[Transcriptional regulation mediated by chromatin remodeling].
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Animals↗
Biomedical subjects
S Hirose
Publications and source records attributed to S Hirose.
Roles of heme oxygenase/carbon monoxide system in genetically hypertensive rats.
Although carbon monoxide (CO) has been suggested to be involved in the regulation of cardiovascular function through activation of soluble guanylyl cyclase, the pathophysiological significance in hypertension remains unknown. We therefore examined the effects of heme oxygenase (HO) inhibitor zinc protoporphyrin IX (ZnPP-IX) on blood pressure and determined HO mRNA expression level in various tissues in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) and Wistar Kyoto rats (WKY/Izm). Although ZnPP-IX significantly increased systolic blood pressure in both strains, the increment of blood pressure was larger in SHR-SP/Izm than in WKY/Izm. An essentially similar increase of blood pressure was demonstrated even in the ganglion blocker-pretreated rats. Constitutive type HO-2 mRNA levels in the aorta and kidney and inducible type HO-1 mRNA levels in the cardiac ventricle were significantly increased in SHR-SP/Izm compared with WKY/Izm. Clearly these results indicate the importance of the endogenous HO/CO system in the peripheral tissues in genetically hypertensive rats.
Animals↗
A Case of Occult Breast Cancer With Paraneoplastic Polyneuropathy.
We encountered a very rarc case of occult breast cancer associated with paraneoplastic sensory polyneuropathy. A 59-year-old woman was admitted to our hospital complaining of numbness in all extremities, ataxia of left extremities and a tumor in the left axilla. From the neurological findings, a malignant tumor was suspected. The immunohistochemical analysis of the axillar swollen lymph node revealed metastasis from breast cancer and confirmed the primary lesion. On a preoperative diagnosis of suspected occult breast cancer, left mastectomy and resection of left axillar lymph nodes were performed. Furthermore, immunohistochemical staining of sural nerves and Western blot analysis of the serum of this patient showed the loss of axons and the presence of antineural antibody in the seurm. Immunological response was considered to be the remote effector system between the breast cancer and sensory polyneuropathy in this disorder.
Journal Article↗
Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats.
Oxidized low-density lipoprotein (Ox-LDL) has been implicated in the attenuated endothelium-dependent vasodilatation in atherosclerotic arteries and, possibly, in hypertension. The aim of the present study was to investigate gene expression of recently-identified endothelial Ox-LDL receptor (LOX-1) in hypertensive state. SHR-SP, WKY, Dahl salt-sensitive (DS) and salt-resistant rats (DR) were fed salt-loaded or control diet. RNA was extracted from the aorta and vein. LOX-1 expression was examined by Northern blotting. LOX-1 mRNA was low in the aorta and vein of WKY, whereas it was markedly upregulated in those of SHR-SP. LOX-1 expression was low in the aorta of DR on both diets and of DS on a control diet, whereas it was elevated in that of salt-loaded DS. These results indicated that LOX-1 expression in the aorta and vein was upregulated in hypertensive rats, which may be involved in the impaired endothelium-dependent vasodilation in these rats.
Animals↗
Precursor B cells for autoantibody production in genomically Fas-intact autoimmune disease are not subject to Fas-mediated immune elimination.
The Fas/Fas ligand (FasL) system participates in regulation of the immune system through the apoptotic process. However, the extent to which abnormalities in this system are involved in the loss of self-tolerance and development of autoimmune disease not associated with Fas/FasL mutations remains unknown. The present study addresses this issue in Fas/FasL-intact, systemic lupus erythematosus (SLE)-prone (NZB x NZW) (NZB/W) F1 mice. While splenic B cells from 2-month-old mice before overt SLE expressed Fas poorly, in vitro stimulation with an agonistic anti-CD40 mAb up-regulated their Fas expression, thus revealing the existence of two populations: one was Fashigh and highly susceptible to anti-Fas mAb-induced apoptosis, and the other was Faslow and apoptosis-resistant. The Faslow cells were included in the CD5(+) B cell subpopulation and contained most of the cells that produced IgM anti-DNA antibodies. The isotype of anti-DNA antibodies switches from IgM to IgG in NZB/W F1 mice at ages beginning at about 6 months. These IgG anti-DNA antibodies were produced almost exclusively by a subpopulation of splenic B cells that spontaneously expressed low levels of Fas in vivo and were apoptosis-resistant. The findings indicate that precursor B cells for autoantibody production and presumably autoantibody-secreting cells in these mice are relatively resistant to Fas-mediated apoptosis, a finding supporting the concept that abnormalities of Fas-mediated apoptotic process are involved in the development of autoreactive B cells in Fas/FasL-intact autoimmune disease.
