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)

Sickle cell anemia occurs in individuals who are homozygous for a single nucleotide substitution in codon 6 of the beta-globin gene. This single mutation leads to the formation of abnormal hemoglobin, HbS (alpha2betas[s]2), which is much less soluble when deoxygenated than hemoglobin A (HbA) (alpha2beta2). This insolubility causes aggregates of HbS to form inside sickle erythrocytes as they traverse the circulation. With full deoxygenation, polymer becomes so extensive that the cells become sickled in shape. Yet, even with high oxygen saturation values, quantities of HbS polymer may be sufficient to alter the rheologic properties of sickle erythrocytes in the absence of morphologic changes, and cells can occlude end arterioles, leading to chronic hemolysis and microinfarction of diverse tissues. Ultimately, this process leads to vaso-occlusive crises and irreversible tissue damage. Nonetheless, the spectrum of disease severity even among patients with grossly equivalent hematologic indices suggests that many other factors-including genetic, cellular, physiologic, and psychosocial-play a substantial role in determining the course of this disorder. Of the genetic factors, the level of fetal hemoglobin in particular has been established to favorably modify the clinical manifestations of patients with sickle cell disease and related conditions. Recent advances in the understanding of the molecular and cellular pathophysiology of sickle cell disease, coupled with new insights into the developmental regulation of human globin gene expression, have provided the scientific impetus and clinical rationale to attempt to augment the postnatal production of fetal hemoglobin. Furthermore, contemporary understanding of the quantitative relationship between the extent of HbS polymerization within the red cells and the degree of red blood cell and/or organ pathology has now enabled investigators to predict to what extent this intracellular pathogenic process must be inhibited to achieve clinically significant amelioration of disease manifestation. These areas will be covered in this overview. This is a US government work. There are no restrictions on its use.
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PMID:Overview of pathophysiology and rationale for treatment of sickle cell anemia. 931 95

In this report we describe the molecular analysis of 795 chromosomes derived from unrelated Turkish beta-thalassemia and sickle cell anemia carriers identified in hematology clinics in Istanbul, Ankara, Izmir, Adana, and Antalya. The determination of the molecular pathology of 754 beta-thalassemia and 42 abnormal hemoglobin genes and analysis of the frequency distribution in six distinct regions of Turkey was accomplished. The experimental strategy, based on PCR amplification of the beta-globin gene, included dot-blot hybridization with 18 probes specific for the Mediterranean populations, denaturing gradient gel electrophoresis, and genomic sequencing. When the regional results are compared with the overall frequency of mutations in the country, it is observed that the frequencies in the western and southern parts of Turkey are in good accordance with the overall distribution, whereas the northern and eastern parts have a more region/population-specific profile with some rare mutations having a significantly high occurrence in these regions. Further evaluation of the data with respect to region- or population-dependent differences will contribute to a better understanding of the mechanisms leading to the marked genetic heterogeneity in Turkey, but could also be extremely valuable in facilitating rapid identification of mutations in families at risk for different hemoglobinopathies.
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PMID:Molecular and population genetic analyses of beta-thalassemia in Turkey. 949 72

Hydroxyurea has been mixed with hemoglobin S and the reaction was studied using electronic absorption spectroscopy as a function of time and wavelength. The rate of conversion of oxyhemoglobin S to other species was determined and the nature of the reaction products was studied. We also report the formation of methemoglobin (and other reaction products) when deoxyhemoglobin S is combined with hydroxyurea. The probable increase in the formation of methemoglobin, and other potential reaction products such as nitric oxide-hemoglobin, in patients with sickle cell anemia who are taking hydroxyurea as a therapeutic drug is discussed in terms of the pathophysiology of the disease. It is proposed that methemoglobin and possibly nitric oxide-hemoglobin formation may partially explain beneficial effects observed in these patients before their levels of fetal hemoglobin have increased.
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PMID:Time resolved absorption study of the reaction of hydroxyurea with sickle cell hemoglobin. 954 36

