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Hemoglobin ; 43(3): 155-161, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31379233


ß-Thalassemia (ß-thal), is an inherited blood disorder caused by reduced or absent synthesis of ß-globin chains leading to imbalance of globin chain synthesis. The clearance of ß-thalassemic abnormal red blood cells (RBCs) that result from excessive unbound α-globin is mainly achieved by activated monocytes. The phagocytic activity of ß-thal monocytes significantly increases when co-cultured with normal and ß-thal RBC individuals compare to that of normal monocytes co-cultured with normal RBCs. The present study indicates that microRNA (miR) plays a role in monocyte activation. In this study, we identified the higher miR-125b expression in CD14 marker-positive monocytic cells of ß-thal patients. Moreover, miR-125b expression levels positively correlate with the phagocytic activity of monocytes. Remarkably, miR-125b expression levels are negatively correlated with RBC count, hemoglobin (Hb) and hematocrit [or packed cell volume (PCV)], which are the indices for the severity of anemia. From these findings, our future studies will be to prove the hypothesis that miR-125b expression in activated monocytes may be a genetic modifier related to the severity of anemia in ß-thal patients.

Ann Hematol ; 98(9): 2045-2052, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31243572


Thalassemia has a high prevalence in Thailand. Oxidative damage to erythroid cells is known to be one of the major etiologies in thalassemia pathophysiology. Oxidative stress status of thalassemia is potentiated by the heme, nonheme iron, and free iron resulting from imbalanced globin synthesis. In addition, levels of antioxidant proteins are reduced in α-thalassemia and ß-thalassemia erythrocytes. However, the primary molecular mechanism for this phenotype remains unknown. Our study showed a high expression of miR-144 in ß- and α-thalassemia. An increased miR-144 expression leads to decreased expression of nuclear factor erythroid 2-related factor 2 (NRF2) target, especially in α-thalassemia. In α-thalassemia, miR-144 and NRF2 target are associated with glutathione level and anemia severity. To study the effect of miR-144 expression, the gain-loss of miR-144 expression was performed by miR inhibitor and mimic transfection in the erythroblastic cell line. This study reveals that miR-144 expression was upregulated, whereas NRF2 expression and glutathione levels were decreased in comparison with the untreated condition after miR mimic transfection, while the reduction of miR-144 expression contributed to the increased NRF2 expression and glutathione level compared with the untreated condition after miR inhibitor transfection. Moreover, miR-144 overexpression leads to significantly increased sensitivity to oxidative stress at indicated concentrations of hydrogen peroxide (H2O2) and rescued by miR-144 inhibitor. Taken together, our findings suggest that dysregulation of miR-144 may play a role in the reduced ability of erythrocyte to deal with oxidative stress and increased RBC hemolysis susceptibility especially in thalassemia.

Eritrócitos/metabolismo , MicroRNAs/biossíntese , Fator 2 Relacionado a NF-E2/biossíntese , Estresse Oxidativo , Regulação para Cima , Talassemia alfa/metabolismo , Talassemia beta/metabolismo , Eritrócitos/patologia , Feminino , Glutationa/biossíntese , Glutationa/genética , Hemólise , Humanos , Peróxido de Hidrogênio/metabolismo , Células K562 , Masculino , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Talassemia alfa/genética , Talassemia alfa/patologia , Talassemia beta/genética , Talassemia beta/patologia
Int J Hematol ; 106(5): 638-647, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28685309


Abnormal red blood cell (RBC) clearance in ß-thalassemia is triggered by activated monocytes. Recent reports indicate that miRNA (miR-) plays a role in monocyte activation. To study phagocytic function, we co-cultured monocytes of normal, non-splenectomized and splenectomized ß-thalassemia/HbE individuals with RBCs obtained from normal, non-splenectomized and splenectomized ß-thalassemia/HbE individuals. The phagocytic activity of ß-thalassemia/HbE monocytes co-cultured with ß-thalassemia/HbE RBCs was significantly higher than that of normal monocytes co-cultured with normal RBCs. Upregulation of monocyte miR-155 was observed in ß-thalassemia/HbE patients. Increased miR-155 was associated with reductions in BTB and CNC Homology1 (BACH1) target gene expression and increased phagocytic activity of ß-thalassemia/HbE monocytes. Taken together, these findings suggested that increased miR-155 expression in activated monocytes leads to enhanced phagocytic activity via BACH-1 regulation in ß-thalassemia/HbE. This provides novel insights into the phagocytic clearance of abnormal RBCs in ß-thalassemia/HbE.

Fatores de Transcrição de Zíper de Leucina Básica/biossíntese , Regulação da Expressão Gênica , Hemoglobina E , MicroRNAs/biossíntese , Monócitos/metabolismo , Fagocitose , Talassemia beta/metabolismo , Adolescente , Adulto , Fatores de Transcrição de Zíper de Leucina Básica/genética , Feminino , Humanos , Masculino , MicroRNAs/genética , Monócitos/patologia , Talassemia beta/genética , Talassemia beta/patologia
Haematologica ; 94(9): 1211-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19608680


BACKGROUND: beta-thalassemia occurs from the imbalanced globin chain synthesis due to the absence or inadequate beta-globin chain production. The excessive unbound alpha-globin chains precipitate in erythroid precursors and mature red blood cells leading to ineffective erythropoiesis and hemolysis. DESIGN AND METHODS: In vitro globin chain synthesis in reticulocytes from different types of thalassemic mice was performed. The effect of imbalanced globin chain synthesis was assessed from changes of red blood cell properties including increased numbers of red blood cells vesicles and apoptotic red blood cells, increased reactive oxygen species and decreased red blood cell survival. RESULTS: The alpha/beta-globin chain ratio in beta(IVSII-654)-thalassemic mice, 1.26+/-0.03, was significantly higher than that of wild type mice, 0.96+/-0.05. The thalassemic mice show abnormal hematologic data and defective red blood cell properties. These values were improved significantly in doubly heterozygous thalassemic mice harboring 4 copies of human beta(E)-globin transgene, with a more balanced globin chain synthesis, 0.92+/-0.05. Moreover, transgenic mice harboring 8 extra copies of the human beta(E)-globin transgene showed inversely imbalanced alpha/beta-globin synthesis ratio, 0.83+/-0.01, that resulted in a mild beta-thalassemia phenotype due to the excessive beta-globin chains. The degree of ineffective erythropoiesis also correlated with the degree of imbalanced globin chain synthesis. Bone marrow and splenic erythroid precursor cells of beta(IVSII-654)-thalassemic mice showed increased phosphatidylserine exposure in basophilic and polychromatophilic stages, which was restored to the normal level in doubly heterozygous mice. CONCLUSIONS: Imbalanced alpha/beta-globin chain as a consequence of either reduction or enhancement of beta-globin chain synthesis can cause abnormal red blood cell properties in mouse models.

Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , alfa-Globinas/biossíntese , Globinas beta/biossíntese , Talassemia beta/metabolismo , Talassemia beta/patologia , Animais , Sobrevivência Celular/genética , Humanos , Camundongos , Camundongos Mutantes , Espécies Reativas de Oxigênio/metabolismo , alfa-Globinas/genética , Globinas beta/genética