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Biomedical subjects

H Hashimoto

Publications and source records attributed to H Hashimoto.

At least 55 records · Page 3Linked to original sources
PubMed2002

Polymorphisms of human CD19 gene: possible association with susceptibility to systemic lupus erythematosus in Japanese.

CD19 regulates the signaling for B lymphocyte development, activation and proliferation. In mice, CD19 deficiency and overexpression were shown to result in hypogammaglobulinemia and autoantibody production, respectively. In the present study, we screened for the polymorphisms of CD19, and examined the detected polymorphisms for the association with rheumatoid arthritis (RA), Crohn's disease and systemic lupus erythematosus (SLE). Two SNPs, c.705G>T (P235P and IVS14-30C>T, were decreased (P = 0.0096 and P = 0.028, respectively), in SLE. A GT repeat polymorphism, c.*132(GT)(12-18), was detected within the 3'-untranslated region, and individuals with > or =15 times repeat was significantly increased in the independent two groups of Japanese SLE patients (P = 0.011 and P = 0.035, respectively); the overall difference between total SLE and controls was striking (P = 0.0061). No association was observed for RA and Crohn's disease. In addition, no variations other than the common polymorphisms were detected in four patients with common variable immunodeficiency, the phenotype of which resembles CD19 deficient mice. In Caucasian SLE families, this GT repeat polymorphism was rare. CD19 mRNA level in the isolated peripheral blood B lymphocytes was lower in individuals possessing (GT)(15-18) alleles compared with those without these alleles, both in controls and in SLE patients; however, the difference did not reach statistical significance. These results suggested that either the slight reduction in the CD19 mRNA level associated with the elongation of GT repeat, or an allele of another locus in linkage disequilibrium with CD19 (GT)(15-18), may be associated with susceptibility to SLE in Japanese.

3' Untranslated Regions↗
PubMed2002

Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis.

Recent studies indicated a substantial role of BLyS (BAFF, TNFSF13B) in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in humans and in animal models. This study was conducted to screen for polymorphisms of human BLYS, and to examine whether they are involved in the genetic susceptibility to human SLE and RA. A systematic polymorphism screening was performed in the coding region, 5' and 3' untranslated regions, and promoter region of human BLYS. Association of the detected polymorphisms with SLE and RA was analyzed in 221 Japanese patients with RA, 156 with SLE, and 227 healthy individuals, using the case-control approach. Four single nucleotide polymorphisms (SNPs) in the promoter, one SNP in intron 1, and one rare nonsynonymous substitution (Ala105Thr) in the coding region were detected. The BLYS SNPs were found to form three common haplotypes. Significant association with the susceptibility to SLE or RA was not observed. However, a tendency for the increase of -871T/T genotype was observed in SLE patients with anti-Sm antibody (P=0.082). BLYS mRNA level was significantly elevated in the monocytes from individuals carrying -871T (P=0.010). In addition, although statistically not significant, 105Thr allele was slightly increased in patients with RA compared with controls (P=0.058). Characterizing the functional and clinical significance of these new SNPs requires further study.

Adult↗
PubMed2002

Lessons from similarities between SLE and HIV infection.

OBJECTIVE: We attempted to obtain deeper understanding of systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection through comparative studies between both diseases. METHOD: For this purpose, we reviewed and discussed lessons from similarities in both diseases based on our own and reported findings in literatures. RESULT: Such comparative studies may contribute to the progress in understanding the clinical or pathogenetic features of these diseases. CONCLUSION: Further studies into the relationship between SLE and HIV infection may bring to light important clues to assist in the development of better treatments for each disease.

HIV Infections↗
PubMed2002

Allergic disorders in systemic lupus erythematosus: prevalence and family history.

The relationship between allergic disorders (such as atopic dermatitis, asthma, allergic rhinitis and allergic conjunctivitis) and systemic lupus erythematosus (SLE) is still unclear and controversial. We investigated the prevalence of these allergic disorders in SLE patients and their families. A questionnaire about the history of allergy was completed by 52 SLE patients and by 52 matched (including race, age, sex and region) non-SLE controls. Our results indicated that there was a significantly lower incidence of these allergic diseases in SLE patients, especially those who had an allergic family histories, when compared with the controls. These findings may be related to the immunological similarities and differences between SLE and various allergic diseases.