Hemoglobin (Hb) S-Oman has two mutations in the beta-chains. In addition to the classic betaS mutation (beta6 Glu --> Val), it contains a second mutation in the same chain (beta121 Glu --> Lys) identical to that of HbOARAB. We have studied a pedigree of heterozygous carriers of HbS-Oman that segregates into two types of patients: those expressing about 20% HbS-Oman and concomitant -/ thalassemia and those with about 14% of HbS-Oman and concomitant -/- thalassemia. The higher expressors of S-Oman have a sickle cell anemia (SS) clinical syndrome of moderate intensity, while the lower expressors have no clinical syndrome, and are comparable to the solitary case first described in Oman. In addition, the higher expressors exhibit a unique form of irreversibly sickled cell reminiscent of a "yarn and knitting needle" shape, in addition to folded and target cells. The CSAT of S-Oman is identical to that of S-Antilles, another supersickling hemoglobin, whose carriers express the abnormal hemoglobin at 40% to 50%, with a very similar clinical picture to HbS-Oman. Because the level of expression is so different and the clinical picture so similar, and based on the hemolysates CSAT's, we conclude that HbS-Oman produces pathology beyond its sickling tendencies. A clue for this additional pathogenesis is found in the fact that homozygous HbOARAB, which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbOARAB is combined with HbS, it makes the phenotype of this double heterozygote as severe as SS. Properties of HbS-Oman red blood cells (RBCs) include reticulocytes that are much denser than normal (similar to those of SC and CC disease), a decrease in the Km for Ca2+ needed to activate the Gardos' channel (making this transporter more sensitive to Ca2+), increased association of HbS-Oman with the RBC membrane, the presence of dense cells by isopycnic gradient, the presence of folded cells, and abundant nidus of polymerization under the membrane. Other properties include a clear increase in volume and N-ethylmaleimide-stimulated K:Cl cotransport in RBCs expressing more than 20% HbS-Oman. We conclude that the pathology of heterozygous S-Oman is the product of the sickling properties of the beta6 Val mutation which are enhanced by the second mutation at beta121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at beta121. We speculate that this pathology results from the abnormal association of the highly positively charged HbS-Oman (3 charges different from normal hemoglobin) with the RBC membrane.
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PMID:HbS-oman heterozygote: a new dominant sickle syndrome. 983 44

K-Cl cotransport (COT) is the coupled movement of K and Cl, present in most cells, associated with regulatory volume decrease, susceptible to oxidation and functionally overexpressed in sickle cell anemia. The aim of this study was to characterize the effect of the oxidant nitrite (NO2-) on K-Cl COT. NO2- is a stable metabolic end product of the short-lived highly reactive free radical nitric oxide (NO), an oxidant and modulator of ion channels, and a vasodilator. In some systems, the response to NO2- is identical to that of NO. We hypothesized that NO2- activates K-Cl COT. Low potassium (LK) sheep red blood cells (SRBCs) were used as a model. The effect of various concentrations (10(-6) to 10(-1) m) of NaNO2 was studied on K efflux in hypotonic Cl and NO3 media, Cl-dependent K efflux (K-Cl COT), glutathione (GSH), and methemoglobin (MetHb) formation. In support of our hypothesis, K efflux and K-Cl COT were stimulated by increasing concentrations of NaNO2. Stimulation of K efflux was dependent upon external Cl and exhibited a lag phase, consistent with activation of K-Cl COT through a regulatory mechanism. Exposure of LK SRBCs to NaNO2 decreased GSH, an effect characteristic of a thiol-oxidizing agent, and induced MetHb formation. K-Cl COT activity was positively correlated with Methb formation. N-ethyl-maleimide (NEM), a potent activator of K-Cl COT, was used to assess the mechanism of NO2- action. The results suggest that NEM and NO2- utilize at least one common pathway for K-Cl COT activation. Since NaNO2 is also a well known vasodilator, the present findings suggest a role of K-Cl COT in vasodilation.
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PMID:Role of nitrite, a nitric oxide derivative, in K-Cl cotransport activation of low-potassium sheep red blood cells. 984 89

