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At least 397 records · Page 22Linked to original sources
PubMed1988

Bis-pyridoxal polyphosphates: a new class of specific intramolecular crosslinking agents for hemoglobin.

A series of compounds related to bis-pyridoxal phosphate has been synthesized and used to crosslink deoxyhemoglobin. The yield of crosslinked hemoglobin increased dramatically from about 15% for the di- or triphosphate to about 70% for the tetraphosphate. The site of attachment of the intramolecular crossbridge was found to be from the N-terminal amino group of one beta chain to lysine 82 of the other. Since the distance between these residues is only 11A, the bis-pyridoxal tetraphosphates probably have a "stacked" conformation. The crosslinked hemoglobins bind oxygen cooperatively but with a greatly decreased affinity. The increased ability to unload oxygen together with the stabilization of the tetramer qualifies them as promising cell-free blood substitutes.

Cross-Linking Reagents↗
PubMed1977

Linear electric field effect in electron paramagnetic resonance for two bisimidazole--heme complexes, model compounds for B and H hemichromes of hemoglobin and for cytochrome b5.

Bisimidazole-ferric heme is considered to be the structure at the heme site of cytochrome b5 and two different low spin ferric hemochromes spontaneously formed from ferric hemoglobin. The addition of strong base to bisimidazole-ferric heme in organic solvents alters the optical and magnetic properties of this compound. With the use of the linear electric field effect in the electron paramagnetic resonance, we demonstrate that addition of base does not lead to the exchange of hydroxide anion for ligated imidazole and that the bisimidazole structure is retained. Analysis of optical titrations indicates that 2 equiv of base react reversibly with bisimidazole-ferric heme. It is suggested that the two hemichromes formed from hemoglobin differ in structure from one another by the state of protonation of N-1 in the bound imidazoles.

Binding Sites↗
PubMed1990

Induction of fetal hemoglobin by cell-cycle-specific drugs and recombinant erythropoietin.

During the last several years, studies in humans and experimental animals have identified several compounds that induce fetal hemoglobin in the adult. These include: cell-cycle-specific drugs, other cytotoxic drugs, butyric acid analogs, and erythropoietin. Several of these compounds induce fetal hemoglobin indirectly by triggering kinetics of rapid erythroid regeneration. High doses of erythropoietin increase the frequency of erythroid progenitors programmed to hemoglobin F. This results in transient increases of hemoglobin F-containing cells (F cells) in the peripheral blood. Erythropoietin and hydroxyurea increase F cells in a cooperative fashion. Although high doses of erythropoietin can induce F cell production in humans, the practical relevance of such observations is unclear

Anemia, Sickle Cell↗
PubMed1993

Hemoglobin adducts of N-substituted aryl compounds in exposure control and risk assessment.

Arylamines, nitroarenes, and azo dyes yield a common type of metabolite, the nitroarene, which produces a hydrolyzable adduct with protein and is closely related to the critical, ultimate toxic and genotoxic metabolite. The target dose as measured by hemoglobin adducts in erythrocytes reflects not only the actual uptake from the environment but also an individual's capacity for metabolic activation and is therefore an improved dosimeter for human exposure. The usefulness of hemoglobin adducts in molecular epidemiology is now widely recognized. With regard to risk assessment, many questions need to be answered. The described experiments in rats address some of these questions. The relationship between binding to hemoglobin in erythrocytes and to proteins in plasma has been found to vary considerably for a number of diamines. The fraction of hydrolyzable adducts out of the total protein adducts formed also varies in both compartments. This indicates that the kind of circulating metabolites and their availability in different compartments is compound specific. This has to do with the complex pattern of competing metabolic pathways, and the role of N-acetylation and deacetylation is emphasized. An example of nonlinear dose dependence adds to the complexity. Analysis of hemoglobin adducts reveals interesting insights into prevailing pathways, which not only apply to the chemical, but may also be useful to assess an individual's metabolic properties. In addition, it is demonstrated that the greater part of erythrocytes and benzidine-hemoglobin adducts are eliminated randomly in rats, i.e., following first-order kinetics.

