T Hirano

Kitakyushu University, Kitakyūshū, Fukuoka-ken, Japan

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Publications (251)1412.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA. Method: We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry. Results: A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups. Conclusion: TCZ and ETN show better retention than IFX or ADA in the treatment of RA.
    Scandinavian journal of rheumatology 03/2013; · 2.51 Impact Factor
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    ABSTRACT: To examine the effects of instant coffee consumption on cancer risk, we analyzed the oxidative DNA damage levels and the DNA repair and redox systems in the livers of coffee-fed mice. Three-week-old male ICR mice were fed with/without 0.1% (w/v) instant coffee solution. At 2, 4, and 8 mo, the levels of 8-hydroxydeoxyguanosine (8-OH-dG), a major form of oxidative DNA damage, and the expression of mouse 8-OH-dG repair-associated genes and redox system-associated genes, the SOD activity, and the LPO level were analyzed. Simultaneously, half of the mice were fed a low vitamin (LV) diet (autoclaved diet) to disturb the defense system against oxidative stresses. As a result, the 8-OH-dG level was increased in the livers of LV diet (+ water)-fed mice for 8 mo, in comparison to those of the 0 M control mice and normal diet (+ water)-fed mice. However, no significant differences between water drinking and coffee drinking were observed, in terms of the 8-OH-dG level. In addition, the 8-OH-dG repair-associated gene expression, the SOD activity, and the LPO level also showed no significant differences between water drinking and coffee drinking in all mouse groups. On the other hand, among the redox system-associated genes, only the expression of GPx1 was changed. These results suggest that instant coffee consumption has little, if any, effect on the risk of liver cancer due to oxidative stresses.
    Journal of Food Science 09/2009; 74(6):H155-61. · 1.78 Impact Factor
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    Annals of the rheumatic diseases 08/2009; 68(7):1235-6. · 8.11 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) are well known hazards for living organisms and are believed to be associated with the induction of cancer. ROS induce many forms of oxidative damage to proteins, nucleic acids, and lipids. Therefore, to diagnose or prevent cancer, analyses of oxidative products in patient samples, including tissue, blood, and urine, are very informative. Amongst the products of DNA oxidation, 8-hydroxy-2′-deoxyguanosine (8-OH-dG) is an important form of damage that leads to point mutations in genomic DNA. Since 8-OH-dG is the most abundant form of oxidative DNA damage and is easy to detect in laboratories, using a high performance liquid chromatography (HPLC) system equipped with an electrochemical detector (ECD), many researchers studying cellular oxidative stress have primarily analyzed 8-OH-dG. In this chapter, we will describe our findings regarding 8-OH-dG generation and its repair, as well as our recent urinary 8-OH-dG data.
    06/2009: pages 178-187;
  • Rheumatology (Oxford, England) 01/2009; 48(3):318-9. · 4.24 Impact Factor
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    ABSTRACT: No objective method to measure skin involvement in SSc has been established. We developed a novel method using a computer-linked device to simultaneously quantify physical properties of the skin such as hardness, elasticity and viscosity. Skin hardness was calculated by measuring the depth of an indenter pressed onto the skin. The Voigt model was used to calculate skin elasticity, viscosity, visco-elastic ratio and relaxation time by analysing the waveform of skin surface behaviour. The results were compared with the modified Rodnan skin score (mRSS) obtained at 17 sites on the bodies of 20 SSc patients and 20 healthy controls. A functional assessment questionnaire was administered to determine how skin hardness represents a patient's disability. We also examined intra- and inter-observer variability to determine the reliability of this method. The crude hardness obtained with this device correlated well with the standard hardness specified by the American Society for Testing and Materials (ASTM, r = 0.957). A close relationship between hardness and total mRSS was also observed (r = 0.832). Skin elasticity correlated positively, and relaxation time negatively with mRSS. Functional disability correlated more closely with skin hardness (r = 0.643) than with mRSS (r = 0.517). Intra- and inter-observer variabilities were 7.63 and 19.76%, respectively, which were lower than those reported for mRSS. Increases in hardness and elasticity as well as shortening of relaxation time constitute objective characteristics of skin involvement in SSc. The system devised by us proved to be able to assess skin abnormalities of SSc with high reliability.
