Toshio Asakura

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

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Publications (87)423.14 Total impact

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    ABSTRACT: The affiliation of one of the authors of Abdulmalik et al. (2011) [Acta Cryst. D67, 920-928] is corrected.
    Acta Crystallographica Section D Biological Crystallography 12/2011; 67(Pt 12):1076. · 7.23 Impact Factor
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    ABSTRACT: Vanillin has previously been studied clinically as an antisickling agent to treat sickle-cell disease. In vitro investigations with pyridyl derivatives of vanillin, including INN-312 and INN-298, showed as much as a 90-fold increase in antisickling activity compared with vanillin. The compounds preferentially bind to and modify sickle hemoglobin (Hb S) to increase the affinity of Hb for oxygen. INN-312 also led to a considerable increase in the solubility of deoxygenated Hb S under completely deoxygenated conditions. Crystallographic studies of normal human Hb with INN-312 and INN-298 showed that the compounds form Schiff-base adducts with the N-terminus of the α-subunits to constrain the liganded (or relaxed-state) Hb conformation relative to the unliganded (or tense-state) Hb conformation. Interestingly, while INN-298 binds and directs its meta-positioned pyridine-methoxy moiety (relative to the aldehyde moiety) further down the central water cavity of the protein, that of INN-312, which is ortho to the aldehyde, extends towards the surface of the protein. These studies suggest that these compounds may act to prevent sickling of SS cells by increasing the fraction of the soluble high-affinity Hb S and/or by stereospecific inhibition of deoxygenated Hb S polymerization.
    Acta Crystallographica Section D Biological Crystallography 11/2011; 67(Pt 11):920-8. · 7.23 Impact Factor
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    ABSTRACT: Hb Baden (β18Val→Met) is a rare variant hemoglobin that has never been functionally or clinically characterized. We describe a Hb Baden heterozygote who exhibits normal growth and development, as well as age- and gender-appropriate hematological values. Surprisingly, in vitro analyses demonstrate that Hb Baden is relatively unstable and exhibits an abnormally high affinity for O₂. These properties are likely to affect the physiologies of individuals who inherit the β(Baden) mutation in trans to a determinant for either a functionally relevant hemoglobinopathy or a mild thalassemia. The data also provide insights into the function of the A-helix/AB-segment of β globin, supporting a structural model in which this poorly understood region serves as a scaffold that fixes the positions of other helices that directly impact β-globin function.
    American Journal of Hematology 11/2010; 85(11):848-52. · 3.48 Impact Factor
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    ABSTRACT: The relationship of hemoglobin stability to ligand state as defined by heat and mechanical shaking tests The molecular stability of Hb Philly (α2 β235 (C1) Tyr→Phe) with different ligand states was compared with that of Hb A and Hb S using mechanical shaking and heat stability tests. The rates of mechanical denaturation of the oxy-forms of these hemoglobins decreased in the order of Hb S, Hb Philly, and Hb A, with relative ratios of 9.5: 5.6: 1.0. Upon oxidation to the met-forms, Hb Philly became mechanically most unstable, with ratios of 13.3: 23.0: 1.8, respectively. The deoxy-forms of Hb A and Hb S were very stable, while that of Hb Philly was as unstable as the oxy-form. The addition of inositol hexaphosphate (IHP) to deoxy-Hb Philly stabilized the molecules. Since IHP restores the cooperative oxygen binding of Hb Philly, deoxy-Hb Philly appears to combine with IHP to change the quaternary structure required for cooperative oxygen binding and for stabilization of the molecule. Heat stability tests on Hb Philly showed that the oxy- and met-forms were slightly more unstable than those of Hb A, while the deoxy- and carbonmonoxy-forms were as stable as those of Hb A. Results for heat stability tests showed that hemoglobin molecules are stabilized when converted to the deoxy- or carbonmonoxy-forms so that oxidation of hemoglobin into the met-form is prevented. These results indicate that the stability of hemoglobin depends highly on its ligand state, and that the stability of various ligand forms should be tested when hemoglobin stability is investigated.
    Hemoglobin 07/2009; 5(2). · 0.96 Impact Factor
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    ABSTRACT: The occurrence of hemoglobin Potomac (8101 Glu→Asp), an abnormal hemoglobin with increased oxygen affinity, has been previously reported in nine members of one kindred (1). We now present the second occurrence of this hemoglobin, in a 26 year old white female of mixed northern European extraction, and report the clinical picture and studies of the stability and biosynthesis of the abnormal hemoglobin.
