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1.
Chem Biol Interact ; 347: 109617, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34391751

RESUMO

PURPOSE: This study was designed to investigate the mechanism of Dapagliflozin (Dapa) cardioprotection against diabetic cardiomyopathy (DCM). Structural and functional changes in the heart as well as decrease of erythropoietin (EPO) levels were reported in DCM. EPO simultaneously activates three pathways: the Janus-activated kinase-signal transducer and activator of transcription (JAK2/STAT5), phosphatidylinositol-3-kinase-Akt (PI3K/Akt), and extracellular signal-related kinase (ERK/MAPK) cascades, that result in proliferation and differentiation of cardiac cells. METHODS AND RESULTS: DCM was induced by a high fat diet for 10 weeks followed by administration of streptozotocin. After confirmation of diabetes, rats were divided randomly to 5 groups: Group 1; normal control group, Group 2; untreated diabetic group and Groups (3-5); diabetic groups received Dapa daily (0.75 mg, 1.5 or 3 mg/Kg, p.o) respectively for a month. At the end of the experiment, full anaesthesia was induced in all rats using ether inhalation and ECG was recorded. Blood samples were collected then rats were sacrificed and their heart were dissected out and processed for biochemical and histopathological studies. Untreated diabetic rats showed abnormal ECG pattern, elevation of serum cardiac enzymes, decrease EPO levels, downregulation of P-Akt, P-JAK2 and pMAPK pathways, abnormal histological structure of the heart and increase immunostaining intensity of P53 and TNF α in the cardiomyocytes. Dapa in a dose dependent manner attenuated the alterations in the previously mentioned parameters. CONCLUSION: The cardioprotective effect of Dapa could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2 and pMAPK signalling cascades which in turn decrease apoptosis.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Eletrocardiografia/efeitos dos fármacos , Eritropoetina/sangue , Eritropoetina/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Wistar , Estreptozocina
2.
Respir Physiol Neurobiol ; 292: 103709, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34087493

RESUMO

Previous studies suggested that erythropoietin (EPO) may protect against severe COVID-19-induced injuries, ultimately preventing mortality. This hypothesis is based on the fact that, in addition to promoting the increase in red blood cells, EPO is an anti-inflammatory, anti-apoptotic and protective factor in several non-erythropoietic tissues. Furthermore, EPO promotes nitric oxide production in the hypoxic lung and stimulates ventilation by interacting with the respiratory centers of the brainstem. Given that EPO in the blood is increased at high-altitude, we evaluated the serum levels of EPO in critical patients with COVID-19 at "Hospital Agramont" in the city of El Alto (4150 masl) in Bolivia. A total of 16 patients, 15 men, one woman, with a mean age of 55.8 ± 8.49 years, admitted to the Intensive Care Unit were studied. All patients were permanent residents of El Alto, with no travel history below 3000 masl for at least one year. Blood samples were collected upon admission to the ICU. Serum EPO concentration was assessed using an ELISA kit, and a standard technique determined hemoglobin concentration. Only half of the observed patients survived the disease. Remarkably, fatal cases showed 2.5 times lower serum EPO than survivors (2.78 ± 0.8643 mU/mL vs 7.06 ± 2.713 mU/mL; p = 0.0096), and 1.24 times lower hemoglobin levels (13.96 ± 2.56 g/dL vs 17.41 ± 1.61 g/dL; p = 0.0159). While the number of cases evaluated in this work is low, our findings strongly warrant further investigation of EPO levels in COVID-19 patients at high and low altitudes. Our results also support the hypothesis that exogenous EPO administration could help critically ill COVID-19 patients overcome the disease.


Assuntos
Altitude , COVID-19/sangue , Eritropoetina/sangue , Pulmão/diagnóstico por imagem , Idoso , Bolívia , COVID-19/diagnóstico por imagem , COVID-19/mortalidade , Feminino , Hemoglobinas/metabolismo , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
3.
Front Immunol ; 12: 624136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995348

RESUMO

Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α+-thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal α+-thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial.


