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1.
Nat Commun ; 11(1): 4075, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796847

RESUMO

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFß signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFß signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFß-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.


Assuntos
Envelhecimento/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Envelhecimento/genética , Animais , Medula Óssea , Ciclo Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Células Precursoras Eritroides , Eritropoese/genética , Eritropoese/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hematopoese , Interleucina-6/genética , Linfopoese/genética , Linfopoese/fisiologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Transdução de Sinais , Nicho de Células-Tronco , Fator de Crescimento Transformador beta1/genética
2.
Nat Commun ; 11(1): 3344, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620751

RESUMO

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.


Assuntos
Anemia de Diamond-Blackfan/patologia , Células-Tronco Hematopoéticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Anemia de Diamond-Blackfan/dietoterapia , Anemia de Diamond-Blackfan/genética , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Modelos Animais de Doenças , Eritropoese/efeitos dos fármacos , Eritropoese/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Proteínas Ribossômicas/genética
5.
Crit Rev Clin Lab Sci ; 57(6): 415-431, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32568604

RESUMO

Many studies have reported hemocytometric changes in COVID-19 infection at admission and during the course of disease, but an overview is lacking. We provide a summary of the literature of hemocytometric changes and evaluate whether these changes may assist clinicians in diagnosing and predicting disease progression of COVID-19. Eighty-three out of 250 articles from December 2019 to 20 May 2020 were included from the databases, PubMed, Web of Science Core Collection, Embase, Cochrane and MedRxiv. Our review of the literature indicates that lymphopenia and an elevated neutrophil/lymphocyte ratio are the most consistent abnormal hemocytometric findings and that these alterations may augment in the course of time, especially in those with severe disease.


Assuntos
Betacoronavirus/fisiologia , Biomarcadores/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Eritropoese , Humanos , Inflamação/sangue , Inflamação/patologia , Pandemias , Prognóstico
6.
Mol Cell ; 78(5): 808-810, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32502420

RESUMO

In a recent issue of Molecular Cell, Kretov et al. (2020) demonstrate that microRNA-144 targets Dicer in a negative feedback loop, affecting global canonical microRNA expression in erythrocytes. MicroRNA-451 is refractory to the loss of Dicer because of its Ago2-dependent processing.


Assuntos
MicroRNAs , Proteínas Argonauta , Eritropoese , Ribonuclease III
7.
Nat Commun ; 11(1): 2763, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488076

RESUMO

Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in multiples of 24 h suggesting a circadian basis, but the mechanism controlling this periodicity is unknown. Combining in vivo and in vitro approaches utilizing rodent and human malaria parasites, we reveal that: (i) 57% of Plasmodium chabaudi genes exhibit daily rhythms in transcription; (ii) 58% of these genes lose transcriptional rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 6% of Plasmodium falciparum genes show 24 h rhythms in expression under free-running conditions; (iv) Serpentine receptor 10 (SR10) has a 24 h transcriptional rhythm and disrupting it in rodent malaria parasites shortens the IDC by 2-3 h; (v) Multiple processes including DNA replication, and the ubiquitin and proteasome pathways, are affected by loss of coordination with host rhythms and by disruption of SR10. Our results reveal malaria parasites are at least partly responsible for scheduling the IDC and coordinating their development with host daily rhythms.


Assuntos
Ritmo Circadiano/fisiologia , Eritropoese/fisiologia , Interações Hospedeiro-Parasita/fisiologia , Malária/metabolismo , Proteínas de Protozoários/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Alcaloides de Triptamina e Secologanina/metabolismo , Animais , Proteínas de Caenorhabditis elegans , Modelos Animais de Doenças , Feminino , Expressão Gênica , Interações Hospedeiro-Parasita/genética , Humanos , Malária/parasitologia , Camundongos , Camundongos Knockout , Plasmodium chabaudi/genética , Plasmodium chabaudi/crescimento & desenvolvimento , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/genética , Receptores Acoplados a Proteínas-G/genética , Roedores , Transcriptoma
8.
PLoS One ; 15(5): e0233751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470079

RESUMO

Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche. Prior studies showed that signaling from members of the transforming growth factor (TGF) superfamily in mesenchymal stromal cells is required for normal niche development. Here, we assessed the impact of TGF family signaling on niche maintenance and stress responses by deleting Smad4 in mesenchymal stromal cells at birth, thereby abrogating canonical TGF signaling. No alteration in the number or spatial organization of CXCL12-abundant reticular (CAR) cells, osteoblasts, or adipocytes was observed in Osx-Cre, Smad4fl/fl mice, and expression of key niche factors was normal. Basal hematopoiesis and stress erythropoiesis responses to acute hemolytic anemia were normal. TGF-ß potently inhibits stromal CXCL12 expression in vitro; however, G-CSF induced decreases in bone marrow CXCL12 expression and subsequent hematopoietic stem/progenitor cell mobilization were normal in Osx-Cre, Tgfbr2fl/fl mice, in which all TGF-ß signaling in mesenchymal stromal is lost. Finally, although a prior study showed that TGF-ß enhances recovery from myeloablative therapy, hematopoietic recovery following single or multiple doses of 5-flurauracil were normal in Osx-Cre, Tgfbr2fl/fl mice. Collectively, these data suggest that TGF family member signaling in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions.


Assuntos
Anemia Hemolítica/metabolismo , Eritropoese , Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Fator de Crescimento Transformador beta/fisiologia , Fatores de Crescimento Transformadores/fisiologia , Doença Aguda , Anemia Hemolítica/patologia , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Células Cultivadas , Quimiocina CXCL12/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nicho de Células-Tronco
9.
PLoS Pathog ; 16(5): e1008579, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32421753

RESUMO

Anti-helminth responses require robust type 2 cytokine production that simultaneously promotes worm expulsion and initiates the resolution of helminth-induced wounds and hemorrhaging. However, how infection-induced changes in hematopoiesis contribute to these seemingly distinct processes remains unknown. Recent studies have suggested the existence of a hematopoietic progenitor with dual mast cell-erythrocyte potential. Nonetheless, whether and how these progenitors contribute to host protection during an active infection remains to be defined. Here, we employed single cell RNA-sequencing and identified that the metabolic enzyme, carbonic anhydrase (Car) 1 marks a predefined bone marrow-resident hematopoietic progenitor cell (HPC) population. Next, we generated a Car1-reporter mouse model and found that Car1-GFP positive progenitors represent bipotent mast cell/erythrocyte precursors. Finally, we show that Car1-expressing HPCs simultaneously support mast cell and erythrocyte responses during Trichinella spiralis infection. Collectively, these data suggest that mast cell/erythrocyte precursors are mobilized to promote type 2 cytokine responses and alleviate helminth-induced blood loss, developmentally linking these processes. Collectively, these studies reveal unappreciated hematopoietic events initiated by the host to combat helminth parasites and provide insight into the evolutionary pressure that may have shaped the developmental relationship between mast cells and erythrocytes.


Assuntos
Células Precursoras Eritroides/imunologia , Eritropoese/imunologia , Mastócitos/imunologia , Mastocitose/imunologia , Trichinella spiralis/imunologia , Triquinelose/imunologia , Animais , Anidrase Carbônica I/genética , Anidrase Carbônica I/imunologia , Células Precursoras Eritroides/parasitologia , Células Precursoras Eritroides/patologia , Feminino , Mastócitos/parasitologia , Mastócitos/patologia , Mastocitose/genética , Mastocitose/patologia , Camundongos , Camundongos Transgênicos , Triquinelose/genética , Triquinelose/patologia
10.
Proc Natl Acad Sci U S A ; 117(23): 12868-12876, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32457162

RESUMO

Fine-resolution differentiation trajectories of adult human hematopoietic stem cells (HSCs) involved in the generation of red cells is critical for understanding dynamic developmental changes that accompany human erythropoiesis. Using single-cell RNA sequencing (scRNA-seq) of primary human terminal erythroid cells (CD34-CD235a+) isolated directly from adult bone marrow (BM) and umbilical cord blood (UCB), we documented the transcriptome of terminally differentiated human erythroblasts at unprecedented resolution. The insights enabled us to distinguish polychromatic erythroblasts (PolyEs) at the early and late stages of development as well as the different development stages of orthochromatic erythroblasts (OrthoEs). We further identified a set of putative regulators of terminal erythroid differentiation and functionally validated three of the identified genes, AKAP8L, TERF2IP, and RNF10, by monitoring cell differentiation and apoptosis. We documented that knockdown of AKAP8L suppressed the commitment of HSCs to erythroid lineage and cell proliferation and delayed differentiation of colony-forming unit-erythroid (CFU-E) to the proerythroblast stage (ProE). In contrast, the knockdown of TERF2IP and RNF10 delayed differentiation of PolyE to OrthoE stage. Taken together, the convergence and divergence of the transcriptional continuums at single-cell resolution underscore the transcriptional regulatory networks that underlie human fetal and adult terminal erythroid differentiation.


Assuntos
Diferenciação Celular/genética , Eritroblastos/fisiologia , Eritropoese/genética , Adulto , Apoptose/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sangue Fetal/citologia , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Família Multigênica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , RNA-Seq , Análise de Célula Única , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Transcrição Genética
11.
Mol Cell ; 78(5): 960-974.e11, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32330456

RESUMO

Dynamic cellular processes such as differentiation are driven by changes in the abundances of transcription factors (TFs). However, despite years of studies, our knowledge about the protein copy number of TFs in the nucleus is limited. Here, by determining the absolute abundances of 103 TFs and co-factors during the course of human erythropoiesis, we provide a dynamic and quantitative scale for TFs in the nucleus. Furthermore, we establish the first gene regulatory network of cell fate commitment that integrates temporal protein stoichiometry data with mRNA measurements. The model revealed quantitative imbalances in TFs' cross-antagonistic relationships that underlie lineage determination. Finally, we made the surprising discovery that, in the nucleus, co-repressors are dramatically more abundant than co-activators at the protein level, but not at the RNA level, with profound implications for understanding transcriptional regulation. These analyses provide a unique quantitative framework to understand transcriptional regulation of cell differentiation in a dynamic context.


Assuntos
Eritropoese/genética , Redes Reguladoras de Genes/genética , Fatores de Transcrição/genética , Bases de Dados Factuais , Regulação da Expressão Gênica/genética , Hematopoese/genética , Humanos , Proteômica/métodos , Fatores de Transcrição/análise , Fatores de Transcrição/metabolismo
12.
DNA Cell Biol ; 39(5): 756-765, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32282232

RESUMO

Iron-sulfur (Fe-S) clusters are required for mitochondrial function. Fe-S cluster synthesis occurs in the mitochondria and iron uptake is required for mitochondrial biogenesis. However, Fe-S clusters inhibit the expression of the iron importer transferrin receptor 1 (TfR1), whereas lack of the Fe-S cluster stimulates TfR1 expression. Yet, it is unclear whether Fe-S cluster synthesis increases with mitochondria biogenesis and, in turn, whether this negatively modulates TfR1 expression. We manipulated peroxisome proliferator-activated receptor-gamma coactivator-1α expression to control mitochondrial biogenesis in a variety of cell types, including erythroid cells. We demonstrated that Fe-S cluster synthesis increases with mitochondria biogenesis but does not interfere with increasing TfR1 expression. In fact, TfR1 expression is stimulated through alternative means to meet iron requirement for mitochondria biogenesis. Furthermore, under enhanced mitochondria biogenesis, increased Fe-S cluster synthesis inhibits the function of iron-regulating protein (IRP)1 and hence stimulates the expression of 5'-aminolevulinate synthase 2 (ALAS2), a target of IRP1 and rate-limiting enzyme in erythroid heme biogenesis. Increased ALAS2 expression leads to enhanced heme production, hemoglobinization, and erythropoiesis. Therefore, our study also provides a mechanism to link mitochondrial biogenesis with erythropoiesis and has a potential therapeutic value in the treatment of blood disorders.


Assuntos
Ferro/metabolismo , Biogênese de Organelas , Enxofre/metabolismo , Células 3T3-L1 , 5-Aminolevulinato Sintetase/genética , Animais , Transporte Biológico/efeitos dos fármacos , Células Eritroides/citologia , Células Eritroides/metabolismo , Eritropoese/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme/biossíntese , Hemoglobinas/metabolismo , Humanos , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/farmacologia
13.
PLoS One ; 15(4): e0231830, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302352

RESUMO

Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO (rhEPO) or a long-acting erythropoiesis-activating agent named darbepoetin alfa, which is a modified rhEPO with a carbohydrate chain structure that differs from native hEPO. We have developed a biosimilar to darbepoetin alfa designated JR-131. Here, we comprehensively compare the physicochemical and biological characteristics of JR-131 to darbepoetin alfa. JR-131 demonstrated similar protein structure to the originator, darbepoetin alfa, by peptide mapping and circular dichroism spectroscopy. Additionally, mass spectroscopic analyses and capillary zone electrophoresis revealed similar glycosylation patterns between the two products. Human bone marrow-derived erythroblasts differentiated and proliferated to form colonies with JR-131 to a similar degree as darbepoetin alfa. Finally, JR-131 stimulated erythropoiesis and improved anemia in rats similarly to darbepoetin alfa. Our data show the similarity in physicochemical and biological properties of JR-131 to those of darbepoetin alfa, and JR-131 therefore represents a biosimilar for use in the treatment of renal anemia.


Assuntos
Medicamentos Biossimilares/farmacologia , Darbepoetina alfa/farmacologia , Eritropoese/efeitos dos fármacos , Anemia/tratamento farmacológico , Animais , Células CHO , Cricetinae , Cricetulus , Darbepoetina alfa/química , Modelos Animais de Doenças , Eletroforese Capilar , Glicosilação/efeitos dos fármacos , Rim/patologia , Masculino , Peso Molecular , Nefrectomia , Mapeamento de Peptídeos , Estrutura Secundária de Proteína , Ratos Sprague-Dawley , Açúcares/análise , Resultado do Tratamento
14.
DNA Cell Biol ; 39(4): 548-554, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32155344

RESUMO

The Qing-Tibet Plateau is characterized by low oxygen pressure, which is an important biomedical and ecological stressor. However, the variation in gene expression during periods of stay on the plateau has not been well studied. We recruited eight volunteers to stay on the plateau for 3, 7, and 30 days. Human Clariom D arrays were used to measure transcriptome changes in the mRNA expression profiles in these volunteers' blood. Analysis of variance (ANOVA) indicated that 699 genes were significantly differentially expressed in response to entering the plateau during hypoxic exposure. The genes with changes in transcript abundance were involved in the terms phosphoprotein, acetylation, protein binding, and protein transport. Furthermore, numerous genes involved in hematopoietic functions, including erythropoiesis and immunoregulation, were differentially expressed in response to hypoxia. This phenomenon may be one of reasons why the majority of people entering the plateau do not have excessive erythrocyte proliferation and are susceptible to infection.


Assuntos
Aclimatação/genética , Doença da Altitude/genética , Doença da Altitude/fisiopatologia , Hipóxia/fisiopatologia , Leucócitos/fisiologia , Altitude , Eritrócitos/citologia , Eritropoese/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Humanos , Leucopoese/genética , Masculino , Oxigênio , Tibet
15.
Mol Cell ; 78(2): 317-328.e6, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32191872

RESUMO

MicroRNAs (miRNAs) are sequentially processed by two RNase III enzymes, Drosha and Dicer. miR-451 is the only known miRNA whose processing bypasses Dicer and instead relies on the slicer activity of Argonaute-2 (Ago2). miR-451 is highly conserved in vertebrates and regulates erythrocyte maturation, where it becomes the most abundant miRNA. However, the basis for the non-canonical biogenesis of miR-451 is unclear. Here, we show that Ago2 is less efficient than Dicer in processing pre-miRNAs, but this deficit is overcome when miR-144 represses Dicer in a negative-feedback loop during erythropoiesis. Loss of miR-144-mediated Dicer repression in zebrafish embryos and human cells leads to increased canonical miRNA production and impaired miR-451 maturation. Overexpression of Ago2 rescues some of the defects of miR-451 processing. Thus, the evolution of Ago2-dependent processing allows miR-451 to circumvent the global repression of canonical miRNAs elicited, in part, by the miR-144 targeting of Dicer during erythropoiesis.


Assuntos
Proteínas Argonauta/genética , Eritropoese/genética , MicroRNAs/genética , Animais , RNA Helicases DEAD-box/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Interferência de RNA , Ribonuclease III/genética , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
16.
Thorax ; 75(6): 494-502, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32217779

RESUMO

BACKGROUND: Although erythropoiesis is impaired and anaemia frequent in neonates born preterm, haematopoiesis in adults born preterm has not been previously studied. OBJECTIVE: We, thus, aimed to evaluate haemoglobin and erythropoietin levels in young adults born preterm, to identify neonatal events associated with erythropoiesis in adulthood and to examine the relationships of haemoglobin levels with respiratory function and blood pressure. METHODS: We assessed a cohort of 101 young adults (ages 18-29) born preterm (≤29 weeks of gestation), in comparison to 105 full-term controls. We measured haemoglobin, erythropoietin levels and blood pressure. We also assessed respiratory function using spirometry. RESULTS: Compared with controls, tobacco use and sex-adjusted haemoglobin levels were 5.3 (95% CI 2.9 to 7.7) g/L higher in preterm-born individuals, but erythropoietin levels were similar. Duration of oxygen supplementation in the neonatal period was independently associated with higher haemoglobin levels in the preterm group. In young adults born preterm with bronchopulmonary dysplasia, airflow limitation was associated with higher haemoglobin levels. Both systolic (SBP) and diastolic (DBP) blood pressure were increased in individuals born preterm (p=0.042 and p=0.0008, respectively). Higher haemoglobin levels were associated with higher SBP and DBP, independently of term or preterm status. Mediation analysis suggests that haemoglobin increase contributes to 37% and 32% of the effect of preterm birth on SBP and DBP, respectively. CONCLUSIONS: Haemoglobin levels are higher in young adults born preterm, while erythropoietin levels are similar, especially in case of bronchopulmonary dysplasia and airflow limitation, and haemoglobin increase is associated with elevated blood pressure in this population.


Assuntos
Eritropoese , Hipertensão/fisiopatologia , Oxigenoterapia , Nascimento Prematuro/fisiopatologia , Adolescente , Adulto , Displasia Broncopulmonar/fisiopatologia , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Testes de Função Respiratória , Fatores de Risco
17.
Klin Lab Diagn ; 65(3): 169-173, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32163691

RESUMO

A study of the main indicators of red blood (RBC, HGB, HCT, MCV, MCH) and the concentration of EPO, sTfR in 9 cancer patients with anemic syndrome (AS) against sepsis was carried out. Among them, patients with chronic disease anemia (ACh), with normocytic, normochromic characteristics of red blood cells and low hematocrit predominated. In 2 patients, microcytosis and erythrocyte hypochromia were noted, the concentration of sTfR was significantly higher than normal (0.9 ± 0.07 µg / ml), amounted to 2.7 µg / ml in one of them and 1.9 µg / ml in the other, which testified to t iron deficiency erythropoiesis (IDE) on the background of the ACh,. In 7 patients with ACh without IDE, sTfR values were within the normal range (0.1-1.2) µg / ml, the median was 0.5 µg/ml. In all patients with sepsis, the production of EPO was inadequate for the severity of the AS, to a lesser extent in patients with IDE. The average EPO production in the group was 19.4 ± 5.1 (7.7-52.8) mU / ml, median = 12.1 mE / ml. Further studies of EPO, sTfR are planned in order to determine their role in therapeutic tactics in the correction of AS in cancer patients with sepsis.


Assuntos
Anemia/diagnóstico , Neoplasias/complicações , Sepse/complicações , Anemia/complicações , Eritropoese , Hematócrito , Humanos
18.
Am J Physiol Renal Physiol ; 318(4): F861-F869, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003597

RESUMO

Serum soluble Fas (sFas) levels are associated with erythropoietin (Epo) hyporesponsiveness in patients with chronic kidney disease (CKD). Whether sFas could predict the need for erythropoiesis-stimulating agent (ESA) usage and its influence in erythropoiesis remain unclear. We evaluated the relation between sFas and ESA therapy in patients with CKD with anemia and its effect on erythropoiesis in vitro. First, we performed a retrospective cohort study with 77 anemic patients with nondialysis CKD. We performed in vitro experiments to investigate whether sFas could interfere with the behavior of hematopoietic stem cells (HSCs). HSCs were isolated from umbilical cord blood and incubated with recombinant sFas protein in a dose-dependent manner. Serum sFas positively correlated with Epo levels (r = 0.30, P = 0.001) but negatively with hemoglobin (r = -0.55, P < 0.001) and glomerular filtration rate (r = -0.58, P < 0.001) in patients with CKD at baseline. Elevated sFas serum levels (4,316 ± 897 vs. 2,776 ± 749, P < 0.001) with lower estimated glomerular filtration rate (26.2 ± 10.1 vs. 33.5 ± 14.3, P = 0.01) and reduced hemoglobin concentration (11.1 ± 0.9 vs. 12.5 ± 1.2, P < 0.001) were identified in patients who required ESA therapy compared with patients with non-ESA. Afterward, we detected that the sFas level was slight correlated with a necessity of ESA therapy in patients with nondialysis CKD and anemia. In vitro assays demonstrated that the erythroid progenitor cell frequency negatively correlated with sFas concentration (r = -0.72, P < 0.001). There was decreased erythroid colony formation in vitro when CD34+ HSCs were incubated with a higher concentration of sFas protein (1.56 ± 0.29, 4.33 ± 0.53, P < 0.001). Our findings suggest that sFas is a potential predictor for ESA therapy in patients with nondialysis CKD and that elevated sFas could affect erythropoiesis in vitro.


Assuntos
Anemia/sangue , Eritropoese , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Multipotentes/metabolismo , Insuficiência Renal Crônica/complicações , Receptor fas/sangue , Adulto , Idoso , Anemia/diagnóstico , Anemia/tratamento farmacológico , Anemia/etiologia , Biomarcadores/sangue , Brasil , Células Cultivadas , Tomada de Decisão Clínica , Bases de Dados Factuais , Eritropoese/efeitos dos fármacos , Eritropoetina/sangue , Feminino , Hematínicos/uso terapêutico , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/efeitos dos fármacos , North Carolina , Seleção de Pacientes , Valor Preditivo dos Testes , Proteínas Recombinantes/farmacologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Estudos Retrospectivos
19.
Adv Exp Med Biol ; 1223: 17-30, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030683

RESUMO

Erythropoietin (EPO), the primary cytokine of erythropoiesis, stimulates both proliferation and differentiation of erythroid progenitors and their maturation to red blood cells. Basal EPO levels maintain the optimum levels of circulating red blood cells. However, during hypoxia, EPO secretion and its expression is elevated drastically in renal interstitial fibroblasts, thereby increasing the number of erythroid progenitors and accelerating their differentiation to mature erythrocytes. A tight regulation of this pathway is therefore of paramount importance. The biological response to EPO is commenced through the involvement of its cognate receptor, EPOR. The receptor-ligand complex results in homodimerization and conformational changes, which trigger downstream signaling events and cause activation or inactivation of critical transcription factors that promote erythroid expansion. In recent years, recombinant human EPO (rEPO) has been widely used as a therapeutic tool to treat a number of anemias induced by infection, and chemotherapy for various cancers. However, several studies have uncovered a tumor promoting ability of EPO in man, which likely occurs through EPOR or alternative receptor(s). On the other hand, some studies have demonstrated a strong anticancer activity of EPO, although the mechanism still remains unclear. A thorough investigation of EPOR signaling could yield enhanced understanding of the pathobiology for a variety of disorders, as well as the potential novel therapeutic strategies. In this chapter, in addition to the clinical relevance of EPO/EPOR signaling, we review its anticancer efficacy within various tumor microenvironments.


Assuntos
Eritropoetina/metabolismo , Saúde , Neoplasias/metabolismo , Receptores da Eritropoetina/metabolismo , Transdução de Sinais , Microambiente Tumoral , Eritropoese , Humanos
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