    Rheumatology (Oxford, England) 08/2008; 47(7):1018-24. · 4.24 Impact Factor
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    ABSTRACT: IL-18 has been shown to exert anti-allergic or allergy-promoting activities, but the existence of genetic polymorphisms in the coding regions of IL-18 gene has not been demonstrated. The aim of this study was to investigate whether polymorphism is present in the coding regions of the IL-18 gene and, if so, to further analyse the association between polymorphism and asthma in a case-control study. We screened the coding regions of the IL-18 gene for polymorphisms by using PCRsingle-stranded conformation polymorphism and direct sequencing of PCR products, followed by analysis of the association between polymorphism and asthma. We identified one polymorphism (105A/C) in the coding regions. The frequency of the 105A allele was significantly higher in asthmatic patients than in controls (P<0.01; odds ratio (OR)=1.83 (1.37-2.26)). Significant linkage disequilibrium was observed between the 105A/C and -137G/C polymorphisms in the 5' flanking region of the IL-18 gene (D=0.58, P<0.0001). However, in asthmatic patients the 105A allele was not associated with either total serum IgE or IL-18 levels. The 105A/C polymorphism of the IL-18 gene may be associated with the pathogenesis of asthma.
    Clinical & Experimental Allergy 08/2003; 33(8):1097-102. · 4.79 Impact Factor
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    ABSTRACT: Interleukin (IL)-18 has been shown to activate basophils to produce histamine and IL-4 and to induce naive T cells to differentiate into T-helper (Th) 2 cells. However, when expressed together with IL-12, IL-18 induces Th1 cell development and inhibits IgE synthesis. Previously we reported that serum IL-18 levels were elevated in the sera from atopic dermatitis-model mice NC/Nga, prior to the onset and during the development of dermatitis. We studied whether neutralization of IL-18 activity might affect dermatitis in NC/Nga mice, to investigate the role of IL-18 on dermatitis. NC/Nga mice were given weekly anti-IL-18 antibody starting at 5 weeks of age to 13 weeks and development of dermatitis, scratching behaviour and serum IgE concentrations were evaluated. Continuous injections of anti-IL-18 antibody failed to inhibit the onset and development of dermatitis and IgE elevation. The treatment, rather, tended to lead to an exacerbation of dermatitis and scratching behaviour. In addition, the administration of anti-IL-18 antibody did not ameliorate the responsiveness of lymphocytes to IL-4, which was previously demonstrated as an immunological abnormality in the mouse. This study demonstrates that, at least in NC/Nga mice, IL-18, although excessively expressed before the onset of dermatitis, shows antiallergic actions.
    British Journal of Dermatology 08/2003; 149(1):39-45. · 3.76 Impact Factor
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    ABSTRACT: Progress in the management of allergic diseases including asthma, pollen diseases and atopic dermatitis has recently improved patients' quality of life. In addition to steroids, which are powerful inhibitors of allergic inflammation, other anti-allergic compounds, humanized anti-IgE antibody and cytokine modulators have been developed. However, the world-wide prevalence of allergic diseases has been increased during the last two decades, making early intervention to prevent the development of such diseases essential. Through analysis of the clinical evaluation of one kind of traditional remedy in patients with atopic dermatitis, flavonoids were shown to possess significant anti-allergic activity. Among the twenty kinds of flavonoids examined, fisetin, luteolin, apigenin, quercetin and kaempferol inhibited not only the release of chemical mediators but also the production of T-helper (Th)-2 type cytokines (Interleukin (IL)-4, IL-5 and IL-13) by basophils. These flavonoids inhibit expression of these cytokines through their inhibitory effect on the activation of several calcium-calmodulin dependent kinases. Administration of either persimmon leaf extract, which is rich in flavonoids, or its major ingredient astragalin (a glycoside of kaempferol), in atopic dermatitis-model mice (NC / Nga) prevented the onset of dermatitis and showed a substantial ameliorative effect even in mice with open dermatitis. Moreover, a double-blind, randomized, placebo-controlled trial of flavonoid in patients with atopic dermatitis showed a significant effect. These results indicate the possibility that flavonoids, which are contained in vegetables, fruits and tea, may constitute a complementary and alternative medicine for allergic patients and may act as a prophylactic substance against the development of allergic diseases.
    Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents 02/2003; 2(1):57-65.
  • D Kamimura, K Ishihara, T Hirano
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    ABSTRACT: Interleukin (IL)-6 is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs. In a target cell, IL-6 can simultaneously generate functionally distinct or sometimes contradictory signals through its receptor complex, IL-6Ralpha and gp130. One good illustration is derived from the in vitro observations that IL-6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated STAT3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects. The final physiological output can be thought of as a consequence of the orchestration of the diverse signaling pathways generated by a given ligand. This concept, the signal orchestration model, may explain how IL-6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances. Elucidation of the molecular mechanisms underlying this issue is a challenging subject for future research. Intriguingly, recent in vivo studies indicated that the SHP-2-binding site- and YXXQ-mediated pathways through gp130 are not mutually exclusive but affect each other: a mutation at the SHP-2-binding site prolongs STAT3 activation, and a loss of STAT activation by gp130 truncation leads to sustained SHP-2/ERK MAPK phosphorylation. Although IL-6/gp130 signaling is a promising target for drug discovery for many human diseases, the interdependence of each signaling pathway may be an obstacle to the development of a nonpeptide orally active small molecule to inhibit one of these IL-6 signaling cascades, because it would disturb the signal orchestration. In mice, a consequence of the imbalanced signals causes unexpected results such as gastrointestinal disorders, autoimmune diseases, and/or chronic inflammatory proliferative diseases. However, lessons learned from IL-6 KO mice indicate that IL-6 is not essential for vital biological processes, but a significant impact on disease progression in many experimental models for human disorders. Thus, IL-6/gp130 signaling will become a more attractive therapeutic target for human inflammatory diseases when a better understanding of IL-6 signaling, including the identification of the conductor for gp130 signal transduction, is achieved.
    Ergebnisse der Physiologie 02/2003; 149:1-38. · 1.00 Impact Factor
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    ABSTRACT: Interleukin-6 family cytokines have been implicated in adaptive and innate immunity, hematopoiesis, and inflammation. This cytokine family shares a signal-transducing receptor subunit called gp130. gp130(F759/F759) knockin mice carry a point mutation at the SHP2-binding site of gp130 due to the replacement of tyrosine-759 (Y759 for human gp130) with phenylalanine (F). To explore the effect of this point mutation on the host response to bacterial infection, gp130(F759/F759) knockin mice were infected with Listeria monocytogenes. gp130(F759/F759) knockin mice began to die at 3 to 4 days post infection (p.i.) and showed higher mortality than did controls. Listeria titers at 3 days p.i. in the peritoneal cavity, spleen, and liver were significantly higher in gp130(F759/F759)knockin mice than in controls. Nitric oxide production, upregulation of the mRNA levels of a variety of cytokines, and listericidal activity in gp130(F759/F759) macrophages were unchanged. However, gp130(F759/F759) knockin mice displayed significantly lower levels of interferon (IFN)gamma in serum and in the culture supernatant from peritoneal exudate cells and splenocytes, in response to Listeria infection. These results suggest that the Y759 point mutation in gp130 attenuates the early phase of defense against Listeria infection, possibly owing to insufficient elevation of IFNgamma levels, and thus gp130 is a possible candidate gene for Listeria susceptibility.