    07/2009; 2(5):447-451.
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    ABSTRACT: The molecular stability and function of hemoglobin (Hb) Hasharon (α2Hβ2) and Hb Hasharon2 (α2 H δ2) were studied and compared to Hbs A, A2 and S. Hb Hasharon and Hb Hasharon had slightly lower P50 values than Hb A and Hb A2 but had normal responses to organic phosphates. The molecular stability of Hb Hasharon and Hb Hasharon (as measured by mechanical shaking and heat denaturation at 60° 6) were less than Hb A and Hb A2 but greater than Hb S in the oxy- and carbonmonoxy-forms. In the met-form, however, Hb Hasharon and Hb Hasharon2 were less stable than hemoglobins S, A and A2. The oxy-form of Hb Hasharon forms methemoglobin at a faster rate than Hb A and Hb S. The mechanical and heat stabilities and the rate formation of oxy-Hb Hasharon were studied in the presence of sulfisoxazole. This drug increased the rate of methemoglobin formation, thus causing a further decrease in the stability of Hb Hasharon. The relationship between these laboratory findings and previously observed clinical findings associated with Hb Hasharon are discussed.
    07/2009; 8(1):61-73.
  • Kou Uchida, Michael P. Reilly, Toshio Asakura
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    ABSTRACT: The hemoglobin types of mouse strains can be distinguished according to patterns observed on cellulose acetate electrophoresis. The two common mouse hemoglobin patterns are single and diffuse. The differences in the patterns result from differences in the β-globin chains of the hemoglobin molecules. Mice with the single hemoglobin pattern have one β-globin type identified as β-single (Hbbs), whereas mice with the diffuse hemoglobin pattern have two different β-globin types identified as β-major (Hbbmaj) and β-minor (Hbbmin). We examined the functional and stability properties in these mouse hemoglobins, and the oxygen binding properties of red blood cells obtained from mice with four different hemoglobin phenotypes: Hbbs/Hbbs, Hbbs/Hbbmin, Hbbmin/Hbbmin and Hbbmaj/Hbbmin. The P50, the partial pressure of oxygen at which hemoglobin is half-saturated, of purified forms of Hbbs, Hbbmin and Hbbmaj was 14.8 ± 0.4 mm Hg, 13.3 ± 0.6 mm Hg and 13.6 ± 0.5 mm Hg, respectively. The n value, determined from the slope of the Hill plot was 2.45 to 2.59 for the mouse hemoglobins. The alkaline Bohr effects of purified HbbS, Hbbmin and Hbbmaj were 0.69, 0.61 and 0.60, respectively. The mechanical stability of Hbbs, Hbbmin and Hbbmaj, expressed by the first order kinetic constant, were 0.098 ± 0.01/min, 0.027 ± 0.013/min and 0.27/min, respectively. The P50 of red blood cell suspensions from lines of mice expressing Hbbs/Hbbs, Hbbmin/Hbbmin, Hbbs/Hbbmin and Hbbmaj/Hbbmin were 40.2 ± 1.8 mm Hg, 40.4 ± 1.5 mm Hg, 38.9 ± 1.4 mm Hg, and 38.7 ± 0.9 mm Hg, respectively.
    ZOOLOGICAL SCIENCE 01/2009; · 0.88 Impact Factor
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    ABSTRACT: Oversaturated deoxy-alpha(2)beta(2)(T4V) aggregated instantly without a delay time, which is in contrast to the delay time before the generation of fibers of deoxy-HbS and deoxy-alpha(2)beta(2)(E6V,D73H). Solubility of deoxy-alpha(2)beta(2)(T4V) was approximately 10-fold lower than that of deoxy-HbS and was similar to oxy- and deoxy-alpha(2)beta(2)(E6V,T4V). These results indicate that beta4Val in HbA in the oxy and deoxy forms with or without beta6Val facilitates hydrophobic interaction of the A-helix with the EF helix of adjacent molecules without forming a beta4/beta73 hydrogen bond. Deoxy-HbA generated crystals following aggregation as does HbC-Harlem(alpha(2)beta(2)(E6V,D73N)), while alpha(2)beta(2)(T4V) and alpha(2)beta(2)(D73H) as well as HbS, alpha(2)beta(2)(E6V,D73H) and alpha(2)beta(2)(E6V,T4V) in the oxy and deoxy forms did not form crystals, indicating in addition to the strength of beta6 amino acid hydrophobicity that the synergism between the beta4Thr hydrogen bond and beta6 hydrophobic interaction free energies on the A-helix play a critical role in formation of fibers versus crystalline nuclei during phase transition.
