Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenylbutyrate has been shown recently to induce fetal hemoglobin (HbF) production in patients with sickle cell anemia and beta thalassemia. We have now examined related aromatic fatty acids in order to define the range of active structures and identify plausible mechanisms of action. Structure-function analysis revealed that for effective stimulation of HbF in erythroid precursors: (1) the ideal length for the aliphatic side chain is four carbons; (2) oxygen or sulfur substitutions in the carboxylic chain are allowed, as evidenced by the equal or increased activity of phenoxypropionate, benzylthioglycolate, and benzyloxyacetate compared with phenylbutyrate; and (3) blocking the carboxylate group by conversion to the amide form greatly reduces potency. Molecular analysis indicated that the prototype agent, phenylbutyrate, increases HbF production through transcriptional activation of the gamma-globin gene. The latter contains a butyrate responsive promoter known to up-regulate transcription in the presence of short-chain fatty acids of three to five carbons. To determine whether stimulation of an element in this promoter by phenylbutyrate and its analogues might contribute to their mechanism of action, we used a transient expression system involving K562 erythroleukemia cells transfected with a luciferase reporter gene driven by the minimum gamma-globin promoter. Transcriptional activation in this experimental system correlated well with the capacity of an aromatic fatty acid to increase HbF production in erythroid precursors (r = 0.94). Our studies identify potent analogues of phenylbutyrate for the treatment of beta-chain hemoglobinopathies, and suggest that stimulation of a butyrate responsive promoter may be responsible for their activity.
 ...
PMID:Transcriptional upregulation of gamma-globin by phenylbutyrate and analogous aromatic fatty acids. 893 30

We studied two members of an African American family with erythrocytosis. An abnormal hemoglobin variant with an electrophoretic pattern on cellulose acetate similar to Hb J was identified. The oxygen dissociation curve using whole blood was biphasic, dramatically left-shifted, and hyperbolic. Sequence analysis of DNA from the proband showed heterozygosity for a T-->A change at the first position of codon 145 in the beta-globin gene which results in the substitution of an asparagine residue for normal tyrosine. The second cycle of C-terminal amino acid sequence analysis of a mixture of alpha- and beta-globin chains showed tyrosine, aspartic acid, and small amounts of asparagine. Collectively, these results indicate the existence of a mutation at codon 145 of the beta-globin gene which encodes for asparagine instead of tyrosine, and that asparagine then undergoes a partial posttranslational deamidation to aspartic acid. This amino acid substitution corresponds to Hb Osler, which is a high oxygen affinity hemoglobin variant, initially described to be caused by a substitution of Tyr-->Asp at beta 145. Posttranslational amino acid modification may constitute an important component in the pathophysiology of hemoglobinopathies.
 ...
PMID:Hb Osler [beta 145(HC2)Tyr-->Asp] results from posttranslational modification. 910 Dec 80

To evaluate the degree of tissue hypoxia in patients with hemoglobinopathy H disease, whole blood oxygen affinity was estimated and analyzed in 33 patients. Twenty patients with iron deficiency anemia, matched for degree of anemia, served as controls. The results were as follows: Whole blood oxygen equilibrium curves of patients with HbH disease are biphasic because of a combination of the rectangular hyperbolic curve of HbH and the normal sigmoid curve of HbA and are shifted toward the left (P50 3.66 +/- 0.33 kPa). Patients with iron deficiency anemia have right-shifted oxygen equilibrium curves (P50 4.02 +/- 0.13 kPa) compared with normal. Oxygen release to the tissues in HbH disease is decreased (1.4 +/- 0.3 mmol/L) as compared with iron-deficient patients (1.6 +/- 0.2 mmol/L) with a similar degree of anemia. Red cell indices vary between the two groups. In patients with HbH disease the mean corpuscular hemoglobin concentration was 268 +/- 17 g/L as compared with 294 +/- 18 g/L in iron deficiency anemia. These findings indicate that whole blood oxygen affinity is a reliable index of tissue oxygenation in patients with hemoglobinopathy H.
 ...
PMID:Tissue oxygenation in patients with hemoglobinopathy H. 921 33

Dissociation curves for oxygen of dilute samples of human adult Hb-A were evaluated on this occasion, by using the Oximeter-539 WTW with its sensor, and a suitable spectrophotometer. At this purpose, Hb samples were desaturated in oxygen upon given experimental conditions, by bubbling pure nitrogen in them, and their re-oxigenation in air was followed, step by step, by multiple oximetries. In addition, all the spectrophotometric measurements of the saturation of Hb-O2%, corresponding to each individual oximetry, were carried out parallely but separately. Dilution of Hb-A was maintained at 0.1 mM in heme. The p50 at pH 7.3 was 4.435 +/- 0.299 Torr, with the n-value of 2.7 +/- 0.2; Bohr effect was -0.55 +/- 0.08, within a pH range between 6.8, 7.3 and 7.8, whereas chloride and DPG effects at pH 7.3 (the most useful value) were 0.42 +/- 0.44 and 0.453 +/- 0.0187 respectively. In conclusion, these results are similar to those obtained with automated procedures, upon comparable experimental conditions, but do not require expensive and sophisticated instruments. Such a technique could be very useful in the hemoglobinopathies, which are common in Italy, and it could be easily adapted to perform comparative studies on animal hemoglobins not far from human species.
 ...
PMID:Use of the Oximeter-539 WTW, equipped with a sensor Trioxmatic-300, for the functional analysis of dilute solutions of human Hb-A. 923 Jun 28

