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

The effects of amino acids, several aromatic compounds, and peptides on the gelation and solubility of deoxyhemoglobin S have been studied. The aromatic amino acids (tryptophan, phenylalanine, and possibly tyrosine) significantly inhibited the rate of gel formation and increased solubility. The dipeptide L-Thr-L-Phe, the tripeptide L-Lys-L-Phe-L-Phe, and various phenylalanine analogues (hydrocinnamic acid, phenethylamine, benzamine, and amphetamine) also inhibited gelation. However, aromaticity is not a sufficient condition for inhibiting gelation as shown by the fact that several aromatic compounds (acetylsalicylic acid, salicyclic acid, aniline, and phenol) enhanced gelation. Surprisingly, several oligopeptides (betaS1--12, betaS4--8, betaS3--13, and betaS4--10) also enhanced gelation. All of these additives follow the supersaturation relationship that the delay time for gelation is proportional to the ratio of the total hemoglobin concentration to the solubility of deoxyhemoglobin S to the nth power (n approximately 35). A possible mechanism for the action of these inhibitors is considered in terms of a specific site of interaction on the hemoglobin molecule. Although none of these compounds may prove to be efficacious in treatment of sickle cell anemia, they should yield information about the structure and process of formation of the deoxyhemoglobin S gel.
 ...
PMID:Inhibition of sickle hemoglobin gelation by amino acids and related compounds. 72 8

A number of tri- and tetrapeptides have been found to inhibit aggregation and gelation of deoxygenated sickle cell hemoglobin. These inhibitors have hydrophobic phenylalanine residues at one end and hydrogen bonding lysine or arginine side chains at the other end. The backbone is not very specific. The inhibitors do not modify the oxygen carrying properties of hemoglobin. When the inhibitor and sickle hemoglobin are put inside reconstituted cells, the erythrocytes do not sickle upon deoxygenation. Compounds of this type may develop useful agents in the therapy of sickle cell anemia.
 ...
PMID:Sickle hemoglobin aggregation: a new class of inhibitors. 87 Sep 76

The amounts of phenylalanine and hydroxybenzoic acid in a Cajanus cajan methanolic extract were estimated. Results showed that the amount of phenylalanine and hydroxybenzoic acid per gram weight of bean was 4.92 mg +/- 0.13 mg and 21.0 mg +/- 3.0 micrograms, respectively. Sickling inhibition was observed to be efficient with the extract which contains a mixture of phenylalanine (0.69 mg/ml) and p-hydroxybenzoic acid (10.5 micrograms/ml), equivalent to those found in bean extract. The additive antisickling effect of both compounds can be therapeutically exploited for the treatment of sickle cell anemia.
 ...
PMID:Antisickling activity of hydroxybenzoic acids in Cajanus cajan. 143 91

Neuraminic (sialic) acid concentrations in serum from normal and sickle cell (HbSS) subjects were determined for discrete age groups from childhood through adolescence. Values in sickle cell disease were consistently lower over the entire age range. We further investigated the effect of exogenous sialic acid on the rate of sickling reversion of HbSS erythrocytes and demonstrated that this compound in millimole per liter concentrations could revert pre-sickled erythrocytes to their normal morphology in a concentration-dependent manner. When subjected to partial de-sialation with sialidase (EC 3.2.1.18), the HbSS erythrocytes not only sickled faster upon deoxygenation, they also reverted more slowly on treatment with phenylalanine (a more efficient anti-sickling agent than sialic acid) than did untreated cells. We conclude that, in sickle cell disease, erythrocyte sialic acid content could play a significant role, not only in the control of the sickling rate in vivo, but also, after sickling has occurred, in the rate of recovery from a sickling crisis.
 ...
PMID:Sialic acid in sickle cell disease. 339 Sep 14

