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)

Trimidox (3,4,5-trihdroxybenzamidoxime) has been shown to reduce the activity of ribonucleotide reductase with accompanied growth inhibition and differentiation of mammalian cells. Hydroxyurea (HU) is the only ribonucleotide reductase inhibitor in clinical use for the treatment and management of sickle cell anemia, since this compound increases fetal hemoglobin (Hb F) production: a potent inhibitor of sickle hemoglobin (Hb SS) polymerization. However, the main limitations of HU is its lack of potency, myelosuppression and short half life. These studies investigated the effects of trimidox on the induction of hemoglobin and F-cells production in K562 erythroleukemia cells. Our study reveals that trimidox exhibits concentration dependent inhibitory effect on K562 cells with increase in benzidine positive normoblasts and F-cells production as well as morphological changes typical of erythroid differentiation. These findings provide the first evidence that the growth inhibitory differentiation of cells induced by trimidox enhance hemoglobin and F-cells production.
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PMID:Trimidox-mediated morphological changes during erythroid differentiation is associated with the stimulation of hemoglobin and F-cell production in human K562 cells. 964 67

Increased levels of fetal hemoglobin (HbF) can ameliorate the clinical course of inherited disorders of beta-globin gene expression, such as beta thalassemia and sickle cell anemia. In a group of disorders called hereditary persistence of fetal hemoglobin (HPFH), expression of the gamma-globin gene of HbF persists at high levels in adult erythroid cells. Molecular studies of the HPFH syndromes have identified several important regulatory elements for the normal pattern of gamma-globin gene expression. Deletion as well as nondeletion types of HPFH have been identified. The nondeletion types of HPFH are characterized by the presence of point mutations, in the promoter region of one or another gamma-globin gene, that are thought to alter interactions between various transcription factors and the promoter. The deletion types of HPFH are thought to deregulate the normal developmental pattern of gamma-globin gene expression due to the juxtaposition of normally distant cis-acting factors into the vicinity of the gamma genes. These findings have provided us with a more sophisticated understanding of the molecular basis for the persistent gamma-gene expression in these syndromes and point to certain strategies for potential future attempts at gene therapy for beta-globin gene disorders.
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PMID:Molecular basis of hereditary persistence of fetal hemoglobin. 966 25

Hydroxyurea (HU) induces HbF production and can reduce painful crises in some patients with sickle cell anemia (SS). However, HbF induction alone cannot explain the beneficial effect of HU treatment as some patients experience clinical improvement while showing only minor increases in HbF. Other actions of HU, in particular its effects on vascular endothelium, adhesion molecule expression and cytokine production may also play a role in the final therapeutic outcome. In order to analyze these effects we studied the levels of interleukin-3 (IL-3), interleukin-6, granulocyte-macrophage colony-stimulating factor, erythropoietin, stem cell factor, soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule-1, soluble E-selectin and soluble P-selectin in 7 SS patients before and during 5 months of HU treatment. Use of HU seems to have no detectable effect on soluble adhesion molecules, but the steady state levels of soluble vascular adhesion molecule-1 are enhanced in SS patients compared to normal controls. Of the cytokines studied, only IL-3 showed an increase during therapy, suggesting HU may induce early erythroid progenitors capable of producing HbF by a direct or indirect effect on IL-3 production. Remarkably, the steady state stem cell factor levels in sickle cell patients seemed to be decreased compared to healthy controls.
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PMID:Cytokines and soluble adhesion molecules in sickle cell anemia patients during hydroxyurea therapy. 969 Nov 43

Sodium butyrate (NaB) is an differentiation inducer currently under clinical investigation as a potential therapy for the treatment of sickle cell disease and prostate cancer. Though the biologic effects of this agent is well documented, its mechanism of action remains largely known. The mechanisms by which it transduces its signal to the nucleus is the subject of intense investigation in our laboratory. In this report, we demonstrate that NaB stimulates PKC activation by 3-fold and induces differential expression of several PKC isoforms. Notably, it upregulates PKC epsilon and downregulates PKC beta during erythroid differentiation. These findings suggest that certain PKC isoforms may play important roles in the signal transduction mechanisms of this agent leading to regulation of erythroid proliferation and differentiation.
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PMID:Sodium butyrate stimulates PKC activation and induces differential expression of certain PKC isoforms during erythroid differentiation. 970 83

