Biomedical subjects

Seiji Tadokoro

Publications and source records attributed to Seiji Tadokoro.

7 recordsLinked to original sources

PubMed2006

[Hypersensitivity reactions to multiple drugs during the course of hairy cell leukemia treated with 2-chlorodeoxyadenosine].

A 38-year-man developed diffuse erythema 3 days after the administration of 2-chlorodeoxyadenosine (cladribine or 2-CdA) and many other drugs for hairy cell leukemia (HCL). Patch-testing and scratch patch-testing showed positive reactions for clindamycin (10%, 30%) at 24 hours and 48 hours. Furthermore, provocation-testing showed positive reactions for sulfamethoxazole.trimethoprim, allopurinol, fluconazole, so our diagnosis was erythroderma-type drug eruption due to clindamycin, sulfamethoxazole-trimethoprim, allopurinol, fluconazole. Cutaneous side-effects associated with cladribine have seldom been described in cases of HCL. Our case suggests that there is a relationship between the drug hypersensitivity and the prolonged suppressed CD4 cell levels caused by cladribine.

Adult↗

PubMed2005

Adiponectin acts as an endogenous antithrombotic factor.

OBJECTIVE: Obesity is a common risk factor in insulin resistance and cardiovascular diseases. Although hypoadiponectinemia is associated with obesity-related metabolic and vascular diseases, the role of adiponectin in thrombosis remains elusive. METHODS AND RESULTS: We investigated platelet thrombus formation in adiponectin knockout (APN-KO) male mice (8 to 12 weeks old) fed on a normal diet. There was no significant difference in platelet counts or coagulation parameters between wild-type (WT) and APN-KO mice. However, APN-KO mice showed an accelerated thrombus formation on carotid arterial injury with a He-Ne laser (total thrombus volume: 13.36+/-4.25 x 10(7) arbitrary units for APN-KO and 6.74+/-2.87x10(7) arbitrary units for WT; n=10; P<0.01). Adenovirus-mediated supplementation of adiponectin attenuated the enhanced thrombus formation. In vitro thrombus formation on a type I collagen at a shear rate of 250 s(-1), as well as platelet aggregation induced by low concentrations of agonists, was enhanced in APN-KO mice, and recombinant adiponectin inhibited the enhanced platelet aggregation. In WT mice, adenovirus-mediated overexpression of adiponectin additionally attenuated thrombus formation. CONCLUSIONS: Adiponectin deficiency leads to enhanced thrombus formation and platelet aggregation. The present study reveals a new role of adiponectin as an endogenous antithrombotic factor.

Adenoviridae↗

PubMed2005

Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A.

Semaphorin 3A (Sema3A) is a secreted disulfide-bound homodimeric molecule that induces growth cone collapse and repulsion of axon growth in the nervous system. Recently, it has been demonstrated that Sema3A is produced by endothelial cells and inhibits integrin function in an autocrine fashion. In this study, we investigated the effects of Sema3A on platelet function by using 2 distinct human Sema3A chimera proteins. We detected expression of functional Sema3A receptors in platelets and dose-dependent and saturable binding of Sema3A to platelets. Sema3A dose-dependently inhibited activation of integrin alphaIIbbeta3 by all agonists examined including adenosine diphosphate (ADP), thrombin, convulxin, phorbol 12-myristate 13-acetate, and A23187. Sema3A inhibited not only platelet aggregation induced by thrombin or collagen but also platelet adhesion and spreading on immobilized fibrinogen. Moreover, Sema3A impaired alphaIIbbeta3-independent spreading on glass coverslips and aggregation-independent granular secretion. Sema3A inhibited agonist-induced elevation of filamentous action (F-actin) contents, phosphorylation of cofilin, and Rac1 activation. In contrast, Sema3A did not affect the levels of cyclic nucleotides or agonist-induced increase of intracellular Ca2+ concentrations. Thus, the extensive inhibition of platelet function by Sema3A appears to be mediated, at least in part, through impairment of agonist-induced Rac1-dependent actin rearrangement.

Actin Depolymerizing Factors↗

PubMed2003

Talin binding to integrin beta tails: a final common step in integrin activation.

Control of integrin affinity for ligands (integrin activation) is essential for normal cell adhesion, migration, and assembly of an extracellular matrix. Integrin activation is usually mediated through the integrin beta subunit cytoplasmic tail and can be regulated by many different biochemical signaling pathways. We report that specific binding of the cytoskeletal protein talin to integrin beta subunit cytoplasmic tails leads to the conformational rearrangements of integrin extracellular domains that increase their affinity. Thus, regulated binding of talin to integrin beta tails is a final common element of cellular signaling cascades that control integrin activation.

Amino Acid Sequence↗

PubMed2002

A naturally occurring Tyr143His alpha IIb mutation abolishes alpha IIb beta 3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects.

