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Biomedical subjects

M Nomoto

Publications and source records attributed to M Nomoto.

At least 55 records · Page 3Linked to original sources
PubMed1999

Catecholamine metabolism inhibitors and receptor blockades only partially suppress cardiac hypertrophy of juvenile visceral steatosis mice with systemic carnitine deficiency.

To clarify the mechanism of cardiac hypertrophy in carnitine-deficient JVS mice, we studied the possible role of catecholamine metabolism. Cardiac hypertrophy occurs 2 weeks after birth. The turnover of norepinephrine in the ventricles of JVS mice at 2 weeks was 3 times that of control, but it was not different from control at 5 days when the heart weight was not changed. To evaluate the accelerated norepinephrine turnover, we examined the effects of catecholamine metabolism inhibitors (alpha-methyltyrosine and 6-hydroxydopamine) and catecholamine receptor blockades (propranolol, prazosin and yohimbine) on the ratio of heart weight to body weight (HW/BW) and on the augmented expression of atrial natriuretic peptide (ANP) and the down-regulated carnitine deficiency-associated gene expressed in ventricle (CDV-1). The HW/BW ratio in JVS mice treated with catecholamine metabolism inhibitors and receptor blockades was significantly lower than in JVS mice without treatment, but still higher than in controls treated with each drug and in JVS mice treated with carnitine. The HW/BW ratio of JVS mice with propranolol was not significantly different from that of JVS mice treated with catecholamine metabolism inhibitors and was significantly lower than that of JVS mice treated with prazosin and yohimbine. Northern blot analysis showed that the altered expression of ANP and CDV-1 was not corrected in the ventricles of JVS mice treated with any of the drugs except carnitine. These results suggest that the catecholamine metabolism accelerated in JVS mice ventricles at 2 weeks is not the major cause of cardiac hypertrophy, but probably promotes cardiac hypertrophy mainly through the beta-adrenergic signaling pathway. The aberrant gene expression of ANP and CDV-1 found in JVS mice seems to be independent of catecholamine metabolism, and mediated primarily by the systemic carnitine deficiency.

Adrenergic Antagonists↗
PubMed1999

Association of 5' CpG demethylation and altered chromatin structure in the promoter region with transcriptional activation of the multidrug resistance 1 gene in human cancer cells.

Selection of human cells for resistance to vincristine or doxorubicin often induces overexpression of the multidrug resistance 1 gene (MDR1), which encodes the cell surface P-glycoprotein, as a result of gene amplification or transcriptional activation. However, the precise mechanism underlying such transcriptional activation of MDR1 remains unclear. The relation between methylation status of CpG sites in the MDR1 promoter region and transcriptional activation of MDR1 has now been investigated. The P-glycoprotein-overexpressing, multidrug-resistant KB/VJ300 and KB-C1 cells, which were established from human cancer KB3-1 cells, were examined; MDR1 is transcriptionally activated but not amplified in KB/VJ300 cells, whereas it is amplified in KB-C1 cells. Determination of the methylation status revealed that the MDR1 promoter region was hypomethylated in KB/VJ300 and KB-C1 cells, but hypermethylated in KB3-1 cells. Prior treatment of KB3-1 cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in a 90-fold increase in the frequency of vincristine-resistance. Of three lines, KB/CdR-1, KB/CdR-2, and KB/CdR-3, established from KB3-1 cells after exposure to 5-aza-2'-deoxycytidine, MspI/HpaII sites in the MDR1 promoter region were hypomethylated in KB/CdR-1 and KB/CdR-2 cells, but not in KB/CdR-3 cells. MDR1 mRNA expression was detected in KB/CdR-1 and KB/CdR-2 cells, but not in KB/CdR-3 cells. The binding of YB-1 and Sp1, transcription factors implicated in MDR1 expression, in the MDR1 promoter was not affected by the methylation status of a neighboring CpG sites. The MDR1 promoter region in KB/VJ300 cells showed an increased sensitivity to DNase I compared with that in KB3-1 cells, suggesting an altered chromatin structure. The methylation status of the promoter region may plays an important role in MDR1 overexpression and in acquisition of the P-glycoprotein-mediated multidrug resistance phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Analysis of 8-hydroxyguanine in rat kidney genomic DNA after administration of a renal carcinogen, ferric nitrilotriacetate.