Amines↗
PubMed2000

AANA journal course: update for nurse anesthetists--the ruddy globule: the erythrocyte--its biology, chemistry, and functional variations.

Red blood cells were first observed in the mid-1600s and termed ruddy globules for their conspicuous shape and color. Since that time, the functional significance of this extraordinary membranous pouch of proteins and electrolytes has been carefully detailed. The architecture of the red blood cell, the biochemistry of hemoglobin, the mechanics of the oxygen-hemoglobin affinity-altering diphosphoglycerate compounds, and the variants of hemoglobin are reviewed. Far from being a simple transport vehicle of oxygen to and from tissues, the red blood cell is a multifunctional entity whose absence would make life as we know it impossible.

2,3-Diphosphoglycerate↗
PubMed2007

Evaluation of different iron sources and their influence in biofilm formation by the dental pathogen Actinobacillus actinomycetemcomitans.

Actinobacillus actinomycetemcomitans, a pathogen associated with oral and extra-oral infections, requires iron to grow under limiting conditions. Although incapable of producing siderophores, this pathogen could acquire iron by direct interaction with compounds such as haemin, haemoglobin, lactoferrin and transferrin. In this work the ability of different A. actinomycetemcomitans strains to bind and use different iron sources was tested. None of the strains tested used haemoglobin, lactoferrin or transferrin as sole sources of iron. However, all of them used FeCl(3) and haemin as iron sources under chelated conditions. Dot-blot binding assays showed that all strains bind lactoferrin, haemoglobin and haemin, but not transferrin. Insertion inactivation of hmsF, which encodes a predicted cell-envelope protein related to haemin-storage proteins produced by other pathogens, reduced haemin and Congo red binding drastically without affecting haemin utilization as an iron source under chelated conditions. Biofilm assays showed that all strains tested attached to and formed biofilms on plastic under iron-rich and iron-chelated conditions. However, scanning electron microscopy showed that smooth strains formed simpler biofilms than rough isolates. Furthermore, the incubation of rough cells in the presence of FeCl(3) or haemin resulted in the formation of more aggregates and microcolonies compared with the fewer cell aggregates formed when cells were grown in the presence of the synthetic iron chelator dipyridyl. These cell responses to changes in extracellular iron concentrations may reflect those that this pathogen expresses under the conditions it encounters in the human oral cavity.

2,2'-Dipyridyl↗
PubMed2000

Oral isobutyramide therapy in patients with thalassemia intermedia: results of a phase II open study.

A pilot phase II open study on 12 patients with thalassemia intermedia (7 men, 5 women; age 31 +/- 2.0 years SE) treated with oral isobutyramide, a derivative of butyric acid (150 mg/kg body wt/day), was performed in order to evaluate the effect of this compound in stimulating hemoglobin F (HbF) production. No patient underwent blood transfusion in the 1-year time frame prior to the study. Nine patients were splenectomized. Safety was monitored by clinical and laboratory tests. Efficacy was assessed in terms of the non-alpha/alpha globin chain biosynthetic ratio and the percentage increase of HbF. The study design consisted of a screening phase, a treatment phase of 28 days, and a posttreatment follow-up of 28 days. All patients completed the study. Compliance to treatment was 100%. No drug-related adverse event was recorded. We observed little or no increase in the non-alpha/alpha ratio in the majority of patients. Six patients showed a percentage increase of HbF at the end of treatment and in 5 of those 6 further increases at the end of the follow-up period were observed. The change in percentage of HbF over time was close to significance both in the treatment period (P = 0. 06) and in the follow-up period (P = 0.08). These results indicate that butyrate derivatives can stimulate fetal hemoglobin in patients with intermediate thalassemia. Testing of the effects of different schedules of administration of isobutyramide will be required in order to determine the optimal use of this compound in the treatment of the beta-thalassemia syndromes.

Administration, Oral↗
PubMed1993

Butyrate-induced reactivation of the fetal globin genes: a molecular treatment for the beta-hemoglobinopathies.