Polymorphonuclear leukocyte (PMN) aggregation and chemotaxis were studied in 27 patients with sickle cell disease (SCD). Pain-free patients with SCD had a significantly impaired aggregation response to stimulation with n-formylmethionyl-leucyl-phenylalanine (FMLP) with or without cytochalasin B (CB), compared with normal volunteers (p less than 0.001). Patients with SCD in vaso-occlusive crisis had PMN aggregation induced by FMLP with or without CB that was significantly increased compared with the cohort of pain-free SCD patients (p less than 0.001). PMN from pain-free patients had normal chemotaxis, whereas patients in vaso-occlusive crisis had a significant impairment in PMN chemotaxis. PMN chemotaxis was inversely related to the PMN aggregation response to FMLP with CB (r = -0.75). Thus, the PMN from pain-free patients with SCD appears to have normal or decreased "stickiness" and to develop increased stickiness during vaso-occlusive crisis. The mechanisms responsible for these changes need further elucidation. Alterations in PMN function may be responsible, in part, for the increased risk of infection noted in individuals with SCD and may play a role in the development of the acute chest syndrome.
 ...
PMID:Vaso-occlusive crisis-associated neutrophil dysfunction in patients with sickle-cell disease. 366 21

Phenylalanine or tryptophan entrapped in small unilamellar liposomes was used to transport Phe or Trp across the red blood cell membrane. The incorporation of Phe or Trp into RBCs via liposomes markedly inhibited and reversed the in vitro sickling of deoxy Hb S. Furthermore, normal and SS RBCs loaded with Phe or Trp did not exhibit significant change in osmotic fragility, mechanical fragility, autohemolysis, and glycolysis when compared to untreated RBCs. In addition, the oxygen affinity measured as the P50 and concentrations of 2,3-DPG and ATP were not affected by the incorporation of Phe or Trp into AA or SS RBCs. These results demonstrate that this liposomal transport system which transferred Phe and Trp into intact RBCs did not have any adverse effect on RBC metabolism and function, and may have therapeutic implications in the treatment of sickle cell disease.
 ...
PMID:Liposome-loaded phenylalanine or tryptophan as sickling inhibitor: a possible therapy for sickle cell disease. 367 19

Phenylalanine or tryptophan was incorporated into AA and SS red blood cells by a liposomal transport system which was previously shown by Kumpati to inhibit and reverse sickling of intact SS red blood cells in vitro. In the present study, the effect of phenylalanine or tryptophan incorporation on the rheological properties was evaluated. The incorporation of phenylalanine or tryptophan into red blood cells decreased the viscosity of deoxy SS red blood cells which reached a level close to that for normal red blood cells due to the antisickling effect. These results demonstrate that this liposomal transport system which transferred phenylalanine or tryptophan into intact red cells and did not have any adverse effect on red cell metabolism or function did correct the viscosity of deoxy SS red cells by its antisickling effect. This method may have significant therapeutic implications in the treatment of sickle cell disease.
 ...
PMID:Effect of phenylalanine- or tryptophan-loaded liposomes on the rheological properties of AA and SS erythrocytes. 367 24

Mixtures of tripeptides of the form Ala-X-Ala-O-tert-butyl with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers have been used as a model system for studying the influence of hydrophobic peptides on membrane order and dynamic properties by means of deuterium NMR spectroscopy. Tripeptides with X = Ala, Leu, Phe, and Trp have been examined. Lipid 2H NMR spectra of acyl chain perdeuteriated DMPC ([2H54]DMPC) show that the addition of peptide disorders the bilayer lipid acyl chains and that the extent of the perturbation increases as the size of the central residue increases. Moment analyses of the spectra indicate that, while the average acyl chain order parameter decreases with increasing central residue size, the order parameter spread across the bilayer (the mean-squared width of the distribution) increases. Lipid segmental 2H longitudinal relaxation rates, 1/T1(i), exhibit a square-law functional dependence on SCD(i) both with and without the addition of peptide. The addition of peptide causes an increase in the slope of plots of 1/T1(i) vs. (SCD(i))2 with little change in the 1/T1(i) intercept, indicating a complex modulation of the acyl chain motions. 2H NMR spectra of Ala-[2H4]Ala-Ala-O-tert-butyl in DMPC bilayers have both isotropic and powder pattern components that vary as a function of temperature. At 30 degrees C the 2H spin-lattice relaxation times for the labeled Ala residue increase in going from bilayer-incorporated peptide to polycrystalline peptide to polycrystalline Ala.HCl. These experiments provide no information on the location of these peptides in the bilayer.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Lipid bilayer perturbations induced by simple hydrophobic peptides. 368 66

