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 sickling process causes secondary changes in cell shape, size, cation and water content, and membrane structure that contribute to the impairment of intrinsic cell deformability (Figure 2). This rheological defect is partially compensated by a low haematocrit, which moderates the rise in whole-blood viscosity, and by a rise in cardiac output which increases capillary flow velocity (Berger and King, 1982). A delicate balance exists between these mechanisms and any local disturbance of this balance by pathological changes in factors extrinsic to the sickle cell (Figure 2) can precipitate vaso-occlusion. There is still considerable controversy over the site (arteriolar, capillary, or venular) of vaso-occlusion, the type of sickle cell (reversibly sickled or irreversibly sickled) that is primarily involved, and the relative importance of extra-erythrocytic precipitating factors such as stasis, hypoxia, hyperosmolality, acidosis, alteration in temperature, acute-phase rise in plasma proteins and leukocytes, prothrombotic changes in coagulation factors and platelets, and adhesion of blood cells to vascular endothelium (Figure 2). A low-grade hypercoagulable state has been described in patients with SS (Leichtman and Brewer, 1978; Richardson et al, 1979) which may be related to the procoagulant effect of the shift of phosphatidyl serine to the outer lipid bilayer of the sickle cell (Chiu et al, 1981; Franck et al, 1985). Platelets appear to accumulate at sites of vaso-occlusion (Siegel et al, 1985) and their migration to the vessel wall may be enhanced by the presence of poorly deformable erythrocytes (Aarts et al, 1984). Endothelial cell damage in the arterial or venous circulation may also contribute (Klug et al, 1982). Thus vaso-occlusion appears to result from a complex interaction between blood cells, plasma proteins and endothelium and any one of several precipitating factors may disturb the fragile steady state and cause a painful crisis. The study of sickle cells by rheological methods has considerable potential for investigating the pathophysiology of vaso-occlusive episodes in the SCD and for monitoring, both in vitro and ex vivo, the efficacy of antisickling compounds. Because of the multiple intrinsic and extrinsic factors that contribute to the rheological defect, it is not yet known which of these should be the primary target for an antisickling agent. In-vitro rheological studies in which different metabolic stresses can be applied to intact sickle cells in the presence of a putative antisickling drug should help to answer this question.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Rheology of the sickle cell disorders. 332 64

A membrane lipid abnormality induced by sickling and found as a permanent alteration in the irreversibly sickled cell (ISC) is the rearrangement of phosphatidyl ethanolamine (PE) and phosphatidyl serine (PS) from the inner to the exterior side of the lipid bilayer. Since PS can provide a catalytic surface for the binding of blood coagulation factors and thus can exhibit procoagulant activity, we investigated the influence of oxy and deoxy reversibly sickled cells (RSC) ass well as ISC on clotting in vitro. Red blood cells (RBC), as the source of phospholipid, were added to platelet-poor citrated plasma containing Russell's viper venom (RVV) and clotting time was measured after recalcification. The clotting time after addition of normal RBC and oxy-RSC was similar to the saline blank (100 sec). In contrast, both oxy-ISC and deoxy completely sickled RSC shortened clotting time by 30%. Using liposomes prepared with identical phospholipid composition to the outer lipid leaflet of either normal RBC, RSC or ISC clotting times similar to those with intact cells were achieved. Since the liposomes did not contain protein, accentuation of clotting appears to be related to abnormal phospholipid organization, in particular to the abnormal exposure to aminophospholipids on the outer surface of the membrane. This abnormality may contribute to the pathogenesis of the vaso-occlusive episode in sickle cell anemia.
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PMID:Sickled erythrocytes accelerate clotting in vitro: an effect of abnormal membrane lipid asymmetry. 724 27

