Defect In Hemoglobin Synthesis Research Articles

BACH1 regulates erythrophagocytosis and iron-recycling in β-thalassemia.

Macrophages play essential roles in erythrophagocytosis and iron recycling. β-thalassemia is characterized by a genetic defect in hemoglobin synthesis, which increases the rate of iron recycling. We previously showed that reduced expression of the BTB and CNC homolog 1 (BACH1) gene leads to increased phagocytosis of abnormal RBCs by activated monocytes. However, the mechanisms underlying this abnormal RBC clearance remained unclear. Herein, the spleen and bone marrow cells of β-thalassemic mice were examined for erythrophagocytosis CD markers and iron-recycling genes. Higher expression levels of CD47 and CD163 on RBCs and macrophages, respectively, were observed in β-thalassemic mice than in wild-type cells. The decreased expression of BACH1 caused an increase in Nrf2, Spic, Slc40a1, and HMOX1 expression in splenic red pulp macrophages of thalassemic mice. To investigate BACH1 regulation, a macrophage cell line was transfected with BACH1-siRNA. Decreased BACH1 expression caused an increase in CD163 expression; however, the expression levels were lower when the cells were cultured in media supplemented with β-thalassemia/HbE patient plasma. Additionally, the iron recycling-related genes SPIC, SLC40A1, and HMOX1 were significantly upregulated in BACH1-suppressed macrophages. Our findings provide insights into BACH1 regulation, which plays an important role in erythrophagocytosis and iron recycling in thalassemic macrophages.

Mechanisms Involved in the Increased Hemolysis in the Fetus and Newborn.

The suicidal death of erythrocytes should be considered a possible cause of hemolysis and plasma bilirubin overload when there is no evidence of an immune-mediated hemolytic anemia, no consumptive red blood cell disorder, no morphologic or laboratory data to suggest a problem of the red cell membrane, and no evidence of a quantitative or qualitative defect in hemoglobin synthesis. In neonatal period, xenobiotics, cytokines, osmotic shock, energy depletion, oxidative stress, and variation of temperature may induce an alteration of balance between damaging and protecting factors which can be followed by red cell death. The intraerythrocyte redox balance plays a pivotal role in orchestrating the complex molecular mechanisms leading to eryptosis. Neonatal erythrocytes are a target of extracellular free radicals and, at the same time, are themselves generators of free radicals through the Fenton reaction. This review clarifies the complex mechanisms underlying the susceptibility of neonatal erythrocytes to increased oxidative stress.

Enzyme Activities in Erythrocytes of Term and Preterm Newborns

The decrease of erythrocyte antioxidant enzyme activity should be considered as a possible cause of hemolysis when there is no evidence of an immune-mediated hemolytic anemia, no consumptive red blood cell disorder, no morphologic or laboratory data to suggest a problem of the red cell membrane, and no evidence of a quantitative or qualitative defect in hemoglobin synthesis. Glutatione has a pilot role in orchestrating the redox balance when there is an excess reactive oxygen species production or defective antioxidant defenses that may have deleterious consequences in various perinatal diseases. Neonatal erythrocytes are a target of extracellular free radicals and in the same time generators of free radicals through Fenton reaction. The complex mechanism underlying the increased oxidative stress susceptibility of neonatal erythrocytes requires further investigation.

Biological index of environmental lead pollution: accumulation of lead in liver and kidney in mice.

Lead (Pb) is known to be highly poisonous, and the acute poisoning of Cd causes the abdominal pains, vomiting, and shock. The digestive and nervous symptom is observed in the chronic lead poisoning. It was also known that the defect in hemoglobin synthesis by Pb produce anemia. The release of Pb into the environment presents a source of exposure for wild animals. In this study, we examined the utility of a new Pb-monitoring index in mice administered Pb. A solution containing 0.02, 0.2, 2, or 4ppm lead chloride (PbCl2) was administered intraperitoneally to mice, and the Pb contents of the kidney and liver were determined at designated time points. The mean Pb content of both organs increased depending on the administered Pb dosage. Although the results of control was near the detection limits, the administration of 4ppm in 4weeks resulted in Pb levels of 260mgppm/wet weight and 110ppm wet weight in the kidney and liver, respectively. However, there were no significant relationships among administered dose, duration of Pb treatment, and liver or kidney Pb content. Then, values in all mice administered control or 0.02mg Pb were located inside the ellipse, representing the confidence area of the new index, and values in all mice administered more than 2mg Pb were located outside the ellipse. These results confirm that animals exposed to high concentrations of Pb would be detected by this new index.

P18.19: Prenatal diagnosis and treatment of alpha‐thalassemia major

A 39-year-old Vietnamese woman was referred for fetal echocardiography at 23 weeks of gestation due to cardiomegaly. Heart to chest area ratio was 0.57. There was holosystolic regurgitation of the TRV, hyperdynamic circulation (MCA PSV 70 cm/s - 2.08 MoM), inconsiderable ascites and hepatomegaly. Fetal anemia was suspected. Fetal blood sampling confirmed anemia with elevated erythroblasts: Hb - 6.3 g/dL, RBC - 2.6 × 106/uL, Hct - 27%, MCV - 101 fL, MCH - 24 pg, WBC - 82 × 103/uL. Intrauterine transfusion of 60 ml packed red cells was performed. The supportive therapy with digoxin was introduced. Alloimmunisation, infection and fetomaternal hemorrhage were excluded. An increase in the MCA PSV to 1.6 MoM was diagnosed again at 30 weeks. At the second cordocentesis Hb was 9.2 g/dL, RBC - 4.1 × 106/uL, Hct -34%, WBC −47 × 103/uL. The unexpected recurrence of anemia 7 weeks after transfusion raised the suspicion of a congenital defect in hemoglobin synthesis. Alpha-thalassemia major, the most common reason of fetal anemia and hydrops in people of Asian origin, was suspected. The next transfusion was not performed due to non-reassuring fetal heart rate pattern. The female neonate (1590 g, Apgar score 4-8-9) was delivered three days later due to threatening asphyxia. The diagnosis of HbBart's hydrops fetalis (SEA/SEA) was confirmed using molecular techniques. The infant is 10 months old now and requires repeated blood transfusions. Supporting information can be found in the online version of this abstract Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Bone Marrow Mesenchymal Stem Cells in Patients with Beta Thalassemia Major: Molecular Analysis with Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy Study as a Novel Method

Bone marrow mesenchymal stem cells (BM-MSCs) are the main cellular components of the bone marrow, providing a supportive cellular microenvironment to maintain healthy hematopoiesis. β-thalassemia major (β-TM) is characterized by anemia that is caused by a genetic defect in hemoglobin synthesis and results in ineffective erythropoiesis (IE). The alterations in the microenvironment in thalassemic bone marrow during IE can cause changes in BM-MSCs. This study aimed to investigate global structural and compositional changes in BM-MSCs in β-TM that may provide a basis in understanding interactions of hematopoietic stem cells (HSCs)-MSCs in such a pathological bone marrow microenvironment. Following characterization of morphological, immunophenotypical, and differentiation properties, the changes in healthy and thalassemic BM-MSCs before and after bone marrow transplantation (BMT) were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR). The significant increase in lipid, protein, glycogen, and nucleic acid contents in thalassemic BM-MSCs with respect to healthy BM-MSCs was attributed to enhanced cell proliferation and BM activity during IE. The significant decreases in the content of mentioned macromolecules in post-transplant group BM-MSCs versus pre-transplant BM-MSCs was interpreted as restoring effect of BMT therapy on IE and defective BM microenvironment. These alterations were also supported by ELISA results of erythropoietin (EPO) and growth differentiation factor (GDF15) in bone marrow plasma samples as a reflection of IE and by MTT proliferation assay on BM-MSCs. Based on these changes, sampling groups were discriminated by cluster analysis. These results provide information for the studies that concentrate on interactions between HSCs-MSCs in bone marrow.

The Impact of Linus Pauling on Modern Medicine and Society

Abstract Linus Pauling (1901-1994) is one of the most distinguished scientists of modern times. During a career spanning over 60 years, he was awarded two unshared Nobel Prizes (chemistry, 1954; peace, 1962). He published more than 600 scientific articles and books. This article reviews the literature pertaining to Pauling's discoveries and their impact on science, medicine, and society. He was the first to describe the alpha-helix structure of protein molecules. The lineage of the double-helix model for deoxyribonucleic acid (DNA) can be traced back to his concept of complementarity and the alpha helix. Pauling also related the mechanism of sickle-cell anemia to a genetic defect in hemoglobin synthesis, and thus defined the first molecular disease. Furthermore, Pauling espoused the virtues of vitamin C, which brought him both fame and criticism. During the Second World War, Pauling was involved in over 18 military projects for which he received the Presidential Medal for outstanding contribution to the war effort. Later, he made many speeches for world peace, for prohibition of nuclear warfare and nuclear weapons, and for a nuclear test ban treaty. This review is a tribute to a humanitarian and scientist who performed groundbreaking chemistry research, struggled against disease, and crusaded for world peace.

Impaired erythrocyte NAD synthesis: a metabolic abnormality in thalassemia.

We have recently demonstrated that phosphoribosylpyrophosphate (PRPP) synthetase activity is decreased in RBC from individuals with thalassemia minor. Because NAD biosynthesis requires PRPP, the product of the PRPP synthetase reaction, we have investigated NAD synthesis in thalassemic RBC. NAD synthesis was measured in intact RBC both by following the accumulation of unlabeled NAD and by following the incorporation of 14C-nicotinic acid into NAD. Using both assay systems, we demonstrate that NAD synthesis is decreased significantly in thalassemic RBC compared to either normal or high reticulocyte red cells. Although this suggested that NAD content should be decreased in thalassemic RBC, no significant difference in NAD content was found among thalassemic, normal, or high reticulocyte red cells. Mechanisms for the lack of a significant decrease in NAD content in thalassemic RBC are discussed. These results indicate that NAD synthesis is impaired in thalassemic RBC possibly as a result of their decrease in PRPP synthetase activity. Our data provide evidence that thalassemic RBC have secondary metabolic abnormalities in addition to their primary defect in hemoglobin synthesis.

Relationship of Mitochondrial Membrane Potential to Hemoglobin Synthesis During Friend Cell Maturation

Abstract Previous studies have shown that exposure to imidazole dissociates hemoglobin synthesis from other aspects of cell maturation in dimethylsulfoxide (DMSO)-treated mouse erythroleukemia (MEL) cells. In the present study, we have found that imidazole causes hyperpolarization of the mitochondrial membrane in MEL cells exposed to DMSO, in contrast to the depolarization observed with DMSO alone. Like the defect in hemoglobin synthesis, membrane hyperpolarization is reversible upon removal of imidazole and incubation of cells with DMSO alone. These correlations suggest that alterations in the electrostatic properties of the mitochondrial membrane, due directly or indirectly to the effects of imidazole, interfere with heme synthesis but not with other aspects of the maturation process in these developing erythroid cells.

Relationship of mitochondrial membrane potential to hemoglobin synthesis during Friend cell maturation

Previous studies have shown that exposure to imidazole dissociates hemoglobin synthesis from other aspects of cell maturation in dimethylsulfoxide (DMSO)-treated mouse erythroleukemia (MEL) cells. In the present study, we have found that imidazole causes hyperpolarization of the mitochondrial membrane in MEL cells exposed to DMSO, in contrast to the depolarization observed with DMSO alone. Like the defect in hemoglobin synthesis, membrane hyperpolarization is reversible upon removal of imidazole and incubation of cells with DMSO alone. These correlations suggest that alterations in the electrostatic properties of the mitochondrial membrane, due directly or indirectly to the effects of imidazole, interfere with heme synthesis but not with other aspects of the maturation process in these developing erythroid cells.

A Screening Test for Assessing Iron Status

Intervention strategies to combat iron deficiency anemia in developing countries may hasten the development of iron overload in patients with an inherited defect in hemoglobin synthesis. This risk could be diminished if there was a rapid and simple method available for detecting iron overload in population screening programs. We have developed such a method, which is in effect a semiquantitative ferritin measurement based on a modification of a two-site enzyme-linked immunoassay. The assay requires only 2 drops of whole blood and a total incubation time of 90 min. The procedure, which can readily distinguish iron deficiency from even a modest increase in storage iron, has a potentially wide application in settings where a prompt assessment of iron status is required.

A screening test for assessing iron status

Intervention strategies to combat iron deficiency anemia in developing countries may hasten the development of iron overload in patients with an inherited defect in hemoglobin synthesis. This risk could be diminished if there was a rapid and simple method available for detecting iron overload in population screening programs. We have developed such a method, which is in effect a semiquantitative ferritin measurement based on a modification of a two-site enzyme-linked immunoassay. The assay requires only 2 drops of whole blood and a total incubation time of 90 min. The procedure, which can readily distinguish iron deficiency from even a modest increase in storage iron, has a potentially wide application in settings where a prompt assessment of iron status is required.

Erythrocyte Enzyme Disorders in Children

Erythrocyte metabolic abnormalities should be considered as a possible cause of hemolysis when there is no evidence of an immune-mediated hemolytic anemia, no consumptive red blood cell disorder, no morophologic or laboratory data to suggest a problem of the red cell membrane, and no evidence of a quantitative or qualitative defect in hemoglobin synthesis. Glucose-6-phosphate dehydrogenase deficiency is clearly the most common enzyme deficiency causing clinical problems.

Defect in hemoglobin synthesis possibly due to a disturbed association

FEBS LettersVolume 45, Issue 1-2 p. 252-255 Full-length articleFree Access Defect in hemoglobin synthesis possibly due to a disturbed association Josée Pagnier, Josée Pagnier Institut de Pathologie Moléculaire 1 Groupe U 15 de l'Institut National de la Santé et de la Recherche Médicale, Laboratoire Associé au Centre National de la Recherche Scientifique.24, rue du faubourg Saint-Jacques, 75014 Paris, FranceSearch for more papers by this authorHenri Wajcman, Henri Wajcman Institut de Pathologie Moléculaire 1 Groupe U 15 de l'Institut National de la Santé et de la Recherche Médicale, Laboratoire Associé au Centre National de la Recherche Scientifique.24, rue du faubourg Saint-Jacques, 75014 Paris, FranceSearch for more papers by this authorAominique Labie, Aominique Labie Institut de Pathologie Moléculaire 1 Groupe U 15 de l'Institut National de la Santé et de la Recherche Médicale, Laboratoire Associé au Centre National de la Recherche Scientifique.24, rue du faubourg Saint-Jacques, 75014 Paris, FranceSearch for more papers by this author Josée Pagnier, Josée Pagnier Institut de Pathologie Moléculaire 1 Groupe U 15 de l'Institut National de la Santé et de la Recherche Médicale, Laboratoire Associé au Centre National de la Recherche Scientifique.24, rue du faubourg Saint-Jacques, 75014 Paris, FranceSearch for more papers by this authorHenri Wajcman, Henri Wajcman Institut de Pathologie Moléculaire 1 Groupe U 15 de l'Institut National de la Santé et de la Recherche Médicale, Laboratoire Associé au Centre National de la Recherche Scientifique.24, rue du faubourg Saint-Jacques, 75014 Paris, FranceSearch for more papers by this authorAominique Labie, Aominique Labie Institut de Pathologie Moléculaire 1 Groupe U 15 de l'Institut National de la Santé et de la Recherche Médicale, Laboratoire Associé au Centre National de la Recherche Scientifique.24, rue du faubourg Saint-Jacques, 75014 Paris, FranceSearch for more papers by this author First published: September 01, 1974 https://doi.org/10.1016/0014-5793(74)80855-0Citations: 8 Groupe U 15 de l'Institut National de la Santé et de la Recherche Médicale, Laboratoire Associé au Centre National de la Recherche Scientifique. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume45, Issue1-2September 01, 1974Pages 252-255 ReferencesRelatedInformation

Erythrocyte Free Globin Levels in Some Anemic States

SummaryThe erythrocyte free globin level was determined in a variety of anemic states. Low free globin levels were found in homozygous β-thalassemia, sickle cell disease and iron-deficiency anemia, even though in these conditions hemoglobin synthesis is decreased for different reasons. Normal amounts of free globin were observed in various other anemias not characterized by a primary defect in hemoglobin synthesis. Therefore, a remarkable degree of coordination exists between globin synthesis and either iron supply or protoporphyrin production. Because of this it is not possible to obtain information about the nature of a defect in hemoglobin synthesis by the amount of free globin present.

Iron-Laden Mitochondria in Reticulum Cells of Hypersiderotic Human Bone Marrows

Abstract Iron-laden mitochondria were observed in three cases of primary nonhereditary sideroblastic anemia. The cells involved are considered to be a peculiar type of reticulum cell, possibly with erythropoietic potentiality. This feature and the rare presence of iron in mitochondria of reticulum cells which are clearly identifiable as macrophages suggest that an enzymatic defect in hemoglobin synthesis may account for the majority, but probably not all instances, of iron-laden mitochondria.

Erythrocyte δ-aminolevulinic acid dehydrase activity in thalassemia major and sickle-cell anemia

An enzyme deficiency has been postulated to account for the defect in hemoglobin synthesis in certain hereditary anemias. The enzyme necessary for the conversion of δ-aminolevulinic acid to porphobilinogen, an obligatory step in heme synthesis, was assayed. The values obtained from the circulating erythrocyte of patients with thalassemia and sickle-cell anemia were higher than normal.

Hemoglobin metabolism in thalassemia: In vivo studies

1. 1. C 14-labeling of heme and globin was measured in three patients with thalassemia major and in two normal subjects after the oral administration of 100 μc. of glycine-2-C 14. The labeling of stercobilin also was measured in one patient with thalassemia. 2. 2. In the patients with thalassemia, the apparent utilization of glycine for hemoglobin synthesis was decreased, and the appearance of radioactivity in circulating hemoglobin was relatively delayed. In contrast, radioactivity appeared extremely rapidly in the fecal stercobilin, reaching a maximum on the third day, when it was over 100 times greater than the maximum radioactivity found in heme. 3. 3. The 50 per cent red cell survival was estimated in two patients with thalassemia as thirty-six and twenty-eight days, and in two normal subjects as 118 and 128 days. 4. 4. The relative labeling of heme and globin was expressed as the heme:globin ratio, which had a mean value of 0.784 in both normal subjects, and fell after the 100th day; it is suggested that the fall may be due to preferential reutilization of C 14 for globin synthesis. The ratio was significantly lower than normal in two of the three patients with thalassemia. 5. 5. These results are compatible with the concept that there is a defect in hemoglobin synthesis as well as an abnormality of erythrocyte production in thalassemia major. The enhanced early labeling of stercobilin implies an abnormal degree of premature destruction of red cells or hemoglobin within the bone marrow, or an anabolic pathway for the production of stercobilin. The basic abnormality would seem to be in the erythroblast, a genetic biochemical lesion, it is suggested, not yet identified.

Chronic Refractory Anemia with Sideroblastic Bone Marrow. A Study of Four Cases

Abstract Four cases of severe refractory anemia with an enormous increase of demonstrable free iron in the normoblasts are reported. Three cases were of unknown etiology and of benign course but in the fourth the anemia was probably related to rheumatoid arthritis or to the onset of myeloblastic leukemia. The significance of the sideroblastic bone marrow in these cases is discussed and the opinion expressed in the literature—that it indicates a defect in hemoglobin synthesis is subscribed to. Thus, it is believed that the anemia in these cases is due to degenerative changes in the bone marrow which also have some morphologic manifestations. The disturbance of marrow activity is probably best reflected in the reticulocyte counts.

Constitutional pathology of erythropoiesis

SummaryThe concept and definition of constitutional pathology. Genetic erythropathies such as constitutional spherocytosis, leptocytosis, ovalocytosis and drepanocytosis and their relation to hemolytic clinical syndromes are discussed. Sickle cell trait, sickle cell anemia, and sickle cell disease have to be distinguished as clinical manifestations of drepanocytosis. They represent a special variety of a « status degenerativus » (Bauer). Four genetic types of human hemoglobin have so far been identified that differ from each other by their molecular architecture and chemical reactivity. Several constitutional abnormalities of erythropoiesis other than those just mentioned are discussed: a hereditary defect in hemoglobin synthesis; erythroid multinuclearity; acanthocytosis; Fanconi's syndrome of hypoplasia and abiotrophy of the bone marrow as another variety of a status degenerativus.