Adolescent↗
PubMed2001

Isolation and structural analyses of positional isomers of 6(1),6(n)-di-O-(N-acetyl-beta-D-glucosaminyl)cyclomaltoheptaose (n=2, 3, and 4) and 6-O-[6-O-(N-acetyl-beta-D-glucosaminyl)-N-acetyl-beta-D-glucosaminyl]cyclomaltoheptaose.

6-O-[6-O-(N-acetyl-beta-D-glucosaminyl)-N-acetyl-beta-D-glucosaminyl]cyclomaltoheptaose (beta CD) and three positional isomers of 6(1),6(n)-di-O-(N-acetyl-beta-D-glucosaminyl)cyclomaltoheptaose (n=2, 3, and 4) in a mixture of products from beta CD and N-acetylglucosamine by the reversed reaction of beta-N-acetylhexosaminidase from jack bean were isolated and purified by HPLC. The structures of four isomers of di-N-acetylglucosaminyl-beta CDs were determined by FABMS and NMR spectroscopy. The degree of polymerization of the branched oligosaccharides produced by enzymatic degradation with bacterial saccharifying alpha-amylase (BSA) was established by LC-MS methods.

Acetylglucosamine↗
PubMed2001

Identification of rabaptin-5, rabex-5, and GM130 as putative effectors of rab33b, a regulator of retrograde traffic between the Golgi apparatus and ER.

The role of rab33b, a Golgi-specific rab protein, was investigated. Microinjection of rab33b mutants stabilised in the GTP-specific state resulted in a marked inhibition of anterograde transport within the Golgi and in the recycling of glycosyltransferases from the Golgi to the ER, respectively. A GST-rab33b fusion protein stabilised in its GTP form was found to interact by Western blotting or mass spectroscopy with Golgi protein GM130 and rabaptin-5 and rabex-5, two rab effector molecules thought to function exclusively in the endocytic pathway. A similar binding was seen to rab1 but not to rab6, both Golgi rabs. In contrast, rab5 was as expected, shown to bind rabaptin-5 and rabex-5 as well as the endosomal effector protein EEA1 but not GM130. No binding of EEA1 was seen to any of the Golgi rabs.

Animals↗
PubMed2001

Preferential blockade of CD8(+) T cell responses by administration of anti-CD137 ligand monoclonal antibody results in differential effect on development of murine acute and chronic graft-versus-host diseases.

We investigated the effect of CD137 costimulatory blockade in the development of murine acute and chronic graft-vs-host diseases (GVHD). The administration of anti-CD137 ligand (anti-CD137L) mAb at the time of GVHD induction ameliorated the lethality of acute GVHD, but enhanced IgE and anti-dsDNA IgG autoantibody production in chronic GVHD. The anti-CD137L mAb treatment efficiently inhibited donor CD8(+) T cell expansion and IFN-gamma expression by CD8(+) T cells in both GVHD models and CD8(+) T cell-mediated cytotoxicity against host-alloantigen in acute GVHD. However, a clear inhibition of donor CD4(+) T cell expansion and activation has not been observed. On the contrary, in chronic GVHD, the number of CD4(+) T cells producing IL-4 was enhanced by anti-CD137L mAb treatment. This suggests that the reduction of CD8(+) T cells producing IFN-gamma promotes Th2 cell differentiation and may result in exacerbation of chronic GVHD. Our results highlight the effective inactivation of CD8(+) T cells and the lesser effect on CD4(+) T cell inactivation by CD137 blockade. Intervention of the CD137 costimulatory pathway may be beneficial for some selected diseases in which CD8(+) T cells are major effector or pathogenic cells. Otherwise, a combinatorial approach will be required for intervention of CD4(+) T cell function.

Acute Disease↗
PubMed2001

Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP).

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been conserved remarkably during evolution and is widely expressed in the mammalian brain. In Drosophila, mutation of the PACAP homologue results in behavioral defects, including impaired olfaction-associated learning and changes in ethanol sensitivity. Here, we report the generation of mice lacking the PACAP gene (PACAP(-/-)). PACAP(-/-) mice were born in the expected Mendelian ratios but had a high early-mortality rate. The surviving adult PACAP(-/-) mice displayed remarkable behavioral changes; they exhibited hyperactive and explosive jumping behaviors in an open field, increased exploratory behavior, and less anxiety in the elevated plus maze, emergence, and novel-object tests. Analysis of PACAP(-/-) mice brains revealed that the serotonin metabolite 5-hydroxyindoleacetic acid was slightly decreased in the cortex and striatum compared with wild-type mice. The present study provides evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors.

