Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of heme, when added as the ferric chloride salt, hemin, on human erythroid cells grown in a two-phase liquid culture system were studied. When added together with erythropoietin, on initiation of the second phase of the culture, hemin greatly accelerated hemoglobin (Hb) accumulation in these cells. The effect was greater during their early stages of maturation, suggesting that heme availability is then a rate-limiting step for Hb synthesis. Hemin increased preferentially the production of fetal Hb (HbF) compared with adult Hb; this was associated with a selective twofold elevation in gamma-mRNA levels. Using succinylacetone, a potent inhibitor of heme synthesis, we showed that exogenously supplied hemin could be incorporated into the de novo formed Hb. Therefore, the mechanism of hemin action may be several fold, including effects on globin gene transcription and posttranslational events, eg, supplying the prosthetic group for Hb assembly. Hemin increased HbF of cells derived from patients with sickle cell anemia and beta-thalassemia as well as that of cells from normal donors. Moreover, when added in combination with other HbF-augmenting agents such as the cytotoxic drug, hydroxyurea, a synergistic effect was obtained, with considerably less cytotoxicity than with hydroxyurea alone. These results have clinical potential in light of the ameliorating effect that increased HbF has in patients with genetic diseases of the beta-globin chain and raise the possibility of combined treatment with hemin and other drugs now being used to treat these diseases.
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PMID:Hemin-induced acceleration of hemoglobin production in immature cultured erythroid cells: preferential enhancement of fetal hemoglobin. 753 86

We have investigated the interaction of clotrimazole (CLT) and related compounds with the erythroid Ca(2+)-activated K+ channel, a mediator of sickle cell dehydration. We measured K+ transport, membrane potential, and cell volume upon activation of this pathway in sickle erythrocytes. CLT blocked almost completely Ca(2+)-activated K+ transport in homozygous hemoglobin S cells, with IC50 values of 29 +/- 15 nM in isotonic 20 mM salt solution and 51 +/- 15 nM in normal saline (n = 3). The inhibition of K+ transport by CLT was caused by a specific interaction with the Ca(2+)-activated K+ channel of human red cells, since it displaced bound 125I-Charybdotoxin, a specific ligand of the Gardos channel, with an IC50 (12 +/- 4 nM in isotonic 20 mM) similar to the IC50 values for flux inhibition. When homozygous hemoglobin S cells were dehydrated by incubation in the presence of 100 microM CaCl2 and the ionophore A23187, or by exposure to cycles of oxygenation and deoxygenation, CLT effectively inhibited cell dehydration and K+ loss. The IC50 of CLT for inhibition of Ca(2+)-activated K+ transport in sickle cells is significantly lower than plasma concentrations of CLT achievable after nontoxic oral doses. We therefore propose that oral administration of CLT may prevent red cell dehydration in patients with sickle cell anemia.
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PMID:Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. 832 74

Erythrocytes resistant to standard lysing reagents are known to occur in sickle cell disease. These lyse-resistant erythrocytes can cause aberrant automated leucocyte counts and differentials. The ability of the Cell-Dyn 3500 automated haematology analyser to eliminate resistant erythrocytes and accurately count and differentiate leucocytes was evaluated. Samples were obtained from paediatric patients with sickle cell disease or haemoglobin SC disease. The Cell-Dyn 3500, using impedance and optical counting with a hypotonic salt "extended lyse mode', was compared to the Cell-Dyn 3000, an optical analyser that also uses a hypotonic salt lyse, the Cell-Dyn 400, a "hard detergent lyse' impedance counter, and a reference 400-cell manual white cell differential (National committee for Clinical Laboratory Standards [NCCLS] Approved Guideline H20-A). Seventy-five samples from patients with sickle cell disease or haemoglobin SC disease were evaluated for total leucocyte count, percentage of lymphocytes, percentage of neutrophils, and nucleated red blood cells (NRBC) flags. The Cell-Dyn 3500 correlated well with Cell-Dyn 400 leucocyte counts, with a correlation coefficient of 0.95. When compared to the manual differential, the correlation coefficient for lymphocytes was 0.93 and for neutrophils 0.95. The Cell-Dyn 3500 NRBC flag had a sensitivity of 47.7% and a specificity of 80.6%. The predictive value of a positive flag was 77.7%. The Cell-Dyn 3500's extended lyse mode clearly enhances the accuracy of leucocyte counts and differentials in patients with sickle cell disease.
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PMID:Evaluation of the automated leucocyte count and differential from the Cell-Dyn 3500 in sickle cell disease. 869 28