    Archives of Biochemistry and Biophysics 01/2009; 481(2):137-44. · 3.04 Impact Factor
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    ABSTRACT: Compounds that bind to sickle hemoglobin (Hb S) producing an allosteric shift to the high-affinity Hb S that does not polymerize are being developed to treat sickle cell anemia (SCA). In this study, three series of pyridyl derivatives of substituted benzaldehydes (Classes I-III) that combine structural features of two previously determined potent antisickling agents, vanillin and pyridoxal, were synthesized. When analyzed with normal human whole blood, the compounds form Schiff-base adducts with Hb and left shift the oxygen equilibrium curve (OEC) to the more soluble high-affinity Hb, more than vanillin or pyridoxal. Generally, Class-I compounds with an aromatic aldehyde located ortho to the pyridyl substituent are the most potent, followed by the Class-II compounds with the aldehyde at the meta-position. Class-III compounds with the aldehyde at the para position show the weakest activity. The structure-activity studies of these pyridyl derivatives of substituted benzaldehydes demonstrate significant allosteric potency that may be useful for treating SCA.
    Chemistry & Biodiversity 10/2008; 5(9):1762-9. · 1.81 Impact Factor
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    ABSTRACT: Several analytical methods have been developed for the determination of arginase (l-arginine amidinohydrolase) activity in physiological samples. These methods are limited by the considerable effort and time required to obtain reliable and reproducible measurements. Here we describe a simple high-throughput colorimetric assay for the determination of arginase activity based on the ornithine-ninhydrin reaction. This method is an improvement over the original single cuvette assay developed by Chinard in that no boiling step is required. The turnaround time has been reduced, with improved precision and reproducibility. The method was extended to the determination of arginase activity in human leukemic (K562) cells and sickle erythrocytes. We believe that the method will find applications for routine analysis as well as for characterizing the action of novel and potent inhibitors on arginase activity.
    Analytical Biochemistry 09/2008; 383(2):332-4. · 2.31 Impact Factor
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    ABSTRACT: Assessment of hepatic iron concentration is important in the management of patients with thalassemia. The goal of this study was to investigate the relationships between the three MR transverse relaxation rates, R*(2), R(2) and R'(2), and hepatic iron content in a mouse model of thalassemia at 1.5 and 3 T field strengths. A GESFIDE (gradient-echo sampling of free induction decay and echo) pulse sequence was used to measure the three parameters efficiently in a single scan in a study examining the livers of normal and thalassemic mice, including a subgroup of the latter that were subjected to periodic transfusions. The results showed that R*(2), R(2) and R'(2) all correlated closely with liver iron concentration at both 1.5 T and 3 T, with correlation coefficients ranging from 0.72 to 0.79. High degrees of correlation (r = 0.93-0.99) were also observed among the three MR parameters at both field strengths. It can be concluded that the three rates could all be effective for assessing hepatic iron concentration and that imaging at higher fields may not offer any advantages over that at lower fields.
    NMR in Biomedicine 08/2008; 21(6):574-80. · 3.56 Impact Factor
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    ABSTRACT: To test the feasibility of a method to quantify regional pulmonary parenchymal motion via nonrigid registration algorithm at small animal scales. Voxel-wise displacement vector field maps were generated between end-inspiratory and end-expiratory coronal thoracic MR images on normal mice (N = 5) to analyze the magnitude and direction of parenchymal motion in the segmented regions. The analysis was repeated before and after short-term exposure to hypoxia to demonstrate the effect of hypoxia on the respiratory motion in transgenic (Tg) mice with sickle cell disease (SCD) (N = 4). Normal mice revealed that the right and left lungs moved symmetrically but that there was greater movement in the lower regions than in the upper regions. Calculated strain was uniform in the entire lung. In the Tg mice, the pulmonary motion before hypoxia was similar to that observed in the normal mice. Upon exposure to hypoxia, the displacement magnitude reduced and the direction of motion in some areas became distorted. MR quantification of pulmonary motion was feasible in mice and the principle that the method could detect mechanical abnormalities due to pathologic changes was proven. Quantification of pulmonary motion has the potential to lead to earlier disease diagnosis and better monitoring of disease treatments.