After studying of familial leukemias, Myelodysplastic Syndrome (MDS) and aplastic anemia (AA), we observed and analysed bone marrow (BM) cells hematologically and molecular-cytogenetically in 36 persons who are first degree relatives (FDRs) of patients with acute leukemias (AL), MDS and AA. The peripheral blood (PB) lymphocyte chromosome fragility sensitive to folic acid and unstability was also analysed in 18 FDRs. The abnormal BM megakaryocystic/erythroid cellularity and the rearrangement of c-erbB were found in 66%-86.1% of parents and siblings of patients. The associations of dysplastic megakaryopoiesis, including the presence of lymphoid small megakaryocytes, with the chromosomal monosomy or/and the rearrangement/amplification of C-erbB, were found in a few parents and siblings. These results were consistent with those of MDS, Fanconi Anemia (FA) and AL. The normal karyotype and SCD positive of BM cells and PB lymphocytes, and PB lymphocyte chromosomal fragility and unstability were found in most of patients' parents, while familial chromosomal monosomy of BM cells and PB lymphocyte chromosomal fragility were found in parents and siblings of familial leukemia patients. Based on the studies of a large family with 7 cases of acute erythroleukamia and relative myeloleukemias in three consecutive generations and a family with 3 CAA and 1 AML, the rearrangement of c-erbB might be inherited. The rearrangement/amplification of c-erbB and its PCR detected results could be the indicators of gene diagnosis of preleukemia and might be useful in genetic conselling of leukemias. The common origin of AL, MDS and AA was discussed.
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PMID:[Relationship between the occurrences of AL, MDS and AA and abnormal BM proliferation of patient's parents]. 975 8

Erythrocyte sodium hydrogen exchanger (NHE) represents one of a limited number of sodium entry pathway in erythrocytes. At least five NHE isoforms have been identified, differing in tissue specificity, regulatory characteristics, and pharmacological sensitivities. Although physiological characteristics of erythrocyte NHE suggest that the widely expressed NHE-1 isoform may be present, evidence is not conclusive and does not exclude the existence of other isoforms. In this study, Northern blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses were used to test for five NHE isoforms in erythroid cells. Blood from patients with sickle cell disease was depleted of white blood cells (WBC) by passage through leukocyte filters and cellulose column. RT-PCR performed on WBC depleted reticulocyte RNA using a NHE-1 primer set yielded product a of expected size, the sequence of which was identical to the published human NHE-1 sequence. Northern blot analysis of the reticulocyte RNA using a 1.6 kb probe revealed a message of approximately 5.0 kb in size. RT-PCR analysis of rat kidney RNA using primers specific for NHE isoforms -2, -3, -4 and rat brain RNA using primer specific for NHE-5 isoform yielded products of expected size, whereas WBC depleted RNA under identical conditions yielded no products. These results identify the erythroid isoform of the sodium hydrogen exchanger as NHE-1.
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PMID:NHE-1 is the sodium-hydrogen exchanger isoform present in erythroid cells. 981 52

Thrombotic events are life-threatening complications of human hemolytic anemias such as paroxysmal nocturnal hemoglobinuria, sickle cell disease, and thalassemia. It is not clear whether these events are solely influenced by aberrant hematopoietic cells or also involve aberrant nonhematopoietic cells. Spherocytosis mutant (Spna1(sph)/Spna1(sph); for simplicity referred to as sph/sph) mice develop a severe hemolytic anemia postnatally due to deficiencies in -spectrin in erythroid and other as yet incompletely defined nonerythroid tissues. Thrombotic lesions occur in all adult sph/sph mice, thus providing a hematopoietically stressed model in which to assess putative causes of thrombus formation. To determine whether hematopoietic cells from sph/sph mice are sufficient to initiate thrombi, bone marrow from sph/sph or +/+ mice was transplanted into mice with no hemolytic anemia. One set of recipients was lethally irradiated; the other set was genetically stem cell deficient. All mice implanted with sph/sph marrow, but not +/+ marrow, developed severe anemia and histopathology typical of sph/sph mice. Histological analyses of marrow recipients showed that thrombi were present in the recipients of sph/sph marrow, but not +/+ marrow. The results indicate that the -spectrin-deficient hematopoietic cells of sph/sph mice are the primary causative agents of the thrombotic events.
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PMID:Hematopoietic cells from -spectrin-deficient mice are sufficient to induce thrombotic events in hematopoietically ablated recipients. 984 53