Animals↗
PubMed2001

Frequent alterations of the p14(ARF) and p16(INK4a) genes in primary central nervous system lymphomas.

To elucidate the role of p53/p16(INK4a)/RB1 pathways in the tumorigenesis of primary central nervous system lymphomas (PCNSLs), we have analyzed p14(ARF), p16(INK4a), RB1, p21(Waf1), and p27(Kip1) status in a series of their 18 sporadic cases of diffuse large B-cell lymphoma, using methylation-specific PCR, differential PCR, and immunohistochemistry. Homozygous deletion or methylation of p14(ARF) was detected in 10 (56%) PCNSLs, and they were almost entirely deletions (except 1 case). A total of 11 (61%) PCNSLs demonstrated homozygous deletion (6 cases) or methylation (5 cases) of p16(INK4a). Six tumors showed both p14(ARF) and p16(INK4a) homozygous deletions. Hypermethylation of the RB1 and the p27(Kip1) promoter region was detected in 2 (11%) cases, whereas p21(Waf1) methylation was not detected in any. Immunohistochemistry revealed loss of p14(ARF) and p16(INK4a) expression in 10 (56%) samples, correlating with the gene status. Four cases showed independent negative immunoreactivity for pRB and p27(Kip1), and nearly one-half of cases (8 of 18; 44%) were characterized by lack of p21(Waf1) expression. These results indicate that inactivation of p14(ARF) and p16(INK4a) by either homozygous deletion or promoter hypermethylation represents an important molecular pathogenesis in PCNSLs. Hypermethylation of RB1, p21(Waf1), and p27(Kip1) appears to be of minor significance, these genes being independently methylated in PCNSLs.

Cell Cycle Proteins↗
PubMed2001

Zero-magnetization ferromagnet proven by helicity-switching Compton scattering.

A single crystal of gadolinium-doped SmAl(2) has zero magnetization in the midst of the ordered temperature region, despite the probable ferromagnetic spin ordering. The asymmetry in Compton-scattering intensity when switching between right- and left-handed polarization of incident 150-keV synchrotron radiation provides decisive proof that ferromagnetic order is really there, and that spin and orbital magnetic contributions cancel. The experiments also show that the spin direction at this zero-magnetization state is rather stable against the external magnetic field and, nevertheless, reversible by a preceding control of temperature and an external field.

Journal Article↗
PubMed2001

Crystallization and preliminary X-ray diffraction analysis of the light-harvesting protein phycocyanin from the thermophilic cyanobacterium Synechococcus elongatus.

The crystallization and preliminary crystallographic study of phycocyanin from the thermophilic cyanobacterium Synechococcus elongatus is reported. Phycocyanin is composed of alpha- and beta-subunits consisting of 162 and 172 amino-acid residues, respectively. These associate to form an alphabeta heterodimer, which further associates to give a ring-shaped trimer (alphabeta)(3). Two trimers bind head-to-head to form a hexamer (alphabeta)(6). Phycocyanin crystals have been obtained by the sitting-drop vapour-diffusion method with a precipitant solution containing 30%(w/v) PEG 4000 and 100 mM MES pH 7.5-8.0. Using synchrotron radiation, the crystals diffract to 2.0 A resolution. They belong to the trigonal space group R32, with unit-cell parameters a = b = 186.75 (3), c = 59.75 (4) A, alpha = beta = 90, gamma = 120 degrees. Assuming that the crystallographic triad is identical to the threefold axis of the hexamer and with three (alphabeta)(6) molecules in a unit cell, the calculated molar volume (V(M)) is 2.64 A(3) Da(-1). This value corresponds to a solvent content of approximately 53%, with one alphabeta heterodimer occupying the asymmetric unit.

Crystallization↗
PubMed2001

Novel transcriptional regulation of the human CYP3A7 gene by Sp1 and Sp3 through nuclear factor kappa B-like element.