Assuntos
Anemia/etiologia , Citocinas/sangue , Eritropoetina/sangue , Doenças Fetais/etiologia , Feto/metabolismo , Malária/parasitologia , Placenta/parasitologia , Complicações Parasitárias na Gravidez/parasitologia , Talassemia alfa/complicações , Adulto , Anemia/sangue , Anemia/imunologia , Anemia/parasitologia , Biomarcadores/sangue , Estudos Transversais , Feminino , Doenças Fetais/sangue , Doenças Fetais/imunologia , Doenças Fetais/parasitologia , Feto/imunologia , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Ferro/sangue , Ferro/deficiência , Malária/sangue , Malária/imunologia , Masculino , Saúde Materna , Paridade , Placenta/imunologia , Placenta/metabolismo , Gravidez , Complicações Parasitárias na Gravidez/sangue , Complicações Parasitárias na Gravidez/imunologia , Medição de Risco , Fatores de Risco , Tanzânia , Transferrina/metabolismo , Adulto Jovem , Talassemia alfa/sangue , Talassemia alfa/imunologia
4.
Int J Hematol ; 114(2): 222-227, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34021850

RESUMO

In the 2016 WHO classification, hemoglobin and hematocrit thresholds for diagnosing polycythemia vera (PV) have been lowered, increasing the number of consultations for polycythemia investigations. In PV, beta-2 microglobulin (B2m) levels are reportedly increased, whereas erythropoietin (EPO) levels are usually low. Most secondary polycythemia cases (SP) are caused by tobacco use. We decided to analyze the relevance of these three parameters in all patients seen for polycythemia investigations to help differentiate PV from SP cases. A cohort of 257 patients (123 PV; 134 SP) was identified. The median B2m level was higher for PV patients (3.16 vs 1.98 mg/l, p < 0.0001). Increased B2m levels were observed in 83.7% of PV patients (11.9% in SP). The median EPO level was lower in PV patients (4.4 vs 12.3 UI/l, p < 0.0001). Tobacco was used by 42.8% of SP patients (8% in PV, p < 0.0001). Increased B2m, low EPO and no tobacco exposure was predictive of PV (specificity and positive predictive value = 100%). Normal B2m, normal EPO and tobacco exposure was predictive of SP (positive predictive value = 100%). These simple and inexpensive parameters could be used to rapidly differentiate PV from SP cases, before prescribing time-consuming JAK2 V617F mutation analysis by specialists.


Assuntos
Biomarcadores , Eritropoetina/sangue , Policitemia/sangue , Policitemia/etiologia , Uso de Tabaco/efeitos adversos , Microglobulina beta-2/sangue , Diagnóstico Diferencial , Suscetibilidade a Doenças , Humanos , Janus Quinase 2/genética , Mutação , Policitemia/diagnóstico , Policitemia/epidemiologia , Policitemia Vera/sangue , Policitemia Vera/diagnóstico , Policitemia Vera/etiologia , Prognóstico
5.
Nat Med ; 27(5): 802-805, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33888901

RESUMO

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.


Assuntos
Antineoplásicos/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/genética , Relação Dose-Resposta a Droga , Eritropoetina/sangue , Feminino , Humanos , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
8.
J Med Case Rep ; 15(1): 76, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33593422