In order to investigate the tyrosine phosphorylation of band 3, we performed immunoblotting of intact red cells using anti-phosphotyrosine antibody of 21 patients with sickle cell disorders (11 SS, 5 Sbeta, 5 SC), 7 patients with beta thalassemias (5 beta thal intermedia, 2 deltabeta thal), 10 normal controls, and 1 patient with hereditary spherocytosis. They had not received transfusion for the last 4 months and all were clinically stable. Our results showed an increased tyrosine phosphorylation of two proteins, in the 100 and 80 kD regions, in sickle cell and beta-thalassemic red cells when compared to the normal controls and to the patient with hereditary spherocytosis. Immunoprecipitation of the lysed red cells with anti-band 3 antibody and immunoblotting with anti-phosphotyrosine antibody confirmed that the 100 kD tyrosine phosphorylated protein was band 3. In the sickle cell disease group, the band 3 tyrosine phosphorylation varied from 2- to 10-fold increase compared to control (x +/- SD; SS = 7.8- +/- 2.7-fold; SC = 3.8- +/- 1.3-fold; Sbeta = 5.2- +/- 2.0-fold). It was also higher in the beta-thalassemic group (beta-thal = 4.3- +/- 3.7-fold). There was no significant difference in tyrosine phosphorylation among the various groups tested, except when we compared the phosphorylation in intact red cells of patients with sickle cell anemia and hemoglobinopathy SC (U = 6, P < 0.02). The tyrosine phosphorylation of band 3 was increased in hemoglobinopathies even in the absence of high reticulocyte count. At least two mechanisms might be involved in the increased tyrosine phosphorylation of band 3 in these hemoglobin disorders, probably related to the endogenous reactive oxygen intermediates generated by the abnormal erythrocyte: an inhibition of protein tyrosine phosphatase activity or an activation of the protein tyrosine kinase p72syk.
 ...
PMID:Increased tyrosine phosphorylation of band 3 in hemoglobinopathies. 966 75

Patients with the nondeletion genotype of hemoglobinopathy H (HbH or beta4) disease have higher proportions of HbH and more severe tissue hypoxia than patients with the deletion genotype. Because these patients' red blood cells (RBCs) contain mainly two Hb species, HbH and HbA, the high proportion of HbA can be exploited by lowering its oxygen affinity; this would probably increase oxygen delivery to the RBCs and improve the patients' clinical phenotype. Allosteric effectors that induce a low-affinity Hb may be useful in this regard. We investigated the effect of a bezafibrate derivative, RSR-4, on the oxygen affinity of RBCs and purified hemolysates containing HbA and HbH. This allosteric effector crosses RBC membranes and binds reversibly to the alpha-chains of deoxy-Hb, decreasing hemoglobin oxygen affinity. The blood used was obtained from a patient with HbH disease (alphaTSaudi homozygote) whose HbH level was 33.5% as measured by high-performance liquid chromatography. Oxygen binding studies were performed in RBCs and purified hemolysates. RBCs incubated in the presence of 500 microM RSR-4 (2-[[[(3,5-dichloroanilino)-carbonyl]methyl]phenoxy]-2-methylpropi onic acid) in standard conditions (pH 7.4, 0.14 M NaCl, 37 degrees C) displayed an increase in their P50 value from 14.5 to 35.2 mm Hg. Oxygen binding studies in purified stripped hemolysates (pH 7.2, 0.1 M NaCl, 25 degrees C) showed that addition of both 500 microM RSR-4 and 1 mM of 2,3 diphosphoglycerate (DPG) led to an 11-fold decrease in oxygen affinity, whereas the addition of the natural effector DPG or RSR-4 alone produced a 2.7- and 5.7-fold decrease, respectively. In both cases, the oxygen equilibrium curves (OECs) were biphasic due to the presence of the noncooperative, high-oxygen-affinity HbH (beta4) component. After addition of RSR-4, the lower part of the OEC (corresponding to HbH) was not shifted compared with the upper part (corresponding to HbA). These results were confirmed by kinetic studies of CO recombination. Both experiments demonstrated that RSR-4 does not affect beta4 Hb. Our findings provide an experimental model for lowering the oxygen affinity of HbA in HbH-containing cells and suggest that the oxygen delivery capability of the latter would be thereby improved.
 ...
PMID:Synthesized allosteric effectors of the hemoglobin molecule: a possible mechanism for improved erythrocyte oxygen release capability in hemoglobinopathy H disease. 972 26