Pulmonary microvascular occlusion by abnormally adherent and/or nondeformable sickle red blood cells (SS cells) may contribute to the pathogenesis of acute chest syndrome of sickle cell disease. We hypothesized that regional alveolar hypoxia reduces SS cell deformability and, by causing regional vasoconstriction, slows regional perfusion, facilitating endothelial adhesion and mechanical entrapment of cells. In isolated rat lungs perfused at constant average flow with physiological salt solution, we separately ventilated the two lungs: one with 95% O2 and the other with 0, 2.5, 5, or 21% O2. We infused a bolus of 99mTc-labeled SS cells or normal human AA cells along with 113Sn-labeled 15-mu m microspheres as a perfusion marker, then sliced the lungs and counted 99mTc and 113Sn. Weight-normalized perfusion decreased with hypoxia (P < 0.02). Retention of AA cells (perfusion-normalized) averaged approximately 1% in lungs ventilated with 95% O2 and increased only twofold with 0% O2. In contrast, retention of SS cells averaged 3-fold higher than that of AA cells at 95 and 5% O2, 15-fold higher at 2.5% O2, and 25-fold higher at 0% O2 (P < 0.01). Histological examination demonstrated entrapment of individual SS cells in alveolar capillaries of hypoxic but not well-oxygenated lungs. Relief of hypoxia, but not increased perfusate flow, caused prompt efflux of most entrapped cells, which were primarily high-density (high mean corpuscular hemoglobin concentration) cells. Thus substantial retention of SS cells does not occur without hypoxia, but regional hypoxia and/or the resulting vasoconstriction causes extraordinary regional retention of dense SS cells, a phenomenon that appears to be due more to mechanical entrapment of nondeformable cells in capillaries than to endothelial adhesion.
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PMID:Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia. 892 95

Normal erythrocytes are under physiological conditions characterized by low cation and high anion conductance. However, in the case of sickle cell anemia the erythrocytes contain a modified haemoglobin, HbS, which under low oxygen tension gives rise to sickling. This condition is preceded by an increase in cation conductance, especially due to the Ca2+-activated K+-channels, leading to net-efflux of KCI and thereby decreased cellular volume, which is part of the pathological condition.A possible symptomatic treatment could be application of conductance blockers, targeting the Ca2+-activated K+-channel or the anion conductance in order to minimize the passive transport of ions and solvent. It has been argued, that due to the high anion conductance, solute loss depended at moderately increased cation conductances on the cation only. Consequently the Ca2+-activated K+-conductance should be the target for attempts to modify solute loss.It is shown that: knowledge of mean conductances (time averages) for pathways showing fluctuations are insufficient to predict the quantitative effect of conductance inhibitors, since inhibition is strongly dependent on the kinetics of the mechanisms mediating the translocation and a block of the high conductance anion pathway can be as effective as inhibition of the Ca+-activated K+-conductance with regard to net salt loss.
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PMID:The feasibility of pharmacological volume control of sickle cells is dependent on the quantization of the transport pathways. A model study. 989 61

A mechanism has been proposed in which nitric oxide (NO) may bind to cysteine beta93 and be transported by haemoglobin from the lungs to the tissues and modify vascular tone. In addition, it has been reported that treatment of sickle cell anaemia blood with 80 p.p.m. NO gas in air shifts the oxygen affinity, as measured by P50 to the left. We exposed normal and sickle cell anaemia blood to 80 p.p.m. NO in air for 1 h in vitro and found no change in P50 of either normal or sickle cell blood. In addition, we exposed normal and sickle cell blood in buffer to aqueous NO (NO gas dissolved in buffer) at varying concentrations and found that the induced left shift in P50 correlates strongly and linearly with methaemoglobin formation. We also treated normal and sickle cell blood with other nitric oxide donors, such as sodium 2-(N, N-diethylamino)-diazenolate-2-oxide (DEANO), S-nitrosocysteine (CysNO) and sodium trioxodinitrate (OXINO, or Angeli's salt). In all cases, we found a dose-dependent increase in methaemoglobin that was strongly correlated with the dose-dependent P50 reduction. Our data do not support the report that low NO concentrations can selectively increase the oxygen affinity of sickle cell blood without affecting methaemoglobin levels significantly. NO, however, may have benefit in sickle cell disease by other mechanisms.
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PMID:Effect of nitric oxide and nitric oxide donors on red blood cell oxygen transport. 1097

Several lines of evidence point to the potential role of nitric oxide (NO) in the pathophysiology, as well as in the therapy, of sickle cell disease (SCD). In this study, we compared the effects of NO on platelets from normal individuals and from patients with SCD. Three NO donors were used to deliver NO to platelets: sodium 2-(N, N-diethylamino)-diazenolate-2-oxide (DEANO), S-nitrosocysteine (CysNO) and sodium trioxdintrate (OXINO or Angeli's salt). ADP-induced platelet aggregation, CD62P expression, PAC-1 binding and calcium elevation were evaluated in paired studies of normal and SCD subjects. DEANO significantly reduced aggregation in SCD platelets compared with normal platelets. DEANO similarly reduced the extent of CD62P expression in SCD platelets. All NO donors reduced PAC-1 binding, but there were no significant differences between platelets from normal or SCD subjects. Calcium elevation, as induced by ADP, was not altered by the presence of NO donors. However, when platelets were stimulated with thrombin, there was an increased initial response of SCD platelets compared with normal platelets. Taken together, these data suggest that the mode of NO delivery to platelets may produce various physiological responses and the optimization of NO delivery may contribute to reducing platelet aggregation in sickle cell disease.
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PMID:Biological action of nitric oxide donor compounds on platelets from patients with sickle cell disease. 1129 5