RESUMO

BACKGROUND: Myeloproliferative neoplasms (MPNs) such as polycythemia Vera (PV) and Essential Thrombocythemia (ET) can be associated with a high risk of both venous and arterial thrombosis. However, the co-existence between these two complications is very rare and has never been described before, especially in young adults with no known history of MPNs. CASE PRESENTATION: We report the case of a 39 year-old Caucasian Moroccan male patient without cardiovascular risk factors (CVRF), who presented with acute chest pain. He also suffered from a severe headache since 2 weeks. Electrocardiogram (ECG) showed ST segment elevation myocardial infarction in the posterolateral leads. Cerebral Computed Tomography (CT) scan revealed subarachnoid hemorrhage (SAH), and cerebral Magnetic Resonance Angiography (MRA) found a Superior Sagittal Sinus Thrombosis (SSST). Routine blood tests showed raised hemoglobin and hematocrit in addition to leukocytosis and thrombocythemia. His coronary angiography revealed a thrombus in the ostial left circumflex artery (LCX). Further testing revealed positive Janus kinase 2 (JAK2) V617F mutation and low erythropoietin level, confirming the diagnosis of PV according to the 2008 World Health Organization (WHO) criteria. Antithrombotic and anti-ischemic treatments, in addition to myelosuppressive therapy with hydroxyurea, were initiated with a good clinical and biological evolution. CONCLUSION: This case shows that MPNs are an important cause of thrombosis, especially in young patients with no other risk factors. Early diagnosis and appropriate management are fundamental before the occurrence of life-threatening complications that can sometimes present in unusual forms associating arterial and venous thrombotic events.


Assuntos
Policitemia Vera/complicações , Policitemia Vera/diagnóstico , Trombose Venosa/etiologia , Adulto , Dor no Peito/etiologia , Vasos Coronários , Eritropoetina/sangue , Cefaleia/etiologia , Humanos , Janus Quinase 2/genética , Masculino , Mutação , Seio Sagital Superior , Trombose Venosa/diagnóstico por imagem
9.
Int J Lab Hematol ; 43 Suppl 1: 142-151, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33554466

RESUMO

INTRODUCTION: Studies have shown that iron metabolism is affected by coronavirus disease 19 (COVID-19), which has spread worldwide and has become a global health problem. Our study aimed to evaluate the relationship between COVID-19 and serum erythropoietin (EPO), hepcidin, and haptoglobin (Hpt) levels with disease severity, and other biochemical values. METHODS: Fifty nine COVID-19 patients hospitalized in the intensive care unit (ICU) and wards in our hospital between March and June 2020 and 19 healthy volunteers were included in the study. Participants were divided into mild, severe, and critical disease severity groups. Group mean values were analyzed with SPSS according to disease severity, mortality, and intubation status. RESULTS: Hemoglobin (Hb) levels were significantly lower in the critical patient group (P < .0001) and deceased group (P < .0001). The red blood cell distribution width-coefficient of variation (RDW-CV) and ferritin values were significantly higher in the intubated (P = .001, P = .005) and deceased (P = .014, P = .003) groups. Ferritin values were positively correlated with disease severity (P < .0001). Serum iron levels were lower in the patient group compared with the reference range. (P < .0001). It was found that the transferrin saturation (TfSat) was lower in the patient group compared with the control group (P < .0001). It was found that the mean EPO of the deceased was lower than the control group and the survived patient group (P = .035). Hepcidin levels were found to be significantly lower in the patient group (P < .0001). Hpt values were found to be significantly lower in the intubated group (P = .004) and the deceased group (P = .042). CONCLUSION: In our study, while serum iron and hepcidin levels decreased in patients diagnosed with COVID-19, we found that EPO and Hpt levels were significantly lower in critical and deceased patient groups. Our study is the first study examining EPO and Hpt levels in patients diagnosed with COVID-19.


Assuntos
COVID-19/sangue , Eritropoetina/sangue , Haptoglobinas/análise , Hepcidinas/sangue , SARS-CoV-2 , Idoso , Biomarcadores , Estudos Transversais , Feminino , Ferritinas/sangue , Hemoglobinas/análise , Homeostase , Humanos , Intubação Intratraqueal/estatística & dados numéricos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transferrina/análise
10.
Blood Cells Mol Dis ; 88: 102536, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33450539

RESUMO

In a two-part process, we assessed elements of the principal hormonal pathway regulating iron homeostasis in human neonates. Part 1: Quantifying erythropoietin (Epo), erythroferrone (ERFE), hepcidin, and relevant serum and erythrocytic iron-related metrics in umbilical cord blood from term (n = 13) and preterm (n = 10) neonates, and from neonates born to mothers with diabetes and obesity (n = 13); Part 2: Quantifying serum Epo, ERFE, and hepcidin before and following darbepoetin administration. Part 1: We measured Epo, ERFE and hepcidin in all cord blood samples. Epo and ERFE levels did not differ between the three groups. Preterm neonates had the lowest hepcidin levels, while neonates born to diabetic women with a very high BMI had the lowest ferritin and RET-He levels. Part 2: Following darbepoetin dosing, ERFE levels generally increased (p < 0.05) and hepcidin levels generally fell (p < 0.05). Our observations suggest that the Epo/ERFE/hepcidin axis is intact in the newborn period.