    Journal of Magnetic Resonance Imaging 02/2008; 27(1):49-56. · 2.79 Impact Factor
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    ABSTRACT: The aim of this study was to clarify the relative contributions of the amount of oxygen in the blood, and vasoconstriction/dilation responsible for changes in T1 and T2 observed in brain during hyperoxia. T1 and T2 values of the cerebral cortex and pituitary gland in mice were determined in room air. After room air was changed to either 100% oxygen (n = 8) or carbogen (n = 8), T1 and T2 values were again determined. Changes in each value with both gases were compared. In both challenges, T1 values of the cerebral cortex decreased, whereas significant T2 prolongation of the cerebral cortex and pituitary gland was demonstrated. However, both cortex and pituitary gland displayed similar responses in T1 and T2 values when exposed to 100% oxygen or carbogen. Reduction of T1 was introduced by the increased amount of dissolved oxygen in blood, and the increased fraction of oxyhemoglobin caused T2 prolongation. The contribution of vasoconstriction/dilation by carbogen to changes in T1 and T2 may be negligible.
    Journal of Computer Assisted Tomography 08/2007; 31(5):662-5. · 1.60 Impact Factor
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    ABSTRACT: We collected venous blood samples from 7 steady-state patients with homozygous sickle cell disease under venous oxygen pressure without exposure to air (UnExp-blood) and compared the morphological, oxygen-binding, and sickling properties with those of SS cells in aliquots of the same venous blood samples that were oxygenated in room air or at a PO2 near 180 mmHg (Exp-blood). Results showed that (1) upon deoxygenation under nitrogen, UnExp-blood generated a significantly higher percentage of elongated reversibly sickled cells (RSCs) than did Exp-blood; (2) upon gradual oxygenation of completely deoxygenated sickled cells, RSCs in UnExp-blood converted to discocytes at a higher oxygen pressure than did those in Exp-blood; (3) the degree of hysteresis between the sickling/desickling curves of UnExp-blood was greater than that of Exp-blood; and (4) deoxy-Hb S in hemolysate prepared from SS cells in UnExp-blood polymerized without a delay time, while those from Exp-blood polymerized with a distinct delay time. The in vivo properties of RSCs significantly changed upon oxygenation. We also found that the various properties of blood samples collected from patients with SCD by the ordinary method were similar to those of Exp-blood, probably because such blood samples are exposed to oxygen through air in the needle, syringe, and Vacutainer. Once SS cells were oxygenated, the in vivo properties of RSCs could not be recovered by partial deoxygenation to venous oxygen pressure.
    American Journal of Hematology 02/2006; 81(1):26-35. · 3.48 Impact Factor
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    ABSTRACT: We found various levels of a new type of reversibly sickled cell (RSC) with blunt edges in 44 blood samples obtained from 32 steady-state patients with sickle cell disease (SCD) without exposure to air (UnExp-blood). Because these RSCs could be generated in vitro by partial oxygenation of once-deoxygenated SS cells to venous oxygen pressure, we named them "partially oxygenated sickled cells" (POSCs). These RSCs were classified into elongated and non-elongated RSCs, depending on the ratio of the short axis to long axis. The presence of these cells was previously unknown because the standard blood collection method oxygenates most of the POSCs to discocytes due to oxygen in the air space in the needle, syringe, and blood collection tube (Exp-blood). Although the shape of elongated POSCs is similar to that of irreversibly sickled cells (ISCs), POSCs revert to discocytes upon exposure to air. We found the following: (1) the percentage of total sickled cells (total POSCs + ISCs) in UnExp-blood (29.0 +/- 14.5%) was significantly higher than the percentage of sickled cells (mainly ISCs) in Exp-blood (7.3 +/- 5.7%); (2) the percentage of sickled cells in UnExp-blood was specific to individual patients during steady state, while it decreased at the onset of a vaso-occlusive event; and (3) the percentage of sickled cells in UnExp-blood varied widely among steady-state patients (4-56%). This new type of RSC may be used as an internal biomarker to evaluate the disease state of individual patients.