Proteins involved in repression of the human beta-globin gene may be useful in the treatment of sickle cell anemia, in conjunction with therapy to reactivate fetal globin genes. If there is a reciprocal elevation of gamma-globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the beta-globin gene appears to be mediated through two DNA sequences, silencers I and II, and identified a protein termed BP1 which binds to both silencer sequences. In this study, we cloned two cDNAs encoding proteins which bind to an oligonucleotide in silencer I containing a BP1 binding site. These cDNAs correspond to HMG-I and HMG-Y, isoforms regarded as architectural proteins. We demonstrate that binding of HMG-I(Y) to this oligonucleotide causes bending/flexure of the DNA. HMG-I(Y) also binds to a second oligonucleotide containing a BP1 binding site located in a negative control region upstream of the delta-globin gene, suggesting a role for HMG-I(Y) in repression of adult globin genes. Expression studies revealed that HMG-I(Y) is ubiquitously expressed in human tissues that do not express beta-globin, being present in 48 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG-I(Y) expression is down-regulated during differentiation of primary erythroid cells. We present a model in which HMG-I(Y) alters DNA conformation to allow binding of repressor proteins, and in which the relative amount of HMG-I(Y) helps to determine the repressive state of the beta-globin gene.
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PMID:Binding of HMG-I(Y) elicits structural changes in a silencer of the human beta-globin gene. 988 3

Butyric acid (BA) is known to induce overexpression of fetal hemoglobin and then erythroid differentiation. Therefore, BA is currently under clinical investigation as a potential therapy for the treatment of sickle cell disease and cancer. Nevertheless, the molecular mechanisms involved in BA-induced differentiation remain largely unknown. Previous reports have shown that BA-induced overexpression of erythroid genes occurred at the transcriptional level, suggesting the involvement of erythroid transcription factors. Here, we intend to demonstrate the requirement of GATA-1 and NF-E2 transcription factors in the BA-induced erythroid differentiation of human leukemic K562 cells. Time-course experiments showed that nuclear levels of GATA-1 and p45 NF-E2 proteins increased during BA treatment. Moreover, antisense oligodeoxynucleotides targeting either GATA-1 or p45 NF-E2 proteins inhibited both protein expression and BA-induced differentiation. In contrast, BA-induced cell growth inhibition was not affected. These results provide the first direct evidence for the requirement of GATA-1 and NF-E2 in BA-induced differentiation process.
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PMID:Requirement of GATA-1 and p45 NF-E2 expression in butyric acid-induced erythroid differentiation. 991 24

A hemoglobin F (HbF) level between eight and nine percent divides sickle cell anemia (SS) patients into two populations, according to the kinetics of circulating burst forming units-erythroid (BFU-E), long term culture-initialing cells (LTC-IC), and cytokine plasma concentrations. The SS patients with HbF levels lower than 8-9% are more anemic (LFSS patients) than those with HbF levels higher than 8-9% who have less severe anemia (HFSS patients). We report here that the level of erythropoiesis [evaluated by the levels of soluble transferin receptors (sTfR)] is not identical in these two patient populations, supporting the idea that a different set of regulatory mechanisms might be required to maintain the two levels of increased hematopoiesis. The plasma sTfR concentration was increased in all SS samples compared with controls (P < 0.002) and sTfR levels were negatively correlated with peripheral HbF%. (r = -0.574, P < 0.002). Furthermore, sTfR levels were higher in LFSS than in HFSS patients. Erythropoietin (Epo) levels were increased in the plasma of LFSS individuals (range = 34-215 ml U/ml), while the values in HFSS patients were in the normal range (3-20 ml U/ml). Furthermore, we identify here stem cell factor (SCF) and transforming growth factor-beta (TGF-beta) as regulatory factors specifically affected by the presence of SS genotype and its level of severity. The plasma concentrations of SCF and TGF-beta were increased compared with normal controls and high levels of SCF (up to 7,000 pg/ml) were detected in LFSS patients. The latter also showed increased proportion of SCF+ CD34 enriched circulating cells (49%). Low SCF in HFSS patients is associated with elevated TGF-beta, suggesting a regulatory role of the latter on either SCF release or c-kit expression in progenitor cells. Occasional elevation of granulocyte macrophage-colony stimulating factor (G-CSF), interleukin (IL)-7, and macrophage inflammatory protein (MIP)-1alpha in plasma of SS patients is not specific because no relation to HbF could be demonstrated. All plasma tested for leukemia inhibitory factor (LIF) were negative. Data presented here, complementing previously published information, supports a model in which HFSS patients achieve a balance between inhibitory (TGF-beta) and stimulatory (SCF, IL-3) factors, resulting in moderate erythropoietic response. In contrast, in LFSS patients, low levels of TGF-beta and the increased release of GM-CSF and SCF maintain the intense erythropoiesis in response to higher erythropoietic stress, in these more severe patients.
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PMID:Circulating cytokines response and the level of erythropoiesis in sickle cell anemia. 992 1


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