Animals↗
Interrelation between nitric oxide synthase and heme oxygenase in rat endothelial cells.
The gene expression and interrelation of the constitutive type nitric oxide (NO) synthase-III as a NO-forming enzyme and heme oxygenase-2 as a carbon monoxide-forming enzyme were studied in cultured rat aortic endothelial cells. Both NO synthase-III and heme oxygenase-2 mRNAs were demonstrated in the endothelial cells by RNAase protection analysis. NO synthase-III mRNA was upregulated in the presence of the heme oxygenase inhibitor, zinc protoporphyrin IX, but not in the presence of the NO synthase inhibitor, N(G)-nitro-L-arginine. Although heme oxygenase-2 mRNA was significantly upregulated in the presence of both NO synthase inhibitor and heme oxygenase inhibitor, the increase was greater with the NO synthase inhibitor. These results provide the first evidence for the concomitant gene expression of NO synthase-III and heme oxygenase-2, and their compensatory interrelation in endothelial cells.
Animals↗
Multiprotein bridging factor 1 (MBF1) is an evolutionarily conserved transcriptional coactivator that connects a regulatory factor and TATA element-binding protein.
Multiprotein bridging factor 1 (MBF1) is a transcriptional cofactor that bridges between the TATA box-binding protein (TBP) and the Drosophila melanogaster nuclear hormone receptor FTZ-F1 or its silkworm counterpart BmFTZ-F1. A cDNA clone encoding MBF1 was isolated from the silkworm Bombyx mori whose sequence predicts a basic protein consisting of 146 amino acids. Bacterially expressed recombinant MBF1 is functional in interactions with TBP and a positive cofactor MBF2. The recombinant MBF1 also makes a direct contact with FTZ-F1 through the C-terminal region of the FTZ-F1 DNA-binding domain and stimulates the FTZ-F1 binding to its recognition site. The central region of MBF1 (residues 35-113) is essential for the binding of FTZ-F1, MBF2, and TBP. When the recombinant MBF1 was added to a HeLa cell nuclear extract in the presence of MBF2 and FTZ622 bearing the FTZ-F1 DNA-binding domain, it supported selective transcriptional activation of the fushi tarazu gene as natural MBF1 did. Mutations disrupting the binding of FTZ622 to DNA or MBF1, or a MBF2 mutation disrupting the binding to MBF1, all abolished the selective activation of transcription. These results suggest that tethering of the positive cofactor MBF2 to a FTZ-F1-binding site through FTZ-F1 and MBF1 is essential for the binding site-dependent activation of transcription. A homology search in the databases revealed that the deduced amino acid sequence of MBF1 is conserved across species from yeast to human.
Amino Acid Sequence↗
Targeting of endopeptidase 24.16 to different subcellular compartments by alternative promoter usage.
Endopeptidase 24.16 or mitochondrial oligopeptidase, abbreviated here as EP 24.16 (MOP), is a thiol- and metal-dependent oligopeptidase that is found in multiple intracellular compartments in mammalian cells. From an analysis of the corresponding gene, we found that the distribution of the enzyme to appropriate subcellular locations is achieved by the use of alternative sites for the initiation of transcription. The pig EP 24.16 (MOP) gene spans over 100 kilobases and is organized into 16 exons. The core protein sequence is encoded by exons 5-16 which match perfectly with exons 2-13 of the gene for endopeptidase 24.15, another member of the thimet oligopeptidase family. These two sets of 11 exons share the same splice sites, suggesting a common ancestor. Multiple species of mRNA for EP 24.16 (MOP) were detected by the 5'-rapid amplification of cDNA ends and they were shown to have been generated from a single gene by alternative choices of sites for the initiation of transcription and splicing. Two types of transcript were prepared, corresponding to transcription from distal and proximal sites. Their expression in vitro in COS-1 cells indicated that they encoded two isoforms (long and short) which differed only at their amino termini: the long form contained a cleavable mitochondrial targeting sequence and was directed to mitochondria; the short form, lacking such a signal sequence, remained in the cytosol. The complex structure of the EP 24.16 (MOP) gene thus allows, by alternative promoter usage, a fine transcriptional regulation of coordinate expression, in the different subcellular compartments, of the two isoforms arising from a single gene.