The D4Valine194Glycine receptor is a variant of the dopamine D4 receptor and is found in 12.5% of the Afro-Caribbean population. Glycine replaces valine at a position one amino acid away from a serine which is critical for the attachment of dopamine. To determine whether this mutation had an effect on the properties of the dopamine D4 receptor, we constructed this variant and tested the sensitivity of the expressed protein with various drugs. We found that the variant receptor was two orders of magnitude less sensitive to dopamine, clozapine and olanzapine. The variant receptor was insensitive to guanine nucleotide, indicating the absence of a high-affinity state or functional state. The one 15-year-old individual found homozygous for this variant also had sickle cell disease. The patient revealed an overall pattern of low weight and no axillary or pubic hair.
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PMID:Dopamine D4 receptor variant in Africans, D4valine194glycine, is insensitive to dopamine and clozapine: report of a homozygous individual. 874 75

Structural abnormalities in erythrocyte membrane are more and more claimed as a determinant factor in the sickle cell disease pathogenesis. This being would have been provided by a new anionic phospholipids distribution and conformation. Phosphatidyl-serine exposing and phosphatidic acid enhancing would induce specific immunoglobulins synthesis. In this study, assessment of antiphospholipid antibodies prevalence was carried out among sickle cell trait patients (n = 35) and homozygous patients (n = 59) as compared to healthy subjects (n = 39). Antiphospholipid antibodies, assayed by ELISA procedure, were significantly higher among the homozygous patients than the sickle cell trait patients ones and highlighted as compared to healthy subjects. Pathologic data were only observed among homozygous patients. These specific antibodies, associated with thrombosis and haemolysis, would have constitute a morbid link and a therapeutic target of this sickness, dominated by homodynamic troubles.
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PMID:[Prevalence of antiphospholipid antibodies in patients with sickle cell disease]. 1521 61

We recently reported that CD47 (integrin-associated protein) on sickle red blood cells (SS RBCs) activates G-protein-dependent signaling, which promotes cell adhesion to immobilized thrombospondin (TSP) under relevant shear stress. These data suggested that signal transduction in SS RBCs may contribute to the vaso-occlusive pathology observed in sickle cell disease. However, the CD47-activated SS RBC adhesion receptor(s) that mediated adhesion to immobilized TSP remained unknown. Here we demonstrate that the alpha4beta1 integrin (VLA-4) is the receptor that mediates CD47-stimulated SS RBC adhesion to immobilized TSP. This adhesion requires both the N-terminal heparin-binding domain and the RGD site of TSP. CD47 signaling induces an "inside-out" activation of alpha4beta1 on SS RBCs as indicated by an RGD-dependent interaction of this integrin with soluble, plasma fibronectin. However, CD47 engagement also induces an alpha4beta1-mediated, RGD-independent adhesion of SS RBCs to immobilized vascular cell adhesion molecule-1 (VCAM-1). CD47 signaling in SS RBCs appears to be independent of large scale changes in cAMP formation but nonetheless promotes alpha4beta1-mediated adhesion via a protein kinase A-dependent, serine phosphorylation of the alpha4 cytoplasmic domain. CD47-activated SS RBC adhesion absolutely requires the Src family tyrosine kinases and is also enhanced by treatment of SS RBCs with low concentrations of cytochalasin D, which may release alpha4beta1 from cytoskeletal restraints. In addition, CD47 co-immunoprecipitates with alpha4beta1 in a sickle reticulocyte-enriched fraction of SS RBCs. These studies therefore identify the alpha4beta1 integrin on SS RBCs as a CD47-activated receptor for TSP, VCAM-1, and plasma fibronectin, revealing novel binding characteristics of this integrin.
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PMID:Mechanism of CD47-induced alpha4beta1 integrin activation and adhesion in sickle reticulocytes. 1529 85

The possible role of physiologic stress hormones in enhancing adhesion of sickle erythrocytes (SS RBCs) to endothelial cells (ECs) in sickle cell disease (SCD) has not been previously explored. We have now found that up-regulation of intracellular cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) by epinephrine significantly increased sickle but not normal erythrocyte adhesion to both primary and immortalized ECs. Inhibition of serine/threonine phosphatases also enhanced sickle erythrocyte adhesion at least partially through a PKA-dependent mechanism. Adhesion was mediated through LW (intercellular adhesion molecule-4 [ICAM-4], CD242) blood group glycoprotein, and immunoprecipitation studies showed that LW on sickle but not on normal erythrocytes undergoes increased PKA-dependent serine phosphorylation as a result of activation. The major counter receptor for LW was identified as the alphavbeta3 integrin on ECs. These data suggest that adrenergic hormones such as epinephrine may initiate or exacerbate vaso-occlusion and thus contribute to the association of vaso-occlusive events with physiologic stress.
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PMID:Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. 1530 66