    Genes and Immunity 06/2002; 3(3):136-43. · 3.68 Impact Factor
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    ABSTRACT: To clarify the role of oxidative stress in aging of colorectal tissue, we analyzed the 8-hydroxydeoxyguanosine (8-OH-dG) levels in colorectal biopsy samples from normal tissue of patients with either colorectal cancer (n = 15) or benign colorectal polyps (n = 40). An age-associated increase of 8-OH-dG was observed (p =.002), although the 8-OH-dG levels were not significantly different between the patients with cancer and those with polyps. These results suggest an increased level of 8-OH-dG formation in human colorectal tissue with age.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 12/2001; 56(11):B483-5. · 4.31 Impact Factor
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    ABSTRACT: The base excision repair system for 8-hydroxyguanine (8-OH-Gua) is believed to play a role in the prevention of mutations, such as GC-to-TA transversion, which leads to cancer development. However, the exact repair mechanism is still unclear. In this study, we examine whether the repair activity level for 8-hydroxyguanine, one of the major forms of oxidative DNA damage, depends on the sequence of the substrate DNA. We prepared six different oligonucleotides containing 8-hydroxyguanine as substrates and reacted them with crude extracts from the livers and kidneys of 8-week-old Sprague-Dawley rats. As a result, up to a 10-fold difference in the repair activity levels was observed, depending on the substrates used. Based on this observation, we suggest that the repair systems may act with sequence specificity on the damaged DNA.
    Journal of Radiation Research 10/2001; 42(3):247-54. · 1.45 Impact Factor
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    ABSTRACT: Cyclic ADP ribose (cADPR) is a novel second messenger that releases calcium from intracellular calcium stores, but works independently of inositol 1,4,5-trisphosphate. In mammals ADP-ribosyl cyclase function is found in two membrane proteins, CD38 and bone marrow stromal cell antigen 1 (BST-1)/CD157. These enzymes are exposed extracellularly and also possess cADPR hydrolase activity, but an intracellular soluble ADP-ribosyl cyclase has been reported in human T-cells. Previously, a soluble form of BST-1/CD157 (sBST-1), which lacked the glycosylphosphatidylinositol-anchored portion, was expressed by a baculovirus-insect-cell system. In this study, we have purified the sBST-1, and it migrated as two major bands by SDS/PAGE, suggesting that it is post-translationally modified. BST-1 contains four putative N-glycosylation sites. Tunicamycin treatment reduced sBST-1 expression in the culture medium, indicating that N-glycosylation is essential for secretion. Site-directed mutagenesis was performed to generate sBST-1 mutants (N1-N4), each preserving a single N-glycosylation site. N1, N3 and N4 were well secreted into the medium, and were each detected as a single band. Although N3 and N4 retained the ADP-ribosyl cyclase activity, the cADPR-hydrolase activity was retained only in N4. We conclude that N-glycosylation of sBST-1 facilitates the folding of the nascent polypeptide chain into a conformation that is conductive for intracellular transport and enzymic activity. Furthermore a crystal has been obtained using the N4 mutant, but not the wild-type sBST-1. Thus the artificial engineering of N-glycosylation sites could be an effective method to generate homogeneous material for structural studies.
    Biochemical Journal 08/2001; 357(Pt 2):385-92. · 4.65 Impact Factor
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    ABSTRACT: Human blood platelets are easily available physiologic target cells for thrombopoietin (TPO). TPO up-regulates platelet aggregation and alpha-granule secretion induced by various agonists. We investigated the role of phosphatidylinositol 3-kinase (PI3K) and its association with Gab1 in TPO-mediated up-regulation of platelet function. PI3K inhibitors (wortmannin and LY294002) and a MAP/ERK-kinase (MEK) inhibitor (PD98059) were used to investigate the role of these kinases in TPO-mediated up-regulation of platelet function. To elucidate the molecules associated with PI3K, we performed immunoprecipitation and pull-down experiments followed by immunoblotting. In vitro kinase assay also was performed to detect extracellular signal-regulated kinase (ERK) kinase activity. TPO up-regulated platelet alpha-granule secretion and aggregation induced by thrombin, which was dose-dependently inhibited by preincubation with wortmannin or LY294002. Immunoprecipitation and pull-down experiments revealed that regulatory subunit of PI3K, p85, was rapidly associated with tyrosine-phosphorylated Gab1 via its n- and c-terminal SH2 domains. Pretreatment of platelets with TPO dramatically augmented the thrombin-induced ERK activation, which was almost completely inhibited by LY294002. Furthermore, a MEK inhibitor, PD98059, not completely but significantly inhibited TPO-mediated up-regulation of thrombin-induced alpha-granule secretion. TPO induces the association of tyrosine-phosphorylated Gab1 with p85-PI3K. In downstream signaling, ERK is PI3K-dependently activated, which plays a critical role for TPO-mediated up-regulation of platelet function.