Human CYP3A7 and CYP3A4 are expressed in fetal and adult livers, respectively, although the 5'-flanking regions of the two genes show 90% homology. The purpose of this study was to clarify the mechanism(s) responsible for the transcriptional regulation of the CYP3A7 gene in human hepatoma HepG2 cells that showed fetal phenotypes. Transfection studies using a series of the CYP3A7 or CYP3A4 promoter-luciferase chimeric genes identified a nuclear factor kappaB (NF-kappaB)-like element between nucleotides -2326 and -2297 that conferred the transcriptional activation of the CYP3A7 gene. A 1-base pair mismatch within the corresponding region of the CYP3A4 gene was sufficient for a differential enhancer activity. A gel shift assay using nuclear extracts from HepG2 cells showed that Sp1 and Sp3 bound to the NF-kappaB-like element of the CYP3A7 but not CYP3A4 gene. Specific activation of the CYP3A7 promoter by Sp1 and Sp3 was confirmed by a co-transfection of the p3A7NF-kappaB or p3A4NF-kappaB reporter gene with Sp1 or Sp3 expression plasmid into Drosophila cells, which lacked endogenous Sp family. Additionally, introduction of mutations into binding sites for hepatocyte nuclear factor 3beta, upstream stimulatory factor 1, and a basic transcription element in the proximal promoter attenuated luciferase activity to 20% of the level seen with the intact CYP3A7 promoter. Thus, we conclude that the expression of the CYP3A7 gene in HepG2 cells is cooperatively regulated by Sp1, Sp3, hepatocyte nuclear factor 3beta, and upstream stimulatory factor 1.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death.

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) were identified as signal transducers for the TNF receptor superfamily. However, the exact roles of TRAF2 and TRAF5 in TNF-induced NF-kappaB activation still remain controversial. To address this issue, we generated TRAF2 and TRAF5 double knockout (DKO) mice. TNF- but not interleukin-1-induced nuclear translocation of NF-kappaB was severely impaired in murine embryonic fibroblasts (MEFs) derived from DKO mice. Moreover, DKO MEFs were more susceptible to TNF-induced cytotoxicity than TRAF2 knockout MEFs. Collectively, these results indicate that both TRAF2 and TRAF5 are involved in TNF-induced NF-kappaB activation and protection from cell death.

Animals↗
PubMed2001

Involvement of p38 MAP kinase pathway in the synergistic activation of PACAP mRNA expression by NGF and PACAP in PC12h cells.

We have recently shown that in PC12 cells, PACAP and NGF synergistically increase PACAP gene transcription and mRNA level, and that the MAPK/ERK kinase inhibitor PD98059 blocks the PACAP mRNA expression induced by either PACAP or NGF, but not that induced by the combination, suggesting involvement of multiple signaling pathways. Here we show that the p38 MAPK inhibitor SB203580 almost completely inhibits the PACAP mRNA expression induced by PACAP alone or in combination with NGF. PACAP induces neurite outgrowth and potentiates NGF-induced neurite outgrowth in PC12h cells. Unlike the case for the PACAP mRNA expression, SB203580 did not affect, but PD98059 reduced, PACAP and NGF-induced neurite outgrowth. These results indicate that PACAP receptors are coupled to the p38 signaling pathway, and that p38 plays a key role in the regulation of PACAP gene expression, while ERK, but not p38, MAPK is involved in PACAP and NGF-induced neurite outgrowth.

Animals↗
PubMed2001

C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis.

BACKGROUND: An elevated plasma concentration of high-sensitivity C-reactive protein (hs-CRP) is a strong predictor of cardiovascular events. However, there have been no longitudinal studies of the relations between development of atherosclerotic lesions and hs-CRP concentrations. Furthermore, it remains unknown whether increased hs-CRP concentrations result in the development of atherosclerosis. METHODS AND RESULTS: The study included 179 outpatients 40 to 79 years of age who were treated at our institute for traditional risk factors for cardiovascular disease. The patients had no evidence of advanced carotid atherosclerosis at the time of baseline examination. Patients underwent repeated ultrasonographic evaluation of the carotid arteries for 35+/-10 months. Blood samples were collected for hs-CRP measurements. Based on focal intima-media thickening >/=1.1 mm representing plaque, plaque number (PN) and plaque score (PS; the sum of all plaque thicknesses) were calculated. The development of atherosclerosis was estimated by the formula Deltavalue/year=(last value-baseline value)/number of follow-up years. Multivariate linear regression analysis revealed that the log-transformed value for hs-CRP concentration was not related to baseline PN or PS but was related to DeltaPN/year and DeltaPS/year (beta=0.29 and 0.30; P<0.001 for both) independently of the effect of traditional risk factors. CONCLUSIONS: During the early stages of carotid atherosclerosis, the hs-CRP concentration is a marker of carotid atherosclerotic activity rather than extent of atherosclerosis.

Adult↗