In addition to its capacity to increase fetal hemoglobin levels, other mechanisms are implicated in hydroxyurea's ability to provide beneficial effects to patients with sickle cell disease. We hypothesize that the reaction of hemoglobin with hydroxyurea may play a role. It is shown that hydroxyurea reacts with deoxy-sickle cell hemoglobin (Hb) to form methemoglobin (metHb) and nitrosyl hemoglobin (HbNO). The products of the reaction as well as the kinetics are followed by absorption spectroscopy and electron paramagnetic resonance (EPR) spectroscopy. Analysis of the kinetics shows that the reaction can be approximated by a pseudo-first order rate constant of 3.7x10(-4) (1/(s.M)) for the disappearance of deoxy-sickle cell hemoglobin. Further analysis shows that HbNO is formed at an observed average rate of 5.25x10(-5) (1/s), three to four times slower than the rate of formation of metHb. EPR spectroscopy is used to show that the formation of HbNO involves the specific transfer of NO from the NHOH group of hydroxyurea. The potential importance of this reaction is discussed in the context of metHb and HbNO being able to increase the delay time for sickle cell hemoglobin polymerization and HbNO's vasodilating capabilities through conversion to S-nitrosohemoglobin.
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PMID:The reaction of deoxy-sickle cell hemoglobin with hydroxyurea. 1043 57

Pulse oximetry is a noninvasive method of measuring oxyhemoglobin saturation. The validity of pulse oximetry in sickle cell disease (SCD) has been questioned. We evaluated pulse oximetry, arterial blood gas analysis, and co-oximetry in patients with SCD, and we assessed the effect of dyshemoglobin and altered blood-oxygen affinity on their accuracy. Sixteen patients with SCD aged 7-21 years had arterial and venous blood drawn and transcutaneous pulse oximetry performed. Oxyhemoglobin dissociation curves were plotted from the venous blood of 15 patients. Oxyhemoglobin saturation estimated by arterial blood gas analysis (SaO(2)) and measured by pulse oximetry (SpO(2)) were both higher than the saturation by co-oximetry (FO(2)Hb) (mean +/- SD = 96.3 +/- 1.6%, 94 +/- 3.1%, and 89.1 +/- 3.8%, respectively). There was a significant, positive correlation between SpO(2) and FO(2)Hb (r = 0.7, P = 0.002). The patients had elevated levels of methemoglobin (MetHb) and carboxyhemoglobin (COHb) (2.3 +/- 1.4% and 4.7 +/- 1.3%, respectively). The oxyhemoglobin dissociation curves were frequently shifted to the right with oxygen tensions elevated when hemoglobin was 50% saturated with oxygen (P(50)) (32.5 +/- 4.5 mm Hg). There was a strong correlation between the amounts of dyshemoglobin (MetHb + COHb) and the difference between SaO(2) and FO(2)Hb (r = 0.7, P = 0.002). There was no correlation between the difference between SaO(2) and FO(2)Hb and the P(50) (r = 0.27, P = 0.33) There was also a strong positive correlation between SaO(2)-SpO(2) and dyshemoglobin fraction (r = 0.77, P = 0.001). We conclude that pulse oximetry and arterial blood gas analysis overestimate oxygen saturation when compared to co-oximetry, but that SpO(2) is consistently closer than SaO(2) to FO(2)Hb. SpO(2) is partially affected by MetHb and COHb. The discrepancy between SaO(2) and FO(2)Hb is due to the presence of dyshemoglobin and a shifted oxyhemoglobin dissociation curve, but the effect from dyshemoglobin predominates.
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PMID:Measurement of hemoglobin saturation by oxygen in children and adolescents with sickle cell disease. 1058 17

