Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroids hormones modify the hematological features of homozygous sickle cell disease, including the levels of fetal hemoglobin. We used semi-quantitative RT-PCR analysis of GATA-1, GATA-2, NF-E2, and gamma-globin mRNA levels in a two-phase liquid culture system of human adult erythroid cells in order to assay the effect of progesterone upon gene expression. The levels of expression of GATA-1 and gamma-globin mRNA were significantly increased in cells treated with progesterone compared to untreated cells (1.7- to 2.0-fold). Progesterone treatment did not produce any stimulatory effect upon GATA-2 and NF-E2 mRNA expression. Differences in the synthesis of HbF protein could not be detected by flow cytometry, although we observed a small difference in mean intensity fluorescence between cells treated and cells untreated with progesterone on days 7 and 9. Using anti-transferrin receptor and anti-glycophorin A antibodies, we verified that addition of progesterone did not cause any change in erythroid proliferation and differentiation. In conclusion, it is possible that the increased expression of gamma-globin mRNA after progesterone treatment observed in this study may be related to the increased GATA-1 mRNA expression. Interactions of the steroid receptors with the basal transcriptional machinery and with transcription factors might mediate their transcriptional effects.
Blood Cells Mol Dis
PMID:Progesterone upregulates GATA-1 on erythroid progenitors cells in liquid culture. 1249 Feb 88

Ovarian steroids appear to influence the manifestations of sickle cell disease (SCD); oestrogens can adversely affect erythrocyte function, whereas progestogens may inhibit sickling and decrease the osmotic fragility of erythrocytes. The aims of the present studies were: (i) to characterise the binding of oestradiol and progesterone to erythrocytes from women with HbSS, HbSC and HbAA genotypes; (ii) to investigate whether steroids modulate susceptibility to sickling or osmotic fragility of HbSS and HbAA erythrocytes. Erythrocytes were incubated for 1h with [3H]-steroids at 4 and 37 degrees C. Binding of both oestradiol and progesterone was independent of temperature and steroid concentration, but was decreased by sequential "washing" of erythrocytes in fresh incubation buffer. Binding capacity was 80 +/- 6% greater for oestradiol (versus progesterone) in all three genotypes, and binding of both steroids was decreased by > or = 70% in HbSS erythrocytes compared to HbSC or HbAA erythrocytes. Pre-incubation of erythrocytes with 35 microM oestradiol or 30 microM progesterone had no significant effect on susceptibility of HbSS and HbAA erythrocytes to sickling, or on osmotic fragility. We conclude that both oestradiol and progesterone bind in a low affinity, non-saturable manner to erythrocytes with decreased binding in cells from women with HbSS. However, steroid binding does not affect susceptibility to sickling or osmotic fragility irrespective of haemoglobin genotype.
J Steroid Biochem Mol Biol 2003 Jan
PMID:Binding of ovarian steroids to erythrocytes in patients with sickle cell disease; effects on cell sickling and osmotic fragility. 1264 26

Altered gene expression in endothelial cells interacting with sickle red blood cells (RBC) and other blood components, in particular the pro-inflammatory cytokines, is an essential step in the pathogenesis of vasoocclusive crises in sickle cell disease (SCD). Using cDNA arrays, we monitored gene expression profiles of human lung microvascular endothelial cells (HMVEC-L) after stimuli that are likely involved in the pathogenesis of vasoocclusion. We detected increased expression of multiple genes in HMVEC-L after their exposure to pro-inflammatory cytokines TNFalpha and IL-1beta and to RBC with increased external exposure of phosphatidylserine and RBC from a patient with SC hemoglobin. While some of these genes have previously been implicated in vascular damage, many represent new targets for investigation of the pathogenesis of vasoocclusion in SCD.
Blood Cells Mol Dis
PMID:Gene expression profiles of microvascular endothelial cells after stimuli implicated in the pathogenesis of vasoocclusion. 1266 88

The clinical picture of sickle cell disease is heterogeneous and varies tremendously among patients and in the same patient from time to time. The level of HbF, alpha-genotype, beta-haplotype, age, sex, and the environment are important factors that modify the clinical picture of sickle cell disease. My paper focuses on the effect of alpha-globin genotype on the pathophysiology of sickle cell anemia, HbSC disease, and sickle beta-thalassemia. The data indicate that the coinheritance of alpha-thalassemia results in some beneficial effects and in some harmful effects. Thus, there are trade-offs involved in this interaction in which the salutary effects are undermined by harmful ones.
Pediatr Pathol Mol Med
PMID:Effect of alpha-globin genotype on the pathophysiology of sickle cell disease. 1267 36