Amino Acid Sequence↗
Crucial role of CD8-positive lymphocytes in glomerular expression of ICAM-1 and cytokines in crescentic glomerulonephritis of WKY rats.
CD8-positive lymphocytes (CD8+ lym) and ICAM-1/LFA-1 interaction have been implicated in the glomerular accumulation of monocytes/macrophages (Mo/Mphi) and crescent formation in antiglomerular basement membrane (anti-GBM) glomerulonephritis of WKY rats. In the present study, the role of CD8+ lym in the expression of ICAM-1 and inflammatory cytokines as well as in the accumulation of Mo/Mphi in the glomeruli was examined by RNase protection assay and immunofluorescence microscopy. ICAM-1 expression was apparent at 1 h and markedly enhanced at day 3 in glomeruli after an anti-GBM Ab injection in parallel with glomerular accumulation of Mo/Mphi. Expression of mRNA for IL-1beta, TNF-alpha, and IFN-gamma, known to enhance ICAM-1 expression, and MIP-1alpha, MIP-1beta, and MCP-1, known to activate leukocyte integrins or to act as chemokines, were also induced in the glomeruli at a mRNA level in a profile similar to that of ICAM-1 expression. By depleting the CD8+ lym in the circulation, the increased glomerular expression of ICAM-1 and the cytokines, except IL-1beta, and the Mo/Mphi accumulation were suppressed, indicating a crucial role of CD8+ lym in the accumulation of Mo/Mphi through stimulation of ICAM-1 and induction of cytokines.
Animals↗
Dimerization of midkine by tissue transglutaminase and its functional implication.
Midkine (MK), a retinoic acid-inducible growth/differentiation factor, serves as a substrate for tissue transglutaminase (Kojima, S. , Muramatsu, H., Amanuma, H., and Muramatsu, T. 1995. J. Biol. Chem. 270, 9590-9596). Upon incubation with transglutaminase MK forms multimers through cross-linkages. Here, we report the following results. 1) Heparin potentiated the multimer formation by MK. 2) The N- and C-terminal half domains each formed a dimer through the action of transglutaminase. 3) Gln42 or Gln44 in the N-terminal half and Gln95 in the C-terminal half served as amine acceptors in the cross-linking reaction, as judged from the incorporation of putrescine into whole MK or each half domain, and the competitive inhibition of the cross-linking by MK-derived peptides containing Gln residue(s). The strongest inhibition was obtained with Ala41-Pro51. 4) This peptide abolished the biological activity of MK to enhance the plasminogen activator activity in bovine aortic endothelial cells. The inhibition was limited against the MK monomer, and not seen against the MK dimer, separated by gel filtration chromatography. These results suggest that dimer formation through transglutaminase-mediated cross-linking is an important step as to the biological activity of MK.
Animals↗
Structural analysis of natriuretic peptide receptor-C by truncation and site-directed mutagenesis.
Natriuretic peptide receptor-C (NPR-C) has a unique structure consisting of pre-existing covalent homodimers, but it is not known whether each subunit has ligand-binding activity or whether the dimeric structure is necessary for binding activity. To answer this question, a number of C-terminally truncated mutants were designed, subcloned into the mammalian expression vector pcDNA3 and expressed by transient transfection in COS-1 cells. Truncation at position 461, which eliminates the residue Cys469 that is involved in disulphide-linked dimerization, produced a soluble and monomeric form of NPR-C, as determined by gel filtration on Superose 12. Binding assays of the gel-filtration fractions clearly demonstrated that even monomeric NPR-C contains a high-affinity binding site for natriuretic peptides. Site-directed mutagenesis of the invariant residues (Asp407-Arg408 and Asp411-Phe412) in a region highly conserved among various species established that these invariant residues are essential for ligand-binding activity.
Amino Acid Sequence↗
Roles of IL-4 and IL-12 in the development of lupus in NZB/W F1 mice.