Erythrocyte magnesium (Mg2+) deficiency has been demonstrated in sickle cell disease to contribute to erythrocyte dehydration, K loss, and thus sickling. No studies have assessed the functional properties of the Na/Mg exchanger in sickle cell disease. Using Mg(2+)-loaded erythrocytes, we measured Mg2+ efflux induced by extracellular Na+. We estimated that the Na/Mg exchanger had higher maximal velocity, higher affinity for Na+, and lower cooperativity for Mg2+ in sickle than in normal erythrocytes. The activity of the exchanger was markedly decreased by hypotonic and hypertonic conditions in normal erythrocytes but not in sickle erythrocytes. Studies of density-separated erythrocytes showed that the activity of the exchanger decreased as the mean cellular hemoglobin concentration increased in normal but not in sickle erythrocytes. Inhibition of protein kinase C (PKC) activity by calphostin C and chelerythrine increased the activity of the exchanger in normal but not in sickle erythrocytes. Inhibition of serine/threonine phosphatases did not affect the activity of the exchanger in either normal or sickle erythrocytes. Altogether, these data indicate that the Na/Mg exchanger is abnormally regulated in sickle erythrocytes. Therefore, Mg2+ depletion in sickle erythrocytes might be mediated by an up-regulated Na/Mg exchanger, possibly by dephosphorylation of the transporter or a closely associated regulator.
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PMID:Abnormal regulation of Mg2+ transport via Na/Mg exchanger in sickle erythrocytes. 1535 77

The aim of the study was to investigate, whether (a) patients with homozygous sickle cell disease (SCD, HbSS) have abnormal blood fatty acids; (b) the abnormality, if it exists, affects all the plasma and erythrocyte lipids or it is restricted to a particular lipid moiety; (c) there is an association between levels of membrane n-3 or n-6 long-chain polyunsaturated fatty acids (LCPUFA) and the degree of anaemia. Fatty acids of erythrocyte choline (CPG), serine (SPG) and ethanolamine (EPG) phosphoglycerides and sphingomyelin (SPM); and plasma CPG, triglycerides and cholesterol esters of 43 steady-state HbSS patients and 43 ethnically matched, healthy, HbAA controls were analysed. The levels of the n-6 LCPUFA, arachidonic (AA), adrenic and docosapentaenoic acids in erythrocyte CPG (P<0.001) and EPG (P<0.01) were higher in the patients compared with the controls. In contrast, the proportions of eicosapentaenoic acid (EPA) in CPG and EPG (P<0.001) and docosahexaenoic acid (DHA) and total n-3 metabolites in CPG (P<0.001) were lower in the patients. The steady-state haemoglobin level of the patients correlated with erythrocyte DHA (r=0.55, P<0.01), EPA (r=0.38, P<0.05) and total n-3 metabolites (r=0.51, P<0.001) in CPG. Also, it correlated with erythrocyte EPA (r=0.64, P<0.01) and total n-3 metabolites (r=0.42, P<0.01) in EPG. The study revealed an imbalance between n-3 and n-6 LCPUFA in erythrocyte and plasma lipid moieties of the HbSS group. Furthermore, it suggested that correction of the imbalance by supplementation with EPA and DHA could ameliorate anaemia in the patients. This observation is consistent with the results of pilot studies, which demonstrated that treatment with n-3 fatty acids confers clinical benefit to sickle cell patients.
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PMID:Steady-state haemoglobin level in sickle cell anaemia increases with an increase in erythrocyte membrane n-3 fatty acids. 1587 28

