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Biomedical subjects

Yasuo Ikeda

Publications and source records attributed to Yasuo Ikeda.

At least 19 recordsLinked to original sources
PubMed2007

NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: molecular targeting of angiogenic growth factor.

Hepatocyte growth factor (HGF) promotes cell growth and motility and also increases neovascularization. Multiple myeloma (MM) cells produce HGF, and the plasma concentration of HGF is significantly elevated in patients with clinically active MM, suggesting that HGF might play a role in the pathogenesis of MM. NK4, an antagonist of HGF, is structurally homologous to angiostatin, and our previous report showed that NK4 inhibited the proliferation of vascular endothelial cells induced by HGF stimulation. The purposes of this study were to elucidate the contribution of HGF to the growth of MM cells as well as to investigate the possibility of the therapeutic use of NK4. In vitro study showed that NK4 protein stabilized the growth of MM cell lines and regulated the activation of c-MET, ERK1/2, STAT3, and AKT-1. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was injected intramuscularly into Icr/scid mice bearing tumors derived from HGF-producing MM cells. AdCMV.NK4 significantly inhibited the growth of these tumors in vivo. Histologic examination revealed that AdCMV.NK4 induced apoptosis of MM cells, accompanied by a reduction in neovascularization in the tumors. Thus, NK4 inhibited the growth of MM cells via antiangiogenic as well as direct antitumor mechanisms. The molecular targeting of HGF by NK4 could be applied as a novel therapeutic approach to MM.

Animals↗
PubMed2007

Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes.

The ataxia telangiectasia-mutated (ATM) gene plays a pivotal role in the maintenance of genomic stability. Although it has been recently shown that antioxidative agents inhibited lymphomagenesis in Atm(-/-) mice, the mechanisms remain unclear. In this study, we intensively investigated the roles of reactive oxygen species (ROS) in phenotypes of Atm(-/-) mice. Reduction of ROS by the antioxidant N-acetyl-l-cysteine (NAC) prevented the emergence of senescent phenotypes in Atm(-/-) mouse embryonic fibroblasts, hypersensitivity to total body irradiation, and thymic lymphomagenesis in Atm(-/-) mice. To understand the mechanisms for prevention of lymphomagenesis, we analyzed development of pretumor lymphocytes in Atm(-/-) mice. Impairment of Ig class switch recombination seen in Atm(-/-) mice was mitigated by NAC, indicating that ROS elevation leads to abnormal response to programmed double-strand breaks in vivo. Significantly, in vivo administration of NAC to Atm(-/-) mice restored normal T cell development and inhibited aberrant V(D)J recombination. We conclude that Atm-mediated ROS regulation is essential for proper DNA recombination, preventing immunodeficiency, and lymphomagenesis.

Acetylcysteine↗
PubMed2007

Risk factors for developing human herpesvirus 6 (HHV-6) reactivation after allogeneic hematopoietic stem cell transplantation and its association with central nervous system disorders.

We prospectively evaluated the incidence of human herpesvirus 6 (HHV-6) DNAemia after allogeneic hematopoietic stem cell transplantation (HSCT) using quantitative plasma real-time polymerase chain reaction. Of 46 recipients of bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT) from related (n = 11) or unrelated donors (n = 22), and cord blood transplantation (CBT) from unrelated donors (n = 13), 22 (47.8%) developed HHV-6 DNAemia. HHV-6 DNA levels ranged from 200 to 200,000 copies/mL of plasma, and HHV-6 DNAemia was observed significantly more frequently after CBT than after BMT/PBSCT (92.3% vs 30.3%; P < .001). Multivariate analyses identified CBT (vs BMT/PBSCT), HLA mismatches between recipient and donor, and low anti-HHV-6 IgG titer before transplantation as the only risk factors for developing HHV-6 DNAemia. Three patients developed central nervous system (CNS) disorders with detectable HHV-6 DNA in the cerebrospinal fluid; all of these patients simultaneously developed HHV-6 DNAemia. These results suggest that HHV-6 DNAemia is frequently observed after allogeneic HSCT, especially in patients with the aforementioned risk factors. Thus, together with the assessment of risk factors, monitoring of HHV-6 DNAemia could be a useful asset in diagnosing HHV-6-associated CNS disorders.

Adult↗
PubMed2007

Zerumbone, a bioactive sesquiterpene, induces G2/M cell cycle arrest and apoptosis in leukemia cells via a Fas- and mitochondria-mediated pathway.