Assuntos
Eritropoetina/sangue , Hepcidinas/sangue , Hormônios Peptídicos/sangue , Transdução de Sinais , Eritropoetina/metabolismo , Feminino , Sangue Fetal/metabolismo , Hepcidinas/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Obesidade/sangue , Obesidade/metabolismo , Hormônios Peptídicos/metabolismo , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/metabolismo , Gravidez em Diabéticas/sangue , Gravidez em Diabéticas/metabolismo , Nascimento Prematuro/sangue , Nascimento Prematuro/metabolismo
11.
Sci Rep ; 10(1): 22023, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328561

RESUMO

We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.


Assuntos
Senescência Celular , Eritrócitos/patologia , Túbulos Renais Proximais/patologia , Animais , Células da Medula Óssea/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Células Eritroides/metabolismo , Eritropoetina/sangue , Meia-Vida , Hematopoese , Hemólise , Quelantes de Ferro/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/fisiopatologia , Túbulos Renais Proximais/ultraestrutura , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta , Baço/metabolismo
12.
Biosci Rep ; 40(12)2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33245095

RESUMO

Iron stores at birth are essential to meet iron needs during the first 4-6 months of life. The present study aimed to investigate iron stores in normal birth weight, healthy, term neonates. Umbilical cord blood samples were collected from apparently normal singleton vaginal deliveries (n=854). Subjects were screened and excluded if C-reactive protein (CRP) > 5 mg/l or α1-acid glycoprotein (AGP) > 1 g/l, preterm (<37 complete weeks), term < 2500g or term > 4000g. In total, 762 samples were included in the study. Serum ferritin, soluble transferrin receptor (sTfR), hepcidin, and erythropoietin (EPO) were measured in umbilical cord blood samples; total body iron (TBI) (mg/kg) was calculated using sTfR and ferritin concentrations. A total of 19.8% newborns were iron deficient (ferritin 35 µg/l) and an additional 46.6% had insufficient iron stores (ferritin < 76 µg/l). There was a positive association between serum ferritin and sTfR, hepcidin, and EPO. Gestational age was positively associated with ferritin, sTfR, EPO, and hepcidin. In conclusion, we demonstrate a high prevalence of insufficient iron stores in a Chinese birth cohort. The value of cord sTfR and TBI in the assessment of iron status in the newborn is questionable, and reference ranges need to be established.


Assuntos
Eritropoetina/sangue , Ferritinas/sangue , Sangue Fetal/química , Hepcidinas/sangue , Inflamação/diagnóstico , Ferro/metabolismo , Receptores da Transferrina/sangue , Adulto , Biomarcadores/sangue , Peso ao Nascer , Proteína C-Reativa/análise , Cordocentese , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Inflamação/sangue , Mediadores da Inflamação/sangue , Ferro/deficiência , Orosomucoide/análise , Gravidez
13.
Eur Rev Med Pharmacol Sci ; 24(21): 11227-11232, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33215441