Lutheran (Lu) blood group and basal cell adhesion molecule (B-CAM) antigens reside on two glycoprotein (gp) isoforms Lu and Lu(v13) that belong to the Ig superfamily and differ only by the size of their cytoplasmic tail. Lu/B-CAM gps have been recognized as laminin alpha5 receptors on red blood cells and epithelial cells in multiple tissues. It has been shown that sickle red cells exhibit enhanced adhesion to laminin alpha5 when intracellular cAMP is up-regulated by physiological stimuli such as epinephrine and that this signaling pathway is protein kinase A- and Lu/B-CAM-dependent. In this study, we analyzed the relationship between the phosphorylation status of Lu/B-CAM gps and their adhesion function to laminin alpha5. We showed that Lu isoform was phosphorylated in sickle red cells as well as in erythroleukemic K562 and epithelial Madin-Darby canine kidney cells and that this phosphorylation is enhanced by different stimuli of the PKA pathway. Lu gp is phosphorylated by glycogen synthase kinase 3 beta, casein kinase II, and PKA at serines 596, 598, and 621, respectively. Alanine substitutions of serines 596 and 598 abolished phosphorylation by glycogen synthase kinase 3 beta and casein kinase II, respectively, but had no effect on adhesion of K562 cells to laminin under flow conditions. Conversely, mutation of serine 621 prevented phosphorylation by PKA and dramatically reduced cell adhesion. Furthermore, stimulation of K562 cells by epinephrine increased Lu gp phosphorylation by PKA and enhanced adhesion to laminin. It is postulated that modulation of the phosphorylation state of Lu gp might be a critical factor for the sickle red cells adhesiveness to laminin alpha5 in sickle cell disease.
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PMID:Protein kinase A-dependent phosphorylation of Lutheran/basal cell adhesion molecule glycoprotein regulates cell adhesion to laminin alpha5. 1597 31

Sickle cell disease (SCD) is a group of inherited blood disorders in which clinical illness results from the presence of erythrocytes with sickled haemoglobin (HbS). Blood vessel occlusion is a fundamental pathological process in SCD. Sickle cell haemoglobin C (HbSC) disease and sickle cell anaemia (HbSS) share some pathophysiology and clinical manifestations. However, the former is generally less severe. Erythrocytes of HbSC patients have longer life span, reduced haemolysis, and lower propensity to adhere to vascular endothelium than those of their HbSS counterparts. The structure and function of erythrocytes are strongly modulated by membrane long chain polyunsaturated fatty acids (LCPUFA). We have tested the possibility that HbSC and HbSS patients have different membrane fatty acid composition consistent with the difference in their clinical severity. Steady-state patients, 9 HbSC and 28 HbSS, and 15 HbAA were studied. The HbSC patients had a higher level of linoleic (LA, P<0.05) and docosahexaenoic (DHA, P<0.05) acids, and lower arachidonic acid (AA, P<0.01) and AA/eicosapentaenoic acid (EPA) ratio (P<0.05) in erythrocyte choline phosphoglycerides (CPG) compared with the HbSS group. Similarly, the level of EPA was higher and AA/EPA ratio (P<0.01) lower in serine phosphoglycerides of the HbSC patients. In contrast to the HbSC, the HbSS group had lower levels of EPA (P<0.001), DHA (P<0.05), total n-3 metabolites and total n-3 fatty acids (P<0.001) in erythrocyte CPG compared with the healthy HbAA controls. Moreover, the HbSS patients with disease complications compared with those without complications had reduced DHA and total n-3 fatty acids (P<0.005) in erythrocyte CPG. The abnormalities in erythrocyte in LCPUFA which is manifested by an increase in AA and a decrease in EPA and DHA in HbSS relative to HbSC disease observed in this study are consistent with the contrast in clinical severity between the two entities.
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PMID:Abnormality of erythrocyte membrane n-3 long chain polyunsaturated fatty acids in sickle cell haemoglobin C (HbSC) disease is not as remarkable as in sickle cell anaemia (HbSS). 1631 81


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