The molecular basis for the interaction between a prototypic non-I-domain integrin, alpha(IIb)beta(3), and its ligands remains to be determined. In this study, we have characterized a novel missense mutation (Tyr143His) in alpha(IIb) associated with a variant of Glanzmann thrombasthenia. Osaka-12 platelets expressed a substantial amount of alpha(IIb)beta(3) (36%-41% of control) but failed to bind soluble ligands, including a high-affinity alpha(IIb)beta(3)-specific peptidomimetic antagonist. Sequence analysis revealed that Osaka-12 is a compound heterozygote for a single (521)T>C substitution leading to a Tyr143His substitution in alpha(IIb) and for the null expression of alpha(IIb) mRNA from the maternal allele. Given that Tyr143 is located in the W3 4-1 loop of the beta-propeller domain of alpha(IIb), we examined the effects of Tyr143His or Tyr143Ala substitution on the expression and function of alpha(IIb)beta(3) and compared them with KO (Arg-Thr insertion between 160 and 161 residues of alpha(IIb)) and with the Asp163Ala mutation located in the same loop by using 293 cells. Each of them abolished the binding function of alpha(IIb)beta(3) for soluble ligands without disturbing alpha(IIb)beta(3) expression. Because immobilized fibrinogen and fibrin are higher affinity/avidity ligands for alpha(IIb)beta(3), we performed cell adhesion and clot retraction assays. In sharp contrast to KO mutation and Asp163Ala alpha(IIb)beta(3), Tyr143His alpha(IIb)beta(3)-expressing cells still had some ability for cell adhesion and clot retraction. Thus, the functional defect induced by Tyr143His alpha(IIb) is likely caused by its allosteric effect rather than by a defect in the ligand-binding site itself. These detailed structure-function analyses provide better understanding of the ligand-binding sites in integrins.

Adult↗

PubMed2002

Relationships between Rap1b, affinity modulation of integrin alpha IIbbeta 3, and the actin cytoskeleton.

The affinity of integrin alpha(IIb)beta(3) for fibrinogen is controlled by inside-out signals that are triggered by agonists like thrombin. Agonist treatment of platelets also activates Rap1b, a small GTPase known to promote integrin-dependent adhesion of other cells. Therefore, we investigated the role of Rap1b in alpha(IIb)beta(3) function by viral transduction of GFP-Rap1 chimeras into murine megakaryocytes, which exhibit inside-out signaling similar to platelets. Expression of constitutively active GFP-Rap1b (V12) had no effect on unstimulated megakaryocytes, but it greatly augmented fibrinogen binding to alpha(IIb)beta(3) induced by a PAR4 thrombin receptor agonist (p < 0.01). The Rap1b effect was cell-autonomous and was prevented by pre-treating cells with cytochalasin D or latrunculin A to inhibit actin polymerization. Rap1b-dependent fibrinogen binding to megakaryocytes was blocked by POW-2, a novel monovalent antibody Fab fragment specific for high affinity murine alpha(IIb)beta(3). In contrast to GFP-Rap1b (V12), expression of GFP-Rap1GAP, which deactivates endogenous Rap1, inhibited agonist-induced fibrinogen binding (p < 0.01), as did dominant-negative GFP-Rap1b (N17) (p < 0.05). None of these treatments affected surface expression of alpha(IIb)beta(3). These studies establish that Rap1b can augment agonist-induced ligand binding to alpha(IIb)beta(3) through effects on integrin affinity, possibly by modulating alpha(IIb)beta(3) interactions with the actin cytoskeleton.

3T3 Cells↗

PubMed2002

Missense mutations in the beta(3) subunit have a different impact on the expression and function between alpha(IIb)beta(3) and alpha(v)beta(3).

Alpha(IIb)beta(3) and alpha(v)beta(3) belong to the beta(3) integrin subfamily. Although the beta(3) subunit is a key regulator for the biosynthesis of beta(3) integrins, it remains obscure whether missense mutations in beta(3) may induce the same defects in both alpha(IIb)beta(3) and alpha(v)beta(3). In this study, it is revealed that thrombasthenic platelets with a His280Pro mutation in beta(3), which is prevalent in Japanese patients with Glanzmann thrombasthenia, did contain significant amounts of alpha(v)beta(3) (about 50% of control) using sensitive enzyme-linked immunosorbent assay. Expression studies showed that the His280Probeta(3) mutation impaired alpha(IIb)beta(3) expression but not alpha(v)beta(3) expression in 293 cells. To extend these findings, the effects of several beta(3) missense mutations leading to an impaired alpha(IIb)beta(3) expression on alpha(v)beta(3) function as well as expression was examined: Leu117Trp, Ser162Leu, Arg216Gln, Cys374Tyr, and a newly created Arg216Gln/Leu292Ser mutation. Leu117Trp and Cys374Tyr beta(3) mutations did impair alpha(v)beta(3) expression, while Ser162Leu, Arg216Gln, and Arg216Gln/Leu292Ser mutations did not. With regard to ligand binding function, Ser162Leu mutation induced especially distinct effects between 2 beta(3) integrins: it markedly impaired ligand binding to alpha(IIb)beta(3) but not to alpha(v)beta(3) at all. These data clearly demonstrate that the biosynthesis and the ligand binding function of alpha(IIb)beta(3) and those of alpha(v)beta(3) are regulated in part by different mechanisms. Present data would be a clue to elucidate the regulatory mechanism of expression and function of beta(3) integrins.

Adult↗