    American Journal of Hematology 01/2006; 80(4):249-56. · 3.48 Impact Factor
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    ABSTRACT: An elevated erythrocyte arginase activity with a corresponding decrease in nitric oxide (NO) level has been implicated in the pathophysiology of sickle cell disease (SCD). Recent studies have shown that hydroxyurea (HU) increases the production of NO, which increases the soluble guanylate cyclase activity and fetal haemoglobin (HbF) synthesis. To study the effects of HU on the arginase and nitric oxide synthase (NOS) activities in SCD patients, we compared levels of arginase activity and NO metabolites in red blood cells and plasma, respectively, from 23 patients with SCD (HbSS) receiving HU therapy, with those of 12 SCD patients not receiving HU treatment. Patients on HU therapy showed significantly lower arginase activity than that of HbSS patients not on HU therapy (1.36+/-0.2 U/10(8) cells vs. 3.31+/-0.29 U/10(8) cells). NOS activity was higher in patients on HU therapy than in untreated patients (0.72+/-0.4 nmol/ml/min vs. 0.35+/-0.15 nmol/ml/min, P<0.05). Among the HU-treated patients, the decreased level of arginase activity correlated (r=0.71) with HbF level as well as the mean corpuscular haemoglobin content. These data suggest that one of the beneficial effects of HU in vivo may involve the regulation of arginase activity and a concomitant induction of NOS activity, which may lead to an increased production of NO. The outcome of this study may lead to the development of improved NO-based treatments for SCD.
    British Journal of Haematology 11/2005; 131(3):389-94. · 4.96 Impact Factor
  • Osheiza Abdulmalik, Daniel Obeng, Toshio Asakura
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    ABSTRACT: Sickle cell disease (SCD) is an inherited blood disorder characterised by polymerisation of deoxygenated intracellular sickle haemoglobin (HbS), leading to the deformation of red blood cells (RBC) and the assumption of various sickled shapes. These rigid sickled cells trigger a cascade of vaso-occlusive events, including local inflammation and endothelial injury, leading to painful episodes, chronic haemolytic anaemia and possible end-organ damage and premature mortality. As the first disease whose genetic aetiology was defined more than half century ago, SCD has attracted a great deal of attention from many scientists and researchers worldwide. This has led to major insights into the natural history of SCD, the pathophysiological importance of polymerisation of deoxygenated HbS, and approaches directed towards the prophylaxis or treatment of the complications associated with the disease. Despite such advances, medical management still remains suboptimal and SCD continues to be a significant cause of mortality, morbidity and health disparities worldwide. Hydroxyurea (HU), a potent inducer of fetal haemoglobin (HbF) that inhibits HbS polymerisation, is currently the only approved therapeutic agent for SCD therapy, but its long-term benefits and toxicities are controversial and are still being investigated. Over the past few decades, other novel mechanisms of SCD pathophysiology have been identified in addition to HbS polymerisation. Several of these mechanisms present appropriate targets for drug development and novel therapy for SCD. This article presents a review of potential candidate drugs that have been recently studied and patented as possible pharmacological treatment/management options for SCD.
    10/2005; 15(11):1497-1506.
  • Efemwonkiekie W Iyamu, Toshio Asakura
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    ABSTRACT: The hallmarks of sickle cell disease (SCD) are sickling-induced chronic haemolytic anaemia and acute painful events due to vaso-occlusion by rigid sickled cells. Repeated vaso-occlusive events may eventually lead to organ damage or death among patients with SCD. Several interrelated factors that may trigger sickling-dependent vaso-occlusion in SCD include infection, fever, dehydration, the density of red blood cells (RBCs), anomalies of the RBC membrane, blood viscosity and endothelial cell adhesion. In view of the remarkable advances in the understanding of the roles of these factors in the pathogenesis of SCD, attempts are being made to modulate these factors by targeting them with appropriate agents. To date, the most successful treatments of SCD include the pharmacological induction of fetal haemoglobin (Hb F) expression using hydroxyurea (HU) or butyrate and its derivatives. However, side effects and poor drug efficacy of some of these agents remain as an obstacle for many patients. In this review, promising agents that have been patented for possible therapeutic use in the treatment/management of SCD will be summarised. New therapeutic agents that have been patented in the last 5 years for possible treatment and management of SCD are catalogued with emphasis placed on new agents that are thought to induce Hb F synthesis or modify either sickle haemoglobin (Hb S) or intact sickle erythrocytes.