RESUMO

OBJECTIVE: To investigate the relationship between electrocardiographic changes and erythropoietin (EPO) level in stable coronary artery disease (CAD) patients with autonomic nerve functional damage. PATIENTS AND METHODS: Clinical data of 96 stable CAD patients who were treated in our hospital from January 2017 to December 2019 were retrospectively analyzed. All patients were grouped according to whether autonomic nerve function damage was combined; the baseline characteristic data and the morphological characteristics of ECG scattergram were compared between 2 groups, and the relationship between ECG scattergram and EPO level & autonomic nerve function was analyzed. RESULTS: The levels of EPO and red cell volume distributing width (RDW) in stable CAD patients with autonomic nerve dysfunction were significantly higher than that of CAD patients without autonomic nerve dysfunction (p<0.05). The length of scattergram in stable CAD patients with autonomic nerve dysfunction was significantly shorter than that of those without autonomic nerve dysfunction (p<0.05). The cometary sign proportion of ECG scattergram in stable CAD patients with autonomic nerve dysfunction was significantly lower than that of stable CAD patients without autonomic nerve dysfunction (p<0.05). There was negative correlation between EPO levels and scattergram length in stable CAD patients with and without autonomic nerve dysfunction (r=0.44, p=0.02). There was no correlation between EPO levels and scatter width in stable CAD patients with and without autonomic nerve dysfunction (r=0.10, p=0.58). The results of binary logistic regression analysis showed that EPO level was the independent risk factor for the occurrence of autonomic dysfunction in patients with stable CAD (p<0.05). The length of scattergram was the independent protective factor of autonomic nerve function impairment in patients with stable CAD (p<0.05). The AUC of EPO level and scattergram was 0.74 and 0.72 respectively, both of which have similar prediction value. CONCLUSIONS: The level of EPO in stable CAD patients with autonomic nerve dysfunction was related to the change of ECG; and the EPO level and scattergram length can be used to predict the occurrence risk of autonomic nerve dysfunction.


Assuntos
Vias Autônomas/metabolismo , Doença da Artéria Coronariana/sangue , Eletrocardiografia , Eritropoetina/sangue , Vias Autônomas/patologia , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Artigo em Inglês | MEDLINE | ID: mdl-33020411

RESUMO

Intermittent hypoxia, defined as alternating bouts of breathing hypoxic and normoxic air, has the potential to improve oxygen-carrying capacity through an erythropoietin-mediated increase in hemoglobin mass. The purpose of this study was to determine the effect of a single session of intermittent hypoxia on erythropoietin levels and hemoglobin mass in young healthy individuals. Nineteen participants were randomly assigned to an intermittent hypoxia group (Hyp, n = 10) or an intermittent normoxia group (Norm, n = 9). Intermittent hypoxia consisted of five 4-min hypoxic cycles at a targeted arterial oxygen saturation of 90% interspersed with 4-min normoxic cycles. Erythropoietin levels were measured before and two hours following completion of the protocol. Hemoglobin mass was assessed the day before and seven days after exposure to intermittent hypoxia or normoxia. As expected, the intermittent hypoxia group had a lower arterial oxygen saturation than the intermittent normoxia group during the intervention (Hyp: 89 ± 1 vs. Norm: 99 ± 1%, p < 0.01). Erythropoietin levels did not significantly increase following exposure to intermittent hypoxia (Hyp: 8.2 ± 4.5 to 9.0 ± 4.8, Norm: 8.9 ± 1.7 to 11.1 ± 2.1 mU·mL-1, p = 0.15). Hemoglobin mass did not change following exposure to intermittent hypoxia. This single session of intermittent hypoxia was not sufficient to elicit a significant rise in erythropoietin levels or hemoglobin mass in young healthy individuals.


Assuntos
Eritrócitos/metabolismo , Eritropoetina/metabolismo , Hipóxia/fisiopatologia , Oxigênio/metabolismo , Adulto , Eritropoetina/sangue , Feminino , Hemoglobinas/análise , Humanos , Hipóxia/sangue , Masculino , Oxigênio/sangue , Consumo de Oxigênio
16.
Sci Rep ; 10(1): 15557, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968161