Hydroxy-urea (OH-U) is used to treat sickle cell anemia by increasing hemoglobin fetal-fraction. It has been suggested that the sickle cell mutations lead to the formation of unstable HbS and release of iron, which can result in lipid peroxidation (LPO), and eventual cell damage. Since oxidative processes might be involved in pathogenesis of sickle cell disease, we investigated the antioxidant property of OH-U in a red blood cell (RBC) model. Intact RBCs or RBC membranes were exposed to t-butyl hydroperoxide (t-BHP, 0.75 mM) or iron (ferrous sulfate; 100 microM) at 37 degrees C for 60 min in the presence or absence of OH-U (1.25 mM). The extent of oxidative damage was measured by LPO (as thiobarbituric acid reactive substances, TBARS), hemoglobin oxidation (as percent of methemoglobin, metHb %), and decrease in the activities of membrane-bound Na+/K+-ATPase and Ca2+-ATPases. Our results show that OH-U inhibited t-BHP-induced LPO in fresh RBC membranes significantly (P <0.01). OH-U significantly inhibited t-BHP-mediated LPO (P <0.01) and metHb formation (P <0.01) in intact RBC. Also, OH-U inhibited iron-induced LPO and metHb formation in intact RBC (P <0.01). In addition, OH-U blocked t-BHP-mediated changes in membrane ATPase activities. Furthermore, OH-U blocked iron-mediated hydroxyl radical generation in a dose-dependent fashion. In conclusion, the observed antioxidant properties of OH-U might contribute to its therapeutic action in sickle cell disease.
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PMID:Hydroxy-urea protects erythrocytes against oxidative damage. 1090 41

Nitric oxide (NO) has been reported to modulate the oxygen affinity of blood from sickle cell patients (SS), but not that of normal adult blood (AA), with little or no heme oxidation. However, we had found that the NO donor compounds 2-(N, N-diethylamino)-diazenolate-2-oxide (DEANO) and S-nitrosocysteine (CysNO) caused increased oxygen affinity of red cells from both AA and SS individuals and also caused significant methemoglobin (metHb) formation. Rapid kinetic experiments in which HbA(0), AA, or SS erythrocytes were mixed with CysNO or DEANO showed biphasic time courses indicative of initial heme oxidation followed by reductive heme nitrosylation, respectively. Hemolysates treated with CysNO showed by electrospray mass spectrometry a peak corresponding to a 29 mass unit increase (consistent with NO binding) of both the beta(A) and beta(S) chains but not of the alpha chains. Therapeutic use of NO in sickle cell disease may ultimately require further optimization of these competing reactions, i.e., heme reactivity (nitrosylation or oxidation) versus direct S-nitrosation of hemoglobin on the beta-globin.
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PMID:Nitric oxide-mediated heme oxidation and selective beta-globin nitrosation of hemoglobin from normal and sickle erythrocytes. 1097 28

Oxidant stress, in vivo or in vitro, is known to induce oxidative changes in human red blood cells (RBCs). Our objective was to examine the effect of augmenting RBC glutathione (GSH) synthesis on 1) degenerative protein loss and 2) RBC chemokine- and free radical-scavenging functions in the oxidatively stressed human RBCs by using banked RBCs as a model. Packed RBCs were stored up to 84 days at 1-6 degrees C in Adsol or in the experimental additive solution (Adsol fortified with glutamine, glycine, and N-acetyl-L-cysteine). Supplementing the conventional additive with GSH precursor amino acids improved RBC GSH synthesis and maintenance. The rise in RBC gamma-glutamylcysteine ligase activity was directly proportional to the GSH content and inversely proportional to extracellular homocysteine concentration, methemoglobin formation, and losses of the RBC proteins band 3, band 4.1, band 4.2, glyceraldehyde-3-phosphate dehydrogenase, and Duffy antigen (P < 0.01). Reduced loss of Duffy antigen correlated well with a decrease in chemokine RANTES (regulated upon activation, normal T-cell expressed, and secreted) concentration. We conclude that the concomitant loss of GSH and proteins in oxidatively stressed RBCs can compromise RBC scavenging function. Upregulating GSH synthesis can protect RBC scavenging (free radical and chemokine) function. These results have implications not only in a transfusion setting but also in conditions like diabetes and sickle cell anemia, in which RBCs are subjected to chronic/acute oxidant stresses.
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PMID:Glutathione protects chemokine-scavenging and antioxidative defense functions in human RBCs. 1124 4


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