Two methods for the routine determination of blood hemoglobin oxygen affinity are described. Both methods use whole blood and do not require special equipment, tonometry, or special gas mixtures. The first method consists of a one-point determination of p 50, and requires only 200 muL to 400 muL of whole blood, therefore making it suitable for the pediatric population. The second method uses multiple points, thereby establishing both the shape and position of the hemoglobin oxygen equilibrium curve between 10 and 99% oxygen saturation. Interpretation of p 50 is discussed in relation to evaluation of patients with hemoglobinopathies and as a parameter in estimating availability of oxygen to the tissues.
 ...
PMID:Guidelines for routine measurement of blood hemoglobin oxygen affinity. IFCC Scientific Division, Committee on pH, Blood Gases, and Electrolytes. 1014 79

Sickle cell disease is an inherited hemoglobinopathy that develops from a genetic mutation and the production of a dysfunctional variant of hemoglobin. A number of physiological disturbances encountered during the perioperative period (blood loss, hypotension, acidosis, and hypoxia) may induce "sickling" of the biochemically altered hemoglobin, producing painful microvascular occlusion, hemolytic anemia, and impaired oxygen delivery. The only available curative therapy requires bone marrow transplantation. The purpose of this article is to review the pathophysiology of sickle cell disease and the pertinent preoperative, intraoperative, and postoperative care of patients with the disease.
 ...
PMID:Sickle cell disease: implications for perioperative care. 1074 92

Oxyhemoglobin dissociation curves measure the most important function of red blood cells - the affinity for oxygen and its delivery to the tissues. This function may be deranged in sickle cell anemia and some other hemoglobinopathies. An automated oxyhemoglobin dissociation curve analyzer constructed dissociation curves in 55 patients with hemoglobinopathies and in 24 control subjects while maintaining constant temperature and pH. Sigmoid curves were converted to rectilinear ones using the Hill equation. Oxygen affinity of red cells was assessed by calculation of P50 (the PO2 at which hemoglobin is half saturated). Results revealed separation of oxyhemoglobin dissociation Hill plots according to phenotype but with wide variability. Mean oxygen affinity of fetal hemoglobin was greatest, whereas that of sickle hemoglobin was least. Other hemoglobins were intermediate. A positive correlation between decreased oxygen affinity and carboxyhemoglobin confirmed the decreased oxygen affinity of sickle hemoglobin and decreased oxygen affinity and increased diphosphoglycerate in red cells. Hill plots are less sensitive discriminators of oxygen affinity than traditional sigmoid dissociation curves and offer no particular advantage. Serial studies in a subset of three sickle cell anemia patients treated conservatively suggest automated oxyhemoglobin dissociation curves may be useful in assessment of effectiveness of newer therapies of sickle cell anemia after refinement of the method and studies of larger populations.
 ...
PMID:Automated oxyhemoglobin dissociation curve construction to assess sickle cell anemia therapy. 1105 56

Blood from seven newborns, a 13-y-old, and seven adult family members with a suspected hemoglobinopathy because of unexplained cyanosis was obtained for analysis to determine Hb oxygen affinity and to characterize and quantify the Hb variants. Their oxygen saturation was 76 to 84%. The P(50) was 30.3 +/- 2.9 for the newborns and 32.5 +/- 2.6 mm Hg for their related adults. In the same order, the plasma erythropoietin was 7.4 +/- 2.9 and 15.9 +/- 3.7 mU/mL, whereas 2,3-diphosphoglycerate was 16.1. +/- 2.9 and 15.9 +/- 3.7 micromol/g Hb. In four of the newborns with increased P(50), the mother had a normal P(50) (27 mm Hg), which indicated a greater maternal oxygen affinity than the fetus with no adverse effects on the fetus. Genetic analysis of alpha-globin genes demonstrated a heterozygous mutation on the alpha2 gene [alpha94(G1)Asp-->His] for each of the newborns and their related adults. The same mutation was found on the alpha1 gene in an adolescent and her father. The mRNA measurements showed that the alpha2- to alpha1-globin mRNA mean ratio was 2.5, alpha2 mutant globin mRNA/total alpha2-globin mRNA was 45.0%, whereas the alpha1 mutant globin mRNA/total alpha1-globin mRNA was 37.8%. The level of alpha2 mutant globin/total alpha-globin was 27.3 +/- 1%, and alpha1 mutant globin/total alpha-globin was 23.8 +/- 1%. The percentage of synthesized alpha2 and alpha1 mutant globins was 27.5 +/- 2 and 26.1 +/- 1, respectively. The ratio of the alpha2/alpha1 mutant globins was 1.1, which corresponded to a ratio at the mRNA level of alpha2/alpha1 of 2.5 +/- 0.5, which suggested that there is a less efficient translation of the alpha2 mRNA than alpha1 mRNA. The reversal of the physiologic fetomaternal oxygen affinity had no effects on fetal development.
 ...
PMID:The biologic implications of a rare hemoglobin mutant that decreases oxygen affinity. 1113 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>