Development of either Th1 or Th2 cell subsets has profound immunologic consequences, either pathogenic or protective, in several autoimmune diseases. However, it remains unclear which subset of Th cells plays a more critical role in lupus. In this study, we examined IL-4 and IL-12, which play decisive roles in the development of Th2 and Th1, respectively, in the IgG autoantibody production and development of lupus nephritis in NZB/W (B/W) F1 mice. Transfer of either IL-4- or IL-12-stimulated splenocytes from 5-mo-old B/W F1 mice into B/W F1 mice of the same age enhanced the production of IgG anti-dsDNA Ab. Consistently, administration of mAb against either IL-4 or IL-12 before the onset of lupus could inhibit the production of IgG anti-dsDNA Ab. However, only anti-IL-4 mAb was effective in preventing the onset of lupus nephritis. This discrepancy appeared to be explained by the differential effect on the production of IgG3-type autoantibody and TNF production. Interestingly, when combined, anti-IL-12 mAb abrogated the beneficial effect of anti-IL-4 mAb. These results indicate that both Th2 and Th1 contribute to the IgG autoantibody production, and IL-4 and IL-12 play key roles in the complexity of cytokine regulation in the pathogenesis of autoimmunity in lupus, but the former is more critical.
Adoptive Transfer↗
Mapping of a gene for the increased susceptibility of B1 cells to Mott cell formation in murine autoimmune disease.
Mott cells, a pathologic state of plasma cells containing intracellular inclusions of Igs (Russell bodies), are frequent in lymphoid tissues of murine and human autoimmune diseases. However, neither the genesis nor the significance of Mott cells in autoimmune diseases is well understood. We found that B1, but not B2, cells were induced in vitro to form Mott cells in the presence of LPS or IL-5, but not other stimulants, in a much higher frequency in autoimmune New Zealand Black (NZB) and NZB x New Zealand White (NZB/W) F1 than in non-autoimmune disease-prone mice and notably athymic nude NZB/W F1 mice. Cell surface phenotypes of Mott cells were B220+ CD5+ CD43+ CD11b(dull), while those of peritoneal macrophages were B220- CD5- CD43(dull) CD11b+. We mapped a locus (provisionally designated Mott-1) controlling Mott cell formation that was tightly linked to microsatellite marker loci, D4 Mit70 and D4 Mit48, of autoimmune NZB mice, which is in close proximity to our recently mapped locus Imh-1 for hypergammaglobulinemia. This region contains candidate genes that may be relevant to the aberrant B cell activation and differentiation. We suggest that while the Mott cell by itself is not the effector for autoimmune disease, the genetically determined aberrant maturational process of B1 cells that underlies the pathogenesis of autoimmune disease forms the basis for Mott cell formation in a T cell-dependent manner.
Animals↗
Angiotensin II stimulates the proliferation of osteoblast-rich populations of cells from rat calvariae.
We examined the effects of angiotensin II (Ang II) on the proliferation of osteoblast-rich populations of cells obtained from calvariae of newborn rat. Addition of Ang II to the culture medium caused dose-dependent increases in the rate of DNA synthesis. Such increases were completely inhibited by the addition of DuP753, an antagonist of AT1 receptor. Ang II potentiated the production of inositol 1,4,5-trisphosphate (IP3) in the culture. Ang II also stimulated the activities of mitogen-activated protein kinases (MAPKs) upon binding to the AT1 receptor. These results suggest that Ang II might be intimately involved in the proliferation of the cells in calvariae through the AT1 receptor.
Angiotensin II↗
Partial cloning of the hormone-binding domain of the cortisol receptor in tilapia, Oreochromis mossambicus, and changes in the mRNA level during embryonic development.
Cortisol is one of the central hormones in osmoregulation in fish, especially in seawater adaptation. A cDNA of 453 bp was cloned from liver mRNA of freshwater-reared tilapia (Oreochromis mossambicus), by reverse transcription polymerase chain reaction (RT-PCR) with primers designed for the hormone-binding domain of glucocorticoid receptors (GRs) in mammals and rainbow trout. The sequence of PCR product has 83% homology to the trout GR at the nucleotide level and 92% at the amino acid level. The PCR product of tilapia showed highest homology (74% at the amino acid level) to GR among human steroid hormone receptors, including mineralocorticoid receptor. The length of the receptor mRNA of tilapia was about 6.5 kb as determined by Northern blot hybridization. The mRNA concentration in the gills was relatively higher among various organs, the highest concentration being observed in blood cells. Signal intensity of the receptor message in the gills was stronger in fish reared in freshwater than in those reared in seawater or in concentrated (160%) seawater. During early development of tilapia, the highest concentration of receptor mRNA in the total RNA extracted from the whole egg was found just after fertilization, and its concentration decreased steadily toward hatching. The absolute amount of receptor mRNA per egg increased gradually before the initiation of cortisol production by the embryo. When embryos were transferred from fresh water to seawater 2 days before hatching, no difference was observed in the signal intensity of the receptor mRNA among embryos after 1, 2 (the day of hatching), 4, and 7 days.