The frequency of oxidative base damage, such as 8-hydroxyguanine (8-OH-Gua), was determined at the nucleotide level of resolution using the ligation-mediated PCR technique. Administration of a renal carcinogen, ferric nitrilotriacetate (Fe-NTA), is known to induce oxidative stress and subsequent formation of 8-OH-Gua in the rat kidney. Whole genomic DNA was isolated from the rat kidney after or without Fe-NTA treatment and then cleaved with hot piperidine. In order to assess the frequency of 8-OH-Gua formation, we chose three genes, the tumor suppressor gene p53, the heat shock protein 70 (HSP70-1) gene and the Na,K-ATPase alpha1 subunit gene. No alteration in the cleavage profile was observed in the p53 and HSP70 genes after Fe-NTA treatment. In the case of the p53 gene, a low incidence of point mutations has been observed in this carcinogenesis system. On the other hand, time-dependent alterations, corresponding to the time course of overall 8-OH-Gua formation and repair, were detected in the promoter region of the Na,K-ATPase alpha1 subunit gene. GpG and GpGpG in specific regions seem to be hotspots for the formation of 8-OH-Gua. These results were confirmed by formamidopyrimidine-DNA glycosylase-dependent DNA cleavage patterns. Thus, oxidative base damage, such as 8-OH-Gua, was not distributed uniformly along the whole genome, but seemed to be restricted to particular genes and regions.

Animals↗
PubMed1999

Complete remission of multiple hepatocellular carcinomas associated with hepatitis C virus-related, decompensated liver cirrhosis by oral administration of enteric-coated tegafur/uracil.

We report a case of complete remission of multiple hepatocellular carcinomas after oral administration of enteric-coated tegafur/uracil. A 77-yr-old woman was diagnosed as having recurrent hepatocellular carcinoma associated with decompensated liver cirrhosis. We administered enteric-coated tegafur/uracil to this patient. After 1 month of oral administration, there was a decrease in tumor markers. An image analysis showed disappearance of hepatocellular carcinoma. No recurrence of the hepatocellular carcinoma was recognized for 18 months up to the time of the patient's death, which was due to massive bleeding from a hemorrhagic rectal ulcer. At autopsy, the tumor lesion had necrotized. Oral administration of enteric-coated granules containing tegafur/uracil may provide an effective treatment for hepatocellular carcinoma.

Administration, Oral↗
PubMed1999

T-Cell hyporesponsiveness induced by activated macrophages through nitric oxide production in mice infected with Mycobacterium tuberculosis.

In active tuberculosis, T-cell response to Mycobacterium tuberculosis is known to be reduced. In the course of Mycobacterium tuberculosis infection in mice, we observed that T-cell proliferation in response to M. tuberculosis purified protein derivative (PPD) reached the maximum level on day 7, then declined to the minimal level on day 14, and persisted at a low level through day 28 postinfection. The frequency of PPD-specific CD4 T cells in the spleen on day 28 decreased to one-sixth on day 7. To further investigate the mechanism of this T-cell hyporesponsiveness, we next analyzed the suppressive activity of spleen macrophages on T-cell function. The nonspecific proliferative response of naive T cells and the PPD-specific proliferative response of T cells were suppressed by day 28 macrophages, but not by day 7 macrophages or naive macrophages. This reduction of proliferative response was restored by addition of nitric oxide synthesis inhibitor, NG-monoethyl-L-arginine monoacetate, but not by monoclonal antibody against interleukin 10 or transforming growth factor beta. These data indicate that the macrophages from mice chronically infected with M. tuberculosis suppress T-cell response through production of nitric oxide, suggesting that nitric oxide-induced elimination mediated by activated macrophages may reduce the T-cell response and the number of mycobacterium-specific CD4 T cells in vivo.

Animals↗
PubMed1999

Efficacy of shitei-to, a traditional Chinese medicine formulation, against convulsions in mice.

The anticonvulsant effects of Shitei-To and its components on maximal electroshock seizures and chemical convulsions were examined. Shitei-To significantly prolonged the latency to bicuculline (2.0 mg/kg, s.c.)-induced clonic convulsions. Repeated treatment with Shitei-To also significantly prolonged the latency to strychnine (1.5 mg/kg, i.p.)- and pentylenetetrazol (90 mg/kg, i.p.)-induced clonic convulsions. On the other hand, Shitei-To had no effect on maximal electroshock seizures. Of the components of Shitei-To, Shitei had almost the same effect as Shitei-To against the clonic convulsions induced by the three chemical agents tested. These findings suggest that Shitei-To has anticonvulsant