathways is essential to both pathogenic microorganisms and their hosts. During evolution, the shared requirement of micro- and macro-organisms for this important nutrient has shaped the pathogen-host relationship. Infectious pancreatic necrosis virus (IPNv) affects salmonids constituting a sanitary problem for this industry as it has an important impact on post-smolt survival. While immune modulation induced by IPNv infection has been widely characterized on Salmo salar, viral impact on iron host metabolism has not yet been elucidated. In the present work, we evaluate short-term effect of IPNv on several infected tissues from Salmo salar. We observed that IPNv displayed high tropism to headkidney, which directly correlates with a rise in oxidative stress and antiviral responses. Transcriptional profiling on headkidney showed a massive modulation of gene expression, from which biological pathways involved with iron metabolism were remarkable. Our findings suggest that IPNv infection increase oxidative stress on headkidney as a consequence of iron overload induced by a massive upregulation of genes involved in iron metabolism.
Asunto(s)
Enfermedades de los Peces/inmunología , Enfermedades de los Peces/virología , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/metabolismo , Fenómenos Fisiológicos de la Nutrición/inmunología , Estrés Oxidativo , Virosis/veterinaria , Animales , Biomarcadores , Enfermedades de los Peces/patología , Perfilación de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Virus de la Necrosis Pancreática Infecciosa/inmunología , Hierro/metabolismo , Sobrecarga de Hierro/patología , Transcriptoma , Carga ViralRESUMEN
OBJECTIVES: A multicenter, noninterventional, observational study was conducted in the Latin American countries including Argentina, Brazil, Colombia, Mexico, and Venezuela to assess the prevalence of liver and cardiac iron overload using magnetic resonance imaging (MRI) in patients with chronic anemias except thalassemia. METHODS: Patients aged >10 years with transfusion-dependent anemias, except thalassemia, either with <20 units of red blood cell (RBC) transfusions with serum ferritin (SF) levels >2000â ng/mL or with ≥20 units of RBC transfusions regardless of SF level in their lifetime, were enrolled. Iron overload was assessed using MRI. RESULTS: Among 175 patients included, the majority had sickle cell disease (SCD; 52%), followed by aplastic anemia (AA; 17.7%), myelodysplastic syndrome (MDS; 8.6%), Diamond-Blackfan anemia (DBA; 4%), pure red cell aplasia (1.1%), and others (16.6%). Liver iron overload was observed in 76.4% of patients, while cardiac iron overload was seen in 19.2% when assessed by MRI. The prevalence of iron overload was 80.2% in patients with SCD, 73.3% in MDS, 77.4% in AA, 100% in pure red cell aplasia, 71.4% in DBA, and 68.9% in other transfusion-related disorders. A moderate correlation between liver iron concentration (LIC) and SF was observed in patients with SCD and MDS (r = 0.47 and r = 0.61, respectively). All adverse events reported were consistent with the published data for deferasirox or underlying disease. CONCLUSION: A high prevalence of iron overload in this patient population in Latin American countries indicates that a better diagnosis and management of iron overload is required in these countries.
Asunto(s)
Anemia/metabolismo , Anemia/terapia , Transfusión de Eritrocitos , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Miocardio/metabolismo , Adolescente , Adulto , Anemia/patología , Enfermedad Crónica , Femenino , Ferritinas/metabolismo , Humanos , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/patología , América Latina/epidemiología , Hígado/patología , Masculino , Persona de Mediana Edad , Miocardio/patología , PrevalenciaRESUMEN
Iron is a chemical element that is active in the fundamental physiological processes for human life, but its burden can be toxic to the body, mainly because of the stimulation of membrane lipid peroxidation. For this reason, the action of iron on many ATPases has been studied, especially on P-ATPases, such as the Na+,K+-ATPase and the Ca2+-ATPase. On the Fe2+-ATPase activity, the free iron acts as an activator, decreasing the intracellular Fe2+ and playing a protection role for the cell. On the Ca2+-ATPase activity, the iron overload decreases the enzyme activity, raising the cytoplasmic Ca2+ and decreasing the sarco/endoplasmic reticulum and the Golgi apparatus Ca2+ concentrations, which could promote an enzyme oxidation, nitration, and fragmentation. However, the iron overload effect on the Na+,K+-ATPase may change according to the tissue expressions. On the renal cells, as well as on the brain and the heart, iron promotes an enzyme inactivation, whereas its effect on the erythrocytes seems to be the opposite, directly stimulating the ATPase activity, or stimulating it by signaling pathways involving ROS and PKC. Modulations in the ATPase activity may impair the ionic transportation, which is essential for cell viability maintenance, inducing irreversible damage to the cell homeostasis. Here, we will discuss about the iron overload effect on the P-ATPases, such as the Na+,K+-ATPase, the Ca2+-ATPase, and the Fe2+-ATPase.
Asunto(s)
ATPasas Transportadoras de Calcio/metabolismo , Sobrecarga de Hierro/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Transporte Biológico , Calcio/metabolismo , Señalización del Calcio/fisiología , Humanos , Hierro/metabolismoRESUMEN
The hypothesis of this study is that the cerebral cortex, hippocampus, and striatum of the rat brain are differentially affected in terms of oxidative stress and antioxidant capacity by acute Fe overload because Fe is distributed in a heterogeneous fashion among different regions and cells of the brain. The effects on the lipophilic and hydrophilic cellular environment were compared between regions and with the whole brain. A single dose of Fe-dextran increased Fe deposits, reaching a maximum after 6 hr. Both in whole brain and in cortex region, the ascorbyl/ascorbate content ratio was increased after 6 hr of Fe administration, while in striatum and hippocampus, there was no significant changes after Fe overload. Total thiol content decreased in whole brain and cortex, while there were no significant changes in striatum and hippocampus after Fe overload. The content of α-tocopherol (α-T), whether measured in the whole brain or in the isolated regions, did not change following Fe treatment. Lipid radical (LRâ¢) generation rate after Fe-dextran overload only increased in the cortex region. The LRâ¢/α-T content ratio was increased by Fe treatment in cortex but not in the whole brain, striatum, or hippocampus, in agreement with the study tested hypothesis.