For various ethnic and socioeconomic reasons the pattern of renal disease in the inner city displays distinctive features. Hypertension is frequent, often intractable, and generally conditioned by salt sensitivity and a high sodium intake. Chronic hypertensive nephrosclerosis, found predominantly in African Americans, comprises marked cardiomegaly, renal shrinkage, and hypertensive retinopathy. It has been overdiagnosed in the past, but actually accounts for less than 20% of end-stage renal disease (ESRD) in African Americans. Malignant hypertension, less frequent nowadays, may cause renal shutdown, which is reversible in a few cases; the heart and kidneys are often of normal size. Idiopathic focal segmental glomerulosclerosis is the most common cause of the primary nephrotic syndrome in blacks, but its incidence has also been rising in whites and Hispanics; it does not respond well to treatment, and almost one half of the patients develop ESRD within 10 years. Systemic lupus erythematosus is also more common in African Americans, in whom the severe proliferative forms of lupus nephritis pursue a more virulent course: one half of such patients develop ESRD in 5 years. Cocaine, the use of which has assumed epidemic proportions, may cause accelerated hypertension, acute renal failure from rhabdomyolysis, and progression of preexisting renal disease. Heroin nephropathy has all but disappeared and has been replaced by human immunodeficiency virus (HIV) nephropathy. The prognosis of HIV-infected patients maintained by dialysis has greatly improved. Sickle glomerulopathy, consisting of mesangial expansion, basement membrane duplication, and the absence of immune deposits, may cause the nephrotic syndrome in 4% of patients with severe sickle cell anemia, heralding death within 2 years in one half of patients and ESRD in two thirds; survival has not improved with dialysis. Diabetes is now the most common cause of ESRD. Familial aggregation of ESRD is frequently encountered. Interventions useful in the general population, such as vascular bypass procedures, should be undertaken with great caution and restraint in dialysis patients.
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PMID:Renal disease in the inner city. 1145 21

Hydroxyurea represents an approved treatment for sickle cell anemia and a number of cancers. Chemiluminescence and electron paramagnetic resonance spectroscopic studies show horseradish peroxidase catalyzes the formation of nitric oxide from hydroxyurea in the presence of hydrogen peroxide. Gas chromatographic headspace analysis and infrared spectroscopy also reveal the production of nitrous oxide in this reaction, which provides evidence for nitroxyl, the one-electron reduced form of nitric oxide. These reactions also generate carbon dioxide, ammonia, nitrite, and nitrate. None of these products form within 1 h in the absence of hydrogen peroxide or horseradish peroxidase. Electron paramagnetic resonance spectroscopy and trapping studies show the intermediacy of a nitroxide radical and a C-nitroso species during this reaction. Absorption spectroscopy indicates that both compounds I and II of horseradish peroxidase act as one-electron oxidants of hydroxyurea. Nitroxyl, generated from Angeli's salt, reacts with ferric horseradish peroxidase to produce a ferrous horseradish peroxidase-nitric oxide complex. Electron paramagnetic resonance experiments with a nitric oxide specific trap reveal that horseradish peroxidase is capable of oxidizing nitroxyl to nitric oxide. A mechanistic model that includes the observed nitroxide radical and C-nitroso compound intermediates has been forwarded to explain the observed product distribution. These studies suggest that direct nitric oxide producing reactions of hydroxyurea and peroxidases may contribute to the overall pharmacological properties of this drug.
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PMID:Horseradish peroxidase catalyzed nitric oxide formation from hydroxyurea. 1191 34

The electrophoretic migration, in routine analysis, is crucial for compound identification especially when multiple components are present in the sample. In complex or crude samples, such as those obtained from biological fluids, electrophoretic migration often does not correspond well to that of a pure standard compound. Several factors, related to the sample itself, have been identified as modulating the electrophoretic migration in zone electrophoresis both in gel and capillary electrophoresis (CE): solute mobility and concentrations, salt content, and protein interaction in the sample. Peak shape asymmetry often signals changes in migration especially when comparing samples with wide differences in concentration or those containing high ionic strength. Also, the migration of a protein can be influenced by the presence of a high concentration of another slowly migrating protein in the sample. A weak interaction during the separation between the two proteins which lead to a decreased velocity has been postulated. This was confirmed by finding a curve-linear relationship between the ratio of the two hemoglobin (Hb) variants, hemoglobin F (Hb F) and hemoglobin S (Hb S), and the distance between the two in gel electrophoresis (GE); and also by the observation of formation of a new small peak based on the analysis of hemoglobin F by capillary electrophoresis upon the addition of Hb S to the separation buffer. These factors when present together have an additive effect on the migration. As an example, Hb F, present in low but variable concentration in patients with sickle cell disease (Hb S), migrates in gel electrophoresis slightly slower than it is expected; enough to be confused with other unknown variants. However, the small peaks with different migration distances between Hb S and the adult Hb (Hb A) correlated well (r = 0.98) with Hb F performed by an alkali-denaturing assay indicating that these peaks are indeed Hb F in spite of the difference in their migration.
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PMID:Effect of sample composition on electrophoretic migration application to hemoglobin analysis by capillary electrophoresis and agarose electrophoresis. 1497 1


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