Animals↗
The R40H mutation in a late onset type of human ornithine transcarbamylase deficiency in male patients.
Ornithine transcarbamylase (OTC) deficiency is an X-linked trait and is one of the most frequent of the inherited urea cycle enzyme deficiencies. Most male patients with OTC deficiency develop a hyperammonemic crisis and die in the neonatal period or in early infancy. In contrast to those patients, in some male patients the disease first becomes overt in adolescence or during the reproductive age period. In the present report, we describe six such male patients who first developed clinical signs at ages ranging from 6 to 58 years, all of whom came from a limited area of the northern part of Kyushu Island in southern Japan. The mutation analysis disclosed a R40H mutation in exon 2 of the OTC gene in each of these patients. Transmission of this mutant gene through paternal lineage as well as through maternal lineage was documented in one family. The levels of mRNA of the mutant OTC gene expressed in transfected Cos 1 cells and in the liver tissue obtained by biopsy in one patient were both similar to those of the wild-type gene. The activity of the mutant OTC was, however, decreased to a level of 28% of the wild-type OTC, and the levels of the mutant OTC protein expressed in Cos 1 cells were decreased, as assessed by western blot analysis. Apparent Km values of the mutant enzyme for ornithine (1.1 mM) and carbamylophosphate (2.0 mM) were similar to those of the wild-type enzyme. Both enzymes gave similar pH-dependency profiles, giving a maximal activity at pH 7.8-7.9. Activity of wild-type OTC expressed in Cos 1 cells did not change after five cycles of freezing and thawing, whereas that of the mutant OTC decreased to 17% by this treatment. These results suggest that deficiency is due to inactivation of the mutant OTC under certain conditions.
Adolescent↗
Histopathological studies on spontaneous occlusion of the circle of Willis (cerebrovascular moyamoya disease).
Spontaneous occlusion of the circle of Willis (cerebrovascular Moyamoya disease; SOCW) was first described by Japanese surgeons and is thought to have a high incidence in the Japanese population. SOCW is characterized by the angiographical findings of the obstructive vascular lesions around the terminal portions of the internal carotid arteries and the formation of abnormal vascular networks visualized in the arterial phase without any definite underlying conditions. Here, we present a detailed histopathological observation of 31 autopsy cases with SOCW to discuss its etiology which is still a matter of dispute. The obstructive vascular lesion around the terminal portions of the internal carotid arteries which is thought to be the primary site affected in SOCW is due to multilayered eccentric intimal fibrous thickening suggestive of organized mural thrombi. In fact, we found thrombotic lesions frequently in the major cerebral arteries, including those of the circle of Willis, of autopsy cases with SOCW. This fact supports the idea that thrombi play an important role in establishment of the vascular lesions. Extracranial vessels are also shown to be involved and it is conceivable that the systemic etiologic factor, such as the systemic background to form thrombi, exists in patients with SOCW.
Adolescent↗
The effectiveness of clonazepam on the Rolandic discharges.
Rolandic discharge (RD), noted in the electroencephalography (EEG) of patients with benign epilepsy in childhood with centrotemporal spikes (BECCT) has several unique features. One feature is that the amount or frequency of RDs does not correlate well with the incidence of seizures in BECCT although it is a key finding in the diagnosis of this epileptic syndrome. In this study, we examined the efficacy of antiepileptic drugs focusing on the disappearance of RDs in relationship with seizure control. Forty patients with BECCT who were not medically treated prior to this study were randomly sorted into three groups. Twenty patients were assigned for clonazepam (CZP) treatment, 10 patients for valproate (VPA) and the remaining 10 patients for carbamazepine (CBZ). Each drug was administered for 4 consecutive weeks. EEGs were recorded twice during the study, before and 4 weeks after the medication trial. The effects of each treatment on RDs were assessed. RDs disappeared in 15 of the 20 cases treated with CZP (75%) within 4 weeks while the same was observed in only one of the 10 cases treated with VPA (10%). CBZ failed to demonstrate any effect on RD. In the group treated with CZP, there were no differences in seizure incidence, seizure type and blood concentration of CZP between the patients whose RDs disappeared and those whose RDs remained.
Anticonvulsants↗