The sickle erythrocyte (RBC) is a pathologic RBC that contains multiple membrane abnormalities. Some of these abnormalities have been implicated in the pathophysiology of vasoocclusive crises characteristic of sickle cell disease; others have yet to be defined in terms of their clinical significance. Recent information has shown that sickle RBC adhere abnormally to cultured endothelial cells yet little is known about the ways in which sickle cells interact with model membranes of defined size and lipid composition. We investigated this phenomenon by interacting sickle RBC with artificial lipid vesicles (liposomes) containing acidic phospholipids. Our results demonstrate that sickle disease (hemoglobin SS) RBC bind more of these liposomes than do normal or sickle trait (hemoglobin AS) RBC and that these differences are accentuated by hypoxia-induced sickling. Binding of liposome phospholipid to sickled RBC was not attributable to phospholipid exchange between liposomes and RBC and was consistent with a mechanism involving both membrane fusion and a stable reversible adhesion of liposomes to the RBC membrane.Investigations into the mechanism(s) underlying increased liposome binding to sickled RBC suggested that the known reversible translocation of aminophospholipids, phosphatidylserine (PS) and phosphatidyl-ethanolamine (PE), from the inner to the outer leaflet of the reversibly sickled RBC (RSC) plasma membrane during sickling may be a component of increased liposome binding to RSC. This idea was supported from results of experiments in which normal RBC were treated with diamide resulting in the expression of outer leaflet PE and PS and a stimulation of liposome binding to these cells. However, sickle RBC separated according to cell density on stractan gradients showed that irreversibly sickled RBC (ISC) were less capable of liposome binding than were discoid RSC. Since ISC are known to contain elevated levels of outer leaflet aminophospholipids, such a result suggests that other changes in the plasma membrane of sickle cells, in addition to phospholipid reorganization, are probably involved in enhanced liposome binding to these cells. In other experiments, we showed that liposomes containing l-phenylalanine were capable of delivering this antisickling agent into intact sickle RBC as demonstrated by the partial inhibition of hypoxia-induced sickling in vitro. Our results suggest that liposomes can be used as sensitive probes for investigating changes in RBC membrane properties, especially those that affect intermembrane interactions, and that liposomal transport systems may have significant implications in the therapy of sickle cell disease.
 ...
PMID:Interaction of phosphatidylserine-phosphatidylcholine liposomes with sickle erythrocytes. Evidence for altered membrane surface properties. 640 22

N-Phenylacetyl-L-phenylalanine (PAP) and L-phenylalanyl-3-aminopyridine ( PAPA ) are biaromatic agents with properties that make them suitable candidates for the development of a useful therapeutic agent for the treatment of sickle cell disease. PAP and PAPA are taken up by the erythrocyte to give intra-/extracellular concentration ratios of 2.2 and 1.5, respectively, after a 2-hr exposure period. The intracellular buildup of PAP and PAPA produces moderate decreases in the mean corpuscular hemoglobin concentration (MCHC) of 6 and 10%, respectively, at 3 mM and a further decline in MCHC with increased concentration. Both PAP and PAPA increase the deoxy-Hb S solubility, CS. If the solubility in the absence of the agent is COS, PAP and PAPA have CS/COS values of 1.21 and 1.14 at 20 mM, respectively, compared with a value of 1.06 for L-phenylalanine itself. Filterability assays of partially dexygenated homozygous sickle cells shows an increase in cell flexibility of 7 to 16 times more than that of untreated cells when these agents are present at 3-6 mM. These results are largely due to the reduction in the Hb S polymer content of the treated cells. At 3 mM or less, both PAP and PAPA delay the onset of gelation in reversible sickle cells for time periods that are likely to be therapeutically useful.
 ...
PMID:Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease. 658 44


1 2 3 Next >>