    Expert Opinion on Therapeutic Patents 03/2005; 13(6):807-813. · 3.44 Impact Factor
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    ABSTRACT: The crystal structures of R- and T-state hemoglobin (Hb) Bassett have been determined to 2.15 and 1.80 A resolution, respectively. Physiologically, Hb Bassett (alphaAsp94-->Ala) is characterized by a low affinity for oxygen, a reduced Bohr effect and low cooperativity, as well as being slightly unstable (compared with normal adult hemoglobin; HbA). Comparisons between the Hb Bassett structures and previously determined R- and T-state HbA structures revealed that this mutant shares similar tertiary and quaternary structures with other Hbs. However, this analysis did identify localized structural differences between R-state Hb Bassett and R-state HbA at the alpha1beta2 (alpha2beta1) dimer interface and at the beta-cleft. Specifically, the beta-FG corner has shifted closer to the alpha-C helix in the mutant R structure. In addition, four intersubunit hydrogen bonds found at the alpha1beta2 interfaces of native R-state Hb structures are abolished or weakened and subsequently replaced by two new intersubunit hydrogen bonds in R-state Hb Bassett. Remarkably, the newly formed hydrogen bonds in the R-state mutant structure are also observed in T-state Hb structures. At the beta-cleft, betaHis46, which is known to contribute to the Bohr effect in Hb, makes a unique hydrogen-bonding interaction with betaAsn139 in the R-state Hb Bassett. Unlike the R-state mutant, the T-state Hb Bassett structure does not display any significant structural changes at both the alpha1beta2 (alpha2beta1) dimer interface and the beta-cleft. Quite significantly, the mutation has led to removal of an interdimer repulsion involving alpha1Asp94 and beta2Asp99. The R- and T-state structures of Hb Bassett suggest a stereochemical basis for the observed functional properties of this mutant.
    Acta Crystallographica Section D Biological Crystallography 03/2005; 61(Pt 2):156-62. · 7.23 Impact Factor
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    ABSTRACT: In an attempt to find new types of anti-sickling agents that specifically bind to intracellular sickle haemoglobin (HbS) without inhibition by plasma and tissue proteins or other undesirable consequences, we identified 5-hydroxymethyl-2-furfural (5HMF), a naturally occurring aromatic aldehyde, as an agent that fulfils this criterion. Preliminary studies in vitro showed that 5HMF forms a high-affinity Schiff-base adduct with HbS and inhibits red cell sickling by allosterically shifting oxygen equilibrium curves towards the left. Further studies with transgenic (Tg) sickle mice showed that orally administered 5HMF was rapidly absorbed into the bloodstream from the gastrointestinal tract without being destroyed, traversed the red blood cell membrane and specifically bound with, and modified, HbS molecules at levels as high as 90%. Pretreatment of Tg sickle mice with 5HMF inhibited the formation of sickle cells and significantly prolonged survival time under severe hypoxia, compared with untreated mice, which died within 15 min because of sickling-dependent pulmonary sequestration. These results indicate the feasibility of 5HMF as an attractive potential candidate for therapy of sickle cell disease.
    British Journal of Haematology 03/2005; 128(4):552-61. · 4.96 Impact Factor

Publication Stats

972 Citations
423.14 Total Impact Points

Institutions

  • 1976–2011
    • The Children's Hospital of Philadelphia
      • • Division of Hematology
      • • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 1974–2009
    • University of Pennsylvania
      • • Department of Biochemistry and Biophysics
      • • Department of Medicine
      • • Department of Pediatrics
      Philadelphia, PA, United States
  • 2008
    • University of Virginia
      • Department of Medicine
      Charlottesville, VA, United States
  • 2007
    • University of Fukui
      • Division of Radiology
      Hukui, Fukui, Japan
  • 2005
    • Children's Mercy Hospital
      Kansas City, Missouri, United States
  • 1968
    • The University of Tokyo
      Tōkyō, Japan