The inherited beta-hemoglobinopathies (sickle cell disease and beta thalassemia) are the result of a mutation in the adult (beta) globin gene. The fetal globin chain, encoded by the gamma globin genes, can substitute for the mutated or defective beta globin chain, but expression of the gamma globin gene is developmentally inactivated prior to birth. Re-inducing expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and the beta thalassemias. Stimulation of as little as 4-8% fetal globin synthesis in the bone marrow can produce > 20% fetal hemoglobin in the peripheral circulation, due to enhanced survival of red blood cells containing both sickle and fetal hemoglobin, compared to those containing sickle hemoglobin alone. Butyric acid and butyrate derivatives are generally safe compounds which induce fetal hemoglobin production by stimulating the promoter of the fetal globin genes. An initial trial with the parent compound, delivered as Arginine Butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that have been shown to ameliorate these conditions. Phase 1 trials of an oral butyrate derivative with a long plasma half-life have just begun. These agents now provide a specific new approach for ameliorating these classic molecular disorders and merit further investigation in larger patient populations.

Amides↗
PubMed1980

Intrahematic crystallization of hemoglobin related to blood preservation with acid citrate dextrose and shock.

In 480 investigations and 40 samples of blood stored liquid with acid citrate dextrose, under adequate conditions for morphological study, many crenated cells of echinocyte types II-III were observed. In 17 samples of blood within 17-21 days of preservation 80-100% crenated red cells were observed including spherocytes. The filterability test performed with significant differences of P < 0.001. In 45 critically ill patients filterability was increased by more than 50%, P < 0.001. Some samples of stored blood appear anisotropic in polarized light microscopy, proving internal crystallization of hemoglobin, the only compound in the blood from some patients in shock and following massive transfusion of 3.5-4 liters. The phenomenon, undoubtedly could give evidence for the participation of internal crystallization of hemoglobin in the late stages of transformation of red cells into crenated shape with two possible factors being incriminated: the participation of membrane or crystallization of Hb. Anisotropic, birefringent, red cells indicate great modification in the specific viscosity of erythrocytes in above conditions. The data are in keeping with the findings of Taube, Massuda and Shoemaker (1973) who suggested that changes in the viscosity of the blood in traumatized patients may be related to alterations in the internal viscosity of the red cell.

Blood Preservation↗
PubMed2005

Hemoglobin D/beta-thalassemia and beta-thalassemia major in a Saudi family.

The present report describes the clinical, hematological and molecular characteristics in a family with unique interaction between 3 different mutations discovered during routine workup for bone marrow transplantation. In this report, complete hematological and molecular studies were performed for a large Saudi family. The family consisted of parents and 9 children, which revealed that the father is compound heterozygous for hemoglobin Hb D Punjab/beta-thalassemia, the mother is a carrier for beta-thalassemia and 3 of their children are transfusion dependent beta-thalassemia. Two of the children are compound heterozygous for Hb D Punjab/beta-thalassemia like the father but with different genotype. The other 2 children have Hb D Punjab traits while 2 other children have beta-thalassemia traits. Although, compound heterozygous for Hb D/beta-thalassemia has been well described in the literature, our report emphasizes the importance of careful analysis of the electrophoresis results and the usefulness of molecular studies in premarital screening and other screening hemoglobinopathy programs.

Adolescent↗
PubMed1992

Comparison of methemoglobin formers in protection against the toxic effects of cyanide.

1. Certain compounds that oxidize hemoglobin to methemoglobin (MHb) also protect against cyanide. 2. Evidence presented here suggests that other mechanisms may be involved. 3. Male Swiss ICR mice were pretreated intraperitoneally (i.p.) with various doses of primaquine phosphate (primaquine), WR6026 (6-methoxy-8-(6-diethylamino-hexylamino) lepidine dihydrochloride), WR238605 (8-[(4-amino-1-methylbutyl) amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy) quinoline succinate), p-aminooctoyl-phenone (PAOP), or p-aminopropiophenone (PAPP). 4. The compounds were administered 15 or 60 min before an intramuscular (i.m.) challenge with a 2 x LD50 dose (5.0-5.6 mg/kg) of sodium cyanide (NaCN). 5. Twenty-four hr mortality was assessed and survivors were tested for motor incapacitation. 6. Primaquine, PAPP and PAOP increased survival compared to untreated controls, while the other MHb formers were not effective (P less than 0.05). 7. PAOP is believed to form sufficient MHb only after 3 to 4 hr after administration; however it was found to be effective when administered 15 min before NaCN challenge in this study. 8. This suggests that MHb formation may not be the only factor responsible for PAOP's anti-cyanide efficacy.