    Experimental Hematology 06/2001; 29(5):616-22. · 2.91 Impact Factor
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    ABSTRACT: We examined 8-hydroxyguanine (8-OH-Gua) formation and 8-OH-Gua repair enzyme activity in pulmonary type-II-like epithelial cells to determine whether oxidative stress induced by asbestos plays a role in its carcinogenic mechanism. A549 cells were incubated with crocidolite asbestos at concentrations of 0, 10, 50 and 100 microg/ml over 27 h. We then evaluated 8-OH-Gua formation, 8-OH-Gua repair enzyme activity and gene expression of 8-oxoguanine-DNA glycosylase 1 (hOGG1) and human MUtT homologue (hMTH1). This was done using a high-performance liquid chromatography system equipped with an electrochemical detector, endonuclease nicking assay and reverse transcription polymerase chain reaction, respectively. Crocidolite induced the formation of 8-OH-Gua in DNA at concentrations of 50 and 100 microg/ml. 8-OH-Gua levels increased at 9 h and had declined to near baseline at 27 h, whereas 8-OH-Gua repair enzyme activity peaked at 18 h post-crocidolite exposure. hOGG1 and hMTH1 mRNA levels were also increased by crocidolite exposure. These data suggest that crocidolite asbestos is associated with epithelial cell injury in the process of carcinogenesis through oxidative stress.
    Carcinogenesis 03/2001; 22(2):265-9. · 5.64 Impact Factor
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    ABSTRACT: Recent advances in our understanding of axis formation and patterning in zebrafish relate the developmental mode of this aspiring genetic model organism to higher vertebrates. The effect of UV irradiation and lithium treatment, as well as detailed early lineage analyses, have shed some light on dorsoventral axis formation. However, the molecular mechanism of axis formation, as well as the identity of a fish Nieuwkoop center, are still open issues. A Vg1 homolog is expressed in zebrafish, and activin as well as the mouse nodal gene product have been demonstrated to induce mesoderm and ectopic axes, respectively, in zebrafish. The zebrafish organizer is defined by the expression domains of goosecoid, axial and lim1. The cyclops gene is involved in maintaining goosecoid expression in axial mesoderm of the head. Large mutageneis screens provide the basis for a genetic analysis of axis formation.
    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 01/2001; 45(17 Suppl):2720-31.
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    ABSTRACT: Gab1 and Gab2 are members of the Gab family which act as adapters for transmitting various signals in response to stimuli through cytokine and growth factor receptors, and T- and B-cell antigen receptors. We determined chromosome locations of the two genes in human, mouse and rat by fluorescence in situ hybridization. The Gab1 gene was localized to chromosome 4q31.1 in human, 8C3 in mouse and 19q11.1--> q11.2 in rat, and the Gab2 gene was located on chromosome 11q13.4-->q13.5 in human, 7E2 in mouse and 1q33.2-->q33.3 in rat. All human, mouse and rat Gab1 and Gab2 genes were localized to chromosome regions where conserved homology has been identified among the three species.
    Cytogenetics and cell genetics 01/2001; 94(1-2):39-42.
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    ABSTRACT: Profilin is known to bind to actin monomers (to regulate actin polymerization) and to phosphatidylinositol-4,5-bisphosphate (to inhibit hydrolysis by unphosphorylated phospholipase C-gammal). It was recently reported that profilin is overexpressed in glomerular mesangial cells (MC) of rats with anti-Thy-1.1-induced glomerulonephritis and is accumulated in the extracellular space around MC. In this study, the biologic activities of extracellular profilin were examined. Scatchard analysis indicated the existence of a single class of cell surface binding sites, with similar equilibrium dissociation constants for purified splenic profilin and recombinant profilin, in cultured rat MC. Profilin increased [(3)H]thymidine incorporation in a dose-dependent manner and produced additive effects on platelet-derived growth factor-induced [(3)H]thymidine incorporation. Profilin increased AP-1 DNA-binding activity in a concentration-dependent (ED(50) = 30 nM) and time-dependent manner after transient c-jun gene expression, as measured using gel-shift assays and competitive reverse transcription-PCR. Pretreatment of profilin with an anti-profilin inhibitory antibody suppressed profilin-induced AP-1 activation and [(3)H]thymidine incorporation. Furthermore, profilin induced rapid transient activation of protein kinase C, and staurosporine and H-7 reduced the profilin-induced activation of AP-1, suggesting protein kinase C-dependent activation of AP-1. These findings indicate that profilin in the extracellular space can bind to cell surface receptors of MC and act as an inducer of signal transduction. These results suggest that extracellular profilin may be involved in the progression of glomerular diseases, by affecting cell growth.
    Journal of the American Society of Nephrology 10/2000; 11(9):1620-30. · 8.99 Impact Factor
  • R Fujii, S Yamashita, M Hibi, T Hirano
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    ABSTRACT: Cleavage is one of the initial steps of embryogenesis, and is characterized by a series of symmetric and synchronous cell divisions. We showed that p38 MAP kinase (p38) is asymmetrically activated on one side of the blastodisc during the early cleavage period in zebrafish (Danio rerio) embryos. When a dominant negative (DN) form of p38 was uniformly expressed, blastomere cleavage was impaired on one side of the blastodisc, resulting in the formation of blastomeres with a large mass of cytoplasm and an enlarged nucleus on the affected side. The area affected by the DN-p38 expression did not correlate with the initial cleavage plane, but coincided with the side where dharma/bozozok, a dorsal-specific zygotic gene, was expressed (Yamanaka et al. 1998). Furthermore, UV irradiation and removal of the vegetal yolk mass before the first cleavage, both of which inhibit the initiation of the dorsalizing signals, abolished the asymmetric p38 activation. Our findings suggest that asymmetric p38 activation is required for symmetric and synchronous cleavage, and may be regulated by the same machinery that controls the initiation of dorsalizing signals.
    The Journal of Cell Biology 09/2000; 150(6):1335-48. · 10.82 Impact Factor

Publication Stats

20k Citations
1,412.69 Total Impact Points


  • 2009
    • Kitakyushu University
      • Graduate School of Environmental Engineering
      Kitakyūshū, Fukuoka-ken, Japan
  • 1999–2009
    • Osaka City University
      • Department of Neurosurgery
      Ōsaka, Ōsaka, Japan
    • Kyushu University
      • Graduate School of Information Science and Electrical Engineering
      Hukuoka, Fukuoka, Japan
  • 1993–2009
    • University of Occupational and Environmental Health
      • • Department of Environmental Oncology
      • • Department of Biochemistry
      • • Department of Orthopedics
      Kitakyūshū, Fukuoka, Japan
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
    • Nara Medical University
      • Department of Internal Medicine
      Nara-shi, Nara, Japan
  • 1987–2003
    • Osaka University
      • • Department of Integrated Medicine
      • • Division of Hematology and Oncology
      • • Immunology Division
      • • Division of Cellular and Molecular Biology
      Ōsaka-shi, Osaka-fu, Japan
  • 1997–1998
    • Kyushu Institute of Technology
      • Faculty of Computer Science & Systems Engineering
      Иидзука, Fukuoka, Japan
  • 1991
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 1990
    • The University of Tokyo
      • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan
    • Showa University
      • Department of Biochemistry
      Shinagawa, Tōkyō, Japan
    • University of California, Los Angeles
      • Division of Hematology and Medical Oncology
      Los Angeles, CA, United States
  • 1988–1990
    • University of Freiburg
      • Institute of Forensic Medicine
      Freiburg, Lower Saxony, Germany
      Edo, Tōkyō, Japan
    • Osaka Minami Medical Center
      Ōsaka, Ōsaka, Japan
  • 1989
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 1983
    • Kumamoto University
      • Department of Medical Biochemistry
      Kumamoto, Kumamoto Prefecture, Japan
  • 1979
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 1976–1977
    • National Institute on Aging
      Baltimore, Maryland, United States