Sickle hemoglobin is the product of one mutated gene, but the disease phenotype is the product of many genes. Polymorphism among the genes responsible for the pleotropic effects can be epistatic (or modifier) genes contributing to interindividual variation that characterizes sickle cell anemia patients. Modulation in the hemoglobin F levels is associated with the beta-globin gene cluster haplotypes and to gender and chromosomal sites different from chromosome 11 influencing the severity of the disease. Coexistence of alpha thalassemia with sickle cell disease produces hematologic and clinical consequences that are beneficial in some complications but deleterious in others. There is little if any modulation of the phenotype of sickle cell anemia by coexistence of G6PD deficiency. Mutations that favor blood coagulation or thrombosis may influence the phenotype of the disease. Improved understanding of the influence of genes involved in modulating the complex pathophysiology of sickle cell disease may allow prediction of the phenotype of sickle cell patients and aid in management decisions.
Pediatr Pathol Mol Med
PMID:Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia. 1267 37

Although hematopoietic stem cell transplantation has curative potential for selected patients with sickle cell disease (SCD), most patients who are eligible for transplantation do not have a suitable donor. Cord blood (CB) from a sibling could provide an alternative stem cell source that, while not as well established as marrow, may offer certain advantages for selected families. These potential advantages include low risk to the infant donor, the possibility that mismatched CB units from sibling donors may be acceptable for transplantation, prompt availability of a stored CB unit for transplant, and decreased risk of clinically significant graft-versus-host disease. When families with SCD (or other transplant-treatable condition) conceive a sibling, no comprehensive research resource exists to assist the family in collecting the new infant's CB. With support from the National Heart Lung and Blood Institute, we are developing a noncommercial research-based CB Banking Program specifically for medically indicated sibling donations. In preliminary experience, we have collected CB from 52 SCD families across 19 states. Of these, 2 CB units have thus far been used for transplantation and 9 others are HLA-identical. We conclude that a CB bank focusing on sibling-donations may be feasible, but further study is required to determine whether such a bank can collect CB units of sufficient quantity and quality to support controlled trials of sibling CB transplantation. Families with a specific medical need, such as those already caring for a child with SCD, should consider collecting sibling CB as part of comprehensive care if the opportunity becomes available.
Pediatr Pathol Mol Med
PMID:Sibling donor cord blood banking for children with sickle cell disease. 1267 40

Although the endocrine pancreas appears to play an important role in the pathophysiology of sickle cell disease, very little is known about the morphologic changes in this tissue. Our study was initiated to delineate the microscopic features of the endocrine pancreas in a large autopsy series of sickle cell hemoglobinopathies. From more than 650 cases archived at the Centralized Pathology Unit for Sickle Cell Disease (Mobile, AL), 224 autopsy cases were identified for review of clinical and gross autopsy findings and/or for microscopic studies, including histochemical stains (trichrome, reticulin, iron), and immunohistochemical stains (insulin, glucagon, somatostatin, and pancreatic polypeptide). The gross examinations were recorded as unremarkable in 65% of the autopsies. In childhood and adolescence (< or = 18 years), pancreas weights (50.76 +/- 5.16SE gm) were significantly greater (p < 0.0001) than age-matched controls (30.42 +/- 3.59SE gm). In adulthood, pancreas weights (108.34 +/- 5.29SE gm) were not significantly different from controls (110 gm). Microscopic findings included vascular congestion (48%), edema (65%), siderosis (31%), and nesidioblastosis (76%), which included islet cell dispersion (53%), hyperplasia (23%), and hypertrophy (25%). Analysis by age groups suggested that islet cell dispersion/hyperplasia persists unchanged, whereas diameters of compact islets tend to increase with age. These findings may be related to local tissue hypoxia and/or increased metabolic energy needs in sickle cell disease.
Pediatr Pathol Mol Med
PMID:Nesidioblastosis in sickle cell disease. 1267 39

During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vasoocclusion. Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies include butyrate compounds, clotrimazole, magnesium supplementation, poloxamer 188, antiadhesion agents, anticoagulant approaches, and nitric oxide. Hemopoietic transplantation remains the only curative therapy. However, several transgenic mouse models are available for studies of gene therapy or other treatment approaches on biochemical, cellular, and pathologic effects of mutant genes.
Pediatr Pathol Mol Med
PMID:Exciting new treatment approaches for pathyphysiologic mechanisms of sickle cell disease. 1267 41

One of the pathogenetic mechanisms responsible for sickling of erythrocytes in patients with sickle cell disease is the decreased hydration status of the cells. In this brief review, we discuss the pathophysiologic background and explore some new treatment options to prevent vaso-occlusive crises or other problems in this patient population.
Pediatr Pathol Mol Med
PMID:Prevention of red cell dehydration: a possible new treatment for sickle cell disease. 1267 42

The protean manifestations of sickle cell disease (SCD), especially, microvessel involvement in the vaso-occlusive process, is classically ascribed to the phenomena of erythrocyte sickling and enhanced red cell-endothelial adherence. Pertubations in various hemostatic systems occurs in SCD, both in steady state and during vaso-occlusion, with the intravascular generation of thrombin. The etiology(s) of thrombin generation in SCD will be described. Whether the activation of the cellular and plasmatic phases of hemostasis is causative or occurs as a result of vascular injury will be discussed.
Pediatr Pathol Mol Med
PMID:Hemostatic alterations in sickle cell disease: relationships to disease pathophysiology. 1267 43


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