Aminoquinolines↗
PubMed1982

Regulation of hemoglobin function and whole blood oxygen affinity by carbon dioxide and pH in the loggerhead (Caretta caretta) and green sea turtle (Chelonia mydas mydas).

The oxygen affinity of suspensions of erythrocytes from juvenile and adult loggerhead (Caretta caretta) and green sea (Chelonia mydas mydas) turtles decreased markedly with increasing concentrations of carbon dioxide (0 to near 15%) or hydrogen ion (pH 7.6 to pH 7.2). The P50's were higher with increases in pCO2, particularly at pH near 7.4, than were the P50's with increases in hydrogen ion concentration at any given CO2 concentration. Solutions of hemoglobins from the juvenile loggerhead (8-9 mos.) and green sea (10 mos.) turtles responded to 2, 3-DPG, ATP, or inositol-P5 when added at molar ratios of phosphate to hemoglobin of 4:1 and 20:1 in 0% and 6.29% CO2 but showed no decrease in oxygen affinity at these two CO2 levels in the green turtle when the molar ratio of phosphate to hemoglobin was 0.4. These compounds had little effect on the P50 of these hemoglobins in 14.6% CO2. The P50 of the adult loggerhead turtle hemoglobin did not increase in the presence of organic phosphates beyond the effect induced by CO2 alone. The P50 of hemoglobin from the adult green sea turtle increased only slightly when the molar ratio of phosphate to hemoglobin was 20:1 and at 0 and 6% CO2 concentration; little effect was observed at 14.6% CO2. These data demonstrate that blood oxygen affinities and hemoglobin function in these two species of marine turtles are altered significantly by CO2 and to a lesser degree by pH. It is suggested that such alterations may be of significance in vivo during prolonged diving when there are dramatic rises in blood pCO2 and [H+] and profound decreases in pO2.

Animals↗
PubMed1994

alpha-Amino butyric acid cannot reactivate the silenced gamma gene of the beta locus YAC transgenic mouse.

Butyric acid, a naturally occurring fatty acid, has been shown to increase fetal hemoglobin in BFUe cultures, in primates, and in patients with beta chain hemoglobinopathies. The precise mechanism of gamma gene induction by butyrate is unknown. Butyrate may induce fetal hemoglobin production in vivo by reactivation of silenced gamma globin genes, by inhibiting the silencing of gamma genes, or by both mechanisms. We examined the effects of butyrate on gamma gene expression in transgenic mice carrying three types of constructs: microLCRA gamma mice, which continue to express the gamma gene in the adult stage of development at a level of one-third to one-fifth of the expression in the fetus; microLCRA gamma psi beta delta beta mice, which display correct developmental regulation of gamma and beta human globin genes and have low level gamma globin expression in the adult; and beta locus YAC mice, which display correct developmental regulation of epsilon, gamma, and beta globin genes and have a totally silenced gamma gene in the adult stage. Animals were treated with a continuous infusion of alpha-amino butyric acid (alpha-ABA) for 7 days. In microLCRA gamma mice alpha-ABA produced up to a 43-fold induction of gamma and 9-fold induction of mouse alpha globin genes. In contrast, butyrate did not induce gamma globin expression in the beta locus YAC mice. However, the gamma globin genes of beta locus YAC mice were activated after administration of 5-azacytidine (5-azaC), and the level of gamma globin expression was further increased by administration of alpha-ABA. These results suggest that butyrate cannot reactivate a totally silenced gamma gene and that induction of fetal hemoglobin by this compound may require the presence of preactivated gamma globin genes.

Aminobutyrates↗