RESUMO

In end-stage renal disease (ESRD) patients receiving dialysis, anemia is common and related to a higher mortality rate. Erythropoietin (EPO) resistance and iron refractory anemia require red blood cell transfusions. Myelodysplastic syndrome (MDS) is a disease with hematopoietic dysplasia. There are limited reports regarding ESRD patients with MDS. We aim to assess whether, for ESRD patients, undergoing dialysis is a predictive factor of MDS by analyzing data from the Taiwan National Health Insurance Research Database. We enrolled 74,712 patients with chronic renal failure (ESRD) who underwent dialysis and matched 74,712 control patients. In our study, we noticed that compared with the non-ESRD controls, in ESRD patients, undergoing dialysis (subdistribution hazard ratio [sHR] = 1.60, 1.16-2.19) and age (sHR = 1.03, 1.02-1.04) had positive predictive value for MDS occurrence. Moreover, more units of red blood cell transfusion (higher than 4 units per month) was also associated with a higher incidence of MDS. The MDS cumulative incidence increased with the duration of dialysis in ESRD patients. These effects may be related to exposure to certain cytokines, including interleukin-1, tumor necrosis factor-α, and tumor growth factor-ß. In conclusion, we report the novel finding that ESRD patients undergoing dialysis have an increased risk of MDS.


Assuntos
Anemia/epidemiologia , Falência Renal Crônica/epidemiologia , Síndromes Mielodisplásicas/epidemiologia , Diálise Renal/efeitos adversos , Adulto , Idoso , Anemia/sangue , Anemia/etiologia , Anemia/patologia , Transfusão de Eritrócitos/efeitos adversos , Eritropoetina/sangue , Feminino , Humanos , Interleucina-1/sangue , Ferro/metabolismo , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/patologia , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue
17.
Biomed Res Int ; 2020: 6479630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32923484

RESUMO

Intermittent exposure to hypoxia (IHE) increases the production of reactive oxygen and nitrogen species as well as erythropoietin (EPO), which stimulates the adaptation to intense physical activity. However, several studies suggest a protective effect of moderate hypoxia in cardiovascular disease (CVD) events. The effects of intense physical activity with IHE on oxi-inflammatory mediators and their interaction with conventional CVD risk factors were investigated. Blood samples were collected from elite athletes (control n = 6, IHE n = 6) during a 6-day IHE cycle using hypoxicator GO2 altitude. IHE was held once a day, at least 2 hours after training. In serum, hydrogen peroxide (H2O2), nitric oxide (NO), 3-nitrotyrosine (3-Nitro), proinflammatory cytokines (IL-1ß and TNFα), high sensitivity C-reactive protein (hsCRP), and heat shock protein 27 (HSP27) were determined by the commercial immunoenzyme (ELISA kits) or colorimetric methods. Serum erythropoietin (EPO) level was measured by ELISA kit every day of hypoxia. IHE was found to significantly increase H2O2, NO, and HSP27 but to decrease 3NT concentrations. The changes in 3NT and HSP27 following hypoxia proved to enhance NO bioavailability and endothelial function. In the present study, the oxi-inflammatory mediators IL-1ß and hsCRP increased in IHE group but they did not exceed the reference values. The serum EPO level increased on the 3rd day of IHE, then decreased on 5th day of IHE, and correlated with NO/H2O2 ratio (r s = 0.640, P < 0.05). There were no changes in haematological markers contrary to lipoproteins such as low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL) which showed a decreasing trend in response to hypoxic exposure. The study demonstrated that IHE combined with sports activity reduced a risk of endothelial dysfunction and atherogenesis in athletes even though the oxi-inflammatory processes were enhanced. Therefore, 6-day IHE seems to be a potential therapeutic and nonpharmacological method to reduce CVD risk, especially in elite athletes participating in strenuous training.