We demonstrated here for the first time that zerumbone (ZER), a natural cyclic sesquiterpene, significantly suppressed the proliferation of promyelocytic leukemia NB4 cells among several leukemia cell lines, but not human umbilical vein endothelial cells (HUVECs), by inducing G2/M cell cycle arrest followed by apoptosis with 10 microM of IC50. Treatment of NB4 cells with growth-suppressive concentrations of ZER resulted in G2/M cell cycle arrest that was associated with a decline of Cyclin B1 protein, but with the phosphorylation of ATM/ Chk1/Chk2. In addition, ZER induced the phosphorylation of Cdc25C at the Thr48 residue and Cdc2 at the Thr14/Tyr15 residues. Furthermore, ZER-induced apoptosis in NB4 cells was initiated by the expression of Fas (CD95)/Fas Ligand (CD95L), concomitant with the activation of caspase-8. ZER was also found to induce the cleavage of Bid, a mediator that is known to connect the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. ZER also induced the cleavage of Bax and Mcl-1 proteins, but not Bcl-2 or Bcl-XL. ZER-induced apoptosis took place in association with a loss of the mitochondrial transmembrane potential as well as the activation of caspase-3 and -9, resulting in the degradation of the proteolytic poly (ADP-ribose) polymerase (PARP). ZER also triggered a release of cytochrome c into the cytoplasm. Both antagonistic anti-Fas antibody ZB4 and pan-caspase inhibitor Z-VAD inhibited ZER-induced apoptosis in NB4 cells. Taken together, ZER is an inducer of apoptosis in leukemic cells that specifically triggers the Fas/CD95- and mitochondria-mediated apoptotic signaling pathway.

Antineoplastic Agents↗
PubMed2007

Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura.

BACKGROUND: Thrombocytopenia is a common manifestation of liver cirrhosis (LC), but its underlying mechanism is not fully understood. The purpose of the present paper was to evaluate the platelet kinetics in LC patients by examining several non-invasive convenient markers. METHODS: Fifty-seven LC patients, 32 patients with idiopathic thrombocytopenic purpura (ITP), 12 with aplastic anemia (AA), and 29 healthy individuals were studied. Plasma thrombopoietin was measured by enzyme-linked immunosorbent assay. Absolute reticulated platelet (RP) count and plasma glycocalicin were used as indices for thrombopoiesis, and the indices for platelet turnover were the RP proportion and the plasma glycocalicin normalized to the individual platelet count (GCI). RESULTS: There was no difference in thrombopoietin levels between LC patients and healthy controls. The RP proportion and GCI were significantly higher and the absolute RP count and glycocalicin significantly lower in LC patients than in healthy controls. These markers in ITP and LC patients were comparable, but significantly different from those in AA patients. The bone marrow megakaryocyte density in LC and ITP patients was similar, and significantly higher than in AA patients. CONCLUSIONS: Cirrhotic thrombocytopenia is a multifactorial condition involving accelerated platelet turnover and moderately impaired thrombopoiesis. Thrombopoietin deficiency is unlikely to be the primary contributor to cirrhotic thrombocytopenia.

Aged↗
PubMed2006

New strategy of platelet substitutes for enhancing platelet aggregation at high shear rates: cooperative effects of a mixed system of fibrinogen gamma-chain dodecapeptide- or glycoprotein Ibalpha-conjugated latex beads under flow conditions.

To construct platelet substitutes that have hemostatic properties over a wide range of shear rates, we used fibrinogen gamma-chain carboxy-terminal sequence HHLGGAKQAGDV (H12), which recognizes activated platelets at low shear rates, and a recombinant water-soluble moiety of the platelet glycoprotein (rGPIbalpha), which recognizes von Willebrand factor at high shear rates. Three kinds of samples were prepared for this purpose: H12-conjugated latex beads (H12-latex beads), rGPIbalpha-latex beads, and H12/rGPIbalpha-latex beads. These samples were evaluated in thrombocytopenia-imitation blood at various flow conditions. Based on ADP-induced platelet aggregation studies, the H12-latex beads significantly enhanced platelet aggregation via H12 binding with GPIIb/IIIa activated on the surface of activated platelets, whereas the rGPIbalpha-latex beads did not support platelet aggregation. In the case of the H12/rGPIbalpha-latex beads, the function of H12 was suppressed by steric hindrance from the larger rGPIbalpha bound to the latex bead. A mixture of the H12-latex beads and the rGPIbalpha-latex beads adhered to a collagen surface over a wide range of shear rates. In particular, at high shear rates, a cooperative effect was observed in the enhancement of platelet thrombus formation compared with H12-latex beads or rGPIbalpha-latex beads alone. We propose that a mixed system of H12- and rGPIbalpha-conjugated nanoparticles is a more effective platelet substitute than each of the beads used alone and has enhanced platelet aggregation properties.

Blood Platelets↗
PubMed2006

Impact of carotid endarterectomy on medical secondary prevention after a stroke or a transient ischemic attack: results from the Reduction of Atherothrombosis for Continued Health (REACH) registry.