Assuntos
Endotélio/fisiopatologia , Hipóxia/fisiopatologia , Adaptação Fisiológica/fisiologia , Altitude , Aterosclerose/sangue , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Citocinas/sangue , Endotélio/metabolismo , Eritropoetina/sangue , Exercício Físico/fisiologia , Humanos , Peróxido de Hidrogênio/sangue , Hipóxia/sangue , Hipóxia/metabolismo , Inflamação/sangue , Inflamação/metabolismo , Inflamação/fisiopatologia , Lipoproteínas/sangue , Masculino , Óxido Nítrico/sangue , Oxigênio/metabolismo , Esportes/fisiologia , Tirosina/análogos & derivados , Tirosina/sangue
18.
J Immunol ; 205(8): 2008-2015, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32907997

RESUMO

Immune complexes (ICs) in blood are efficiently removed mainly by liver reticuloendothelial systems consisting of sinusoidal endothelial cells and Kupffer cells expressing FcγR. The bone marrow (BM) also has sinusoidal vasculatures, and sinusoidal BM endothelial cells (BMECs) bear unique function, including hematopoietic niches and traffic regulation of hematopoietic cells. In this study, we found that sinusoidal BMECs express FcγRIIb2, which is markedly increased in anemic conditions or by the administration of erythropoietin (Epo) in healthy mice. BMECs expressed Epo receptor (EpoR), and the Epo-induced increase in FcγRIIb2 expression was abolished in Epor-/- ::HG1-Epor transgenic mice, which lack EpoR in BMECs except for BM erythroblasts, suggesting the effect was directly mediated via EpoR on BMECs. Further, although BMECs hardly captured i.v.-injected soluble ICs in healthy mice, Epo administration induced a remarkable increase in the uptake of ICs in a FcγRIIb-dependent manner. Enhancement of the IC incorporation capacity by Epo was also observed in cultured BMECs in vitro, suggesting the direct effect of Epo on BMECs. Moreover, we found that i.v.-injected ICs in Epo-treated mice were more rapidly removed from the circulation than in PBS-treated mice. These results reveal a novel function of BMECs to efficiently remove circulating blood-borne ICs in an FcγRIIb2-mediated manner.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Células da Medula Óssea/imunologia , Células Endoteliais/imunologia , Eritropoetina/imunologia , Receptores de IgG/imunologia , Animais , Complexo Antígeno-Anticorpo/sangue , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Eritropoetina/sangue , Eritropoetina/genética , Camundongos , Camundongos Knockout , Receptores de IgG/sangue , Receptores de IgG/genética
20.
Front Immunol ; 11: 1403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733466

RESUMO

Patients who have experienced a first cerebral ischemic event are at increased risk of recurrent stroke. There is strong evidence that low-level inflammation as measured by high sensitivity C-reactive protein (hs-CRP) is a predictor of further ischemic events. Other mechanisms implicated in the pathogenesis of stroke may play a role in determining the risk of secondary events, including oxidative stress and the adaptive response to it and activation of neuroprotective pathways by hypoxia, for instance through induction of erythropoietin (EPO). This study investigated the association of the levels of CRP, peroxiredoxin 1 (PRDX1, an indicator of the physiological response to oxidative stress) and EPO (a neuroprotective factor produced in response to hypoxia) with the risk of a second ischemic event. Eighty patients with a diagnosis of lacunar stroke or transient ischemic attack (TIA) were included in the study and a blood sample was collected within 14 days from the initial event. Hs-CRP, PRDX1, and EPO were measured by ELISA. Further ischemic events were recorded with a mean follow-up of 42 months (min 24, max 64). Multivariate analysis showed that only CRP was an independent predictor of further events with an observed risk (OR) of 1.14 (P = 0.034, 95% CI 1.01-1.29). No association was observed with the levels of PRDX1 or EPO. A receiver operating curve (ROC) determined a cut-off CRP level of 3.25 µg/ml, with a 46% sensitivity and 81% specificity. Low-level inflammation as detected by hs-CRP is an independent predictor of recurrent cerebrovascular ischemic events.


Assuntos
Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Ataque Isquêmico Transitório/patologia , Acidente Vascular Cerebral Lacunar/patologia , Idoso , Eritropoetina/sangue , Feminino , Humanos , Inflamação/sangue , Ataque Isquêmico Transitório/sangue , Masculino , Pessoa de Meia-Idade , Peroxirredoxinas/sangue , Recidiva , Sensibilidade e Especificidade , Acidente Vascular Cerebral Lacunar/sangue
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