BACKGROUND AND PURPOSE: Whether a history of carotid endarterectomy influences patient compliance with medical treatments and physician attitude toward treatments after ischemic stroke or transient ischemic attack (TIA) is not well known. METHODS: We studied the baseline data of 18,467 ischemic stroke and TIA patients from the international REduction of Atherothrombosis for Continued Health (REACH) Registry and investigated the impact of a history of endarterectomy on the secondary medical prevention measured by the use of antiplatelet agents and statins, and by the control of cholesterol level, glucose level, and blood pressure. RESULTS: Among the patients with a history of ischemic stroke or TIA, those with a history of endarterectomy (n=1474) were more likely to receive antiplatelet agents and statins, to have a blood pressure <140/90 mm Hg, and a fasting total cholesterol <200 mg/dL. In diabetic patients, endarterectomy was associated with lower fasting blood glucose levels. In multivariate logistic regression analyses, endarterectomy was significantly associated with the use of antiplatelet agents (odds ratio [OR], 1.6; 95% CI, 1.3 to 1.9; P<0.0001) and statins (OR, 1.8; 1.6 to 2.0; P<0.0001), and with a cholesterol level <200 mg/dL (OR, 1.3; 1.2 to 1.5; P<0.0001). By contrast, the associations with blood pressure and blood glucose levels were no longer significant. There was no heterogeneity across the world regions or among the specialists who enrolled the patients. CONCLUSIONS: Carotid endarterectomy is associated with a higher use of antiplatelet agents and statins in stroke/TIA patients. The absence of such an association with blood pressure and blood glucose control suggests that the individual determinants of the quality of the secondary medical prevention vary from one risk factor to another and from one class of drugs to another.

Aged↗
PubMed2006

Effects of a Helicobacter pylori eradication regimen on anti-platelet autoantibody response in infected and uninfected patients with idiopathic thrombocytopenic purpura.

Thirty-seven patients with idiopathic thrombocytopenic purpura (ITP) were treated with a standard Helicobacter pylori eradication regimen irrespective of H. pylori infection. Our results indicate that platelet recovery results from the disappearance of H. pylori itself, and is mediated, in part, through suppression of anti-platelet autoantibody production.

Adult↗
PubMed2006

T helper type 2-biased natural killer cell phenotype in patients with pemphigus vulgaris.

Pemphigus vulgaris (PV) is an autoantibody-mediated bullous disease, but the role of natural killer (NK) cells in its pathogenic process has never been examined in detail. Circulating CD56+ CD3- NK cells as well as CD69+-activated NK cells were increased in PV patients compared with healthy controls and patients with other autoantibody-mediated autoimmune diseases, including immune thrombocytopenic purpura and myasthenia gravis. Gene expression analysis of highly purified NK cells demonstrated an increased expression of IL-10 and decreased expression of IL-12Rbeta2, perforin, and granzyme B ex vivo in PV patients versus healthy controls. The NK cells from PV patients also showed impaired signal transducer and activator of transduction4 phosphorylation upon in vitro IL-12 stimulation. Moreover, NK cells from PV patients exhibited reduced IL-10 production in response to in vitro stimulation with IL-2/IL-12. Finally, IL-5 expression in NK cells was exclusively detected ex vivo in PV patients with active disease, and was lost in subsequent analyses performed during disease remission. Together these findings suggest that NK cells contribute to a T helper type 2-biased immune response in PV patients through impaired IL-12 signaling and an upregulation of IL-10 and IL-5.

Adult↗
PubMed2006

Endothelial differentiation potential of human monocyte-derived multipotential cells.

We previously reported a unique CD14(+)CD45(+)CD34(+) type I collagen(+) cell fraction derived from human circulating CD14(+) monocytes, named monocyte-derived multipotential cells (MOMCs). This primitive cell population contains progenitors capable of differentiating along the mesenchymal and neuronal lineages. Here, we investigated whether MOMCs can also differentiate along the endothelial lineage. MOMCs treated with angiogenic growth factors for 7 days changed morphologically and adopted a caudate appearance with rod-shaped microtubulated structures resembling Weibel-Palade bodies. Almost every cell expressed CD31, CD144, vascular endothelial growth factor (VEGF) type 1 and 2 receptors, Tie-2, von Willebrand factor (vWF), endothelial nitric-oxide synthase, and CD146, but CD14/CD45 expression was markedly downregulated. Under these culture conditions, the MOMCs continued to proliferate for up to 7 days. Functional characteristics, including vWF release upon histamine stimulation and upregulated expression of VEGF and VEGF type 1 receptor in response to hypoxia, were indistinguishable between the MOMC-derived endothelial-like cells and cultured mature endothelial cells. The MOMCs responded to angiogenic stimuli and promoted the formation of mature endothelial cell tubules in Matrigel cultures. Finally, in xenogenic transplantation studies using a severe combined immunodeficient mouse model, syngeneic colon carcinoma cells were injected subcutaneously with or without human MOMCs. Cotransplantation of the MOMCs promoted the formation of blood vessels, and more than 40% of the tumor vessel sections incorporated human endothelial cells derived from MOMCs. These findings indicate that human MOMCs can proliferate and differentiate along the endothelial lineage in a specific permissive environment and thus represent an autologous transplantable cell source for therapeutic neovasculogenesis.

Animals↗
PubMed2006

Coronary artery disease and a functional polymorphism of hTERT.

Genetic variation, a -1327T/C polymorphism, of human telomerase reverse transcriptase (hTERT) is associated with leukocyte telomere length in healthy subjects, but clinical significances of this functional polymorphism are not clear. Recently, the relationship between the telomere system and coronary artery disease (CAD) was reported. We investigated the association between the -1327T/C polymorphism and (a) susceptibility to CAD and (b) telomere length in CAD patients. In a case-control study, 104 patients confirmed by coronary angiography and 115 age- and sex-matched controls were enrolled. There was a higher frequency of the -1327C/C genotype in CAD patients (51.9%) compared with controls (36.5%, p = 0.0218). Among the 104 CAD patients, leukocyte telomere length in the -1327C/C genotype (7.62+/-2.19 kb, mean+/-SD) was shorter than that in the -1327T/C and -1327T/T genotypes (8.74+/-2.92, p = 0.0287). These findings suggest that the -1327C/C genotype is a genetic risk factor for CAD and relates to shorter telomere length among CAD patients.

Case-Control Studies↗
PubMed2006

Identification of ADRA2A polymorphisms related to shear-mediated platelet function.

alpha2A adrenergic receptor (ADRA2A) on platelets interacts with epinephrine, which has a key role in regulating platelet functions. There is familial clustering of inter-individual variations in the epinephrine-induced platelet aggregation, the molecular basis of which, however, has not been fully understood. In this study, we screened the sequence variations in the transcriptional region of ADRA2A gene and analyzed the relationship between the two common polymorphisms and platelet function using epinephrine/collagen cartridge in the platelet function analyzer-100 system, in a healthy Japanese male population (n=211). Among the identified 16 sequence variations including five novel variations, 1780GG genotype was associated with longer closure time which represents low platelet function under high shear-stress conditions (p=0.0478). We also observed enhanced effect of the combination of 1780GG and 2372AA genotypes on longer closure time (p=0.0319). These findings suggest that 1780A/G and 2372A/G polymorphisms are associated with platelet function in interactions with collagen/epinephrine.

Asian People↗
PubMed2006

Increased basal platelet activity, plasma adiponectin levels, and diabetes mellitus are associated with poor platelet responsiveness to in vitro effect of aspirin.

INTRODUCTION: Aspirin is one of the most effective antiplatelet agents and is now commonly used to prevent vascular events. In some patients, however, recurrent vascular events have been demonstrated despite aspirin therapy. Our objective was to characterize individuals showing poor response to in vitro effect of aspirin, using PFA-100. METHODS: One hundred sixty-eight healthy male subjects were analyzed. We assessed platelet function tests, including PFA-100, whole blood aggregation, and optical platelet aggregation. Also measured were hemostatic and other parameters including von Willebrand factor (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), soluble vascular adhesion molecule-1 (sVCAM-1), high sensitive C-reactive protein (hs-CRP), and adiponectin. Poor responders were defined as having a collagen/epinephrine-induced closure time (CEPI-CT) under 250 s with PFA-100 when incubated with 10 microM aspirin, whereas good responders were defined as having a CEPI-CT of more than 250 s. RESULTS AND CONCLUSIONS: PFA-100 tests revealed that 40 subjects (24%) were poor responders (PR) and 128 (76%) were good responders (GR). Poor responsiveness was significantly associated with (1) higher basal platelet activities in PFA-100, as well as in whole blood aggregation and aggregometer;(2) increased level of adiponectin (8.8+/-4.1 micro g/mL [PR] vs 7.3+/-2.9 micro g/mL [GR], p=0.010);and (3) the presence of diabetes mellitus (17.5% [PR] vs 4.7% [GR], p=0.009). Importantly, whereas 24% of the subjects showed insufficient inhibition in PFA-100 when incubated with 10 microM aspirin, almost all subjects showed maximum inhibition with 30 microM aspirin. These observations suggest that higher doses of aspirin might overcome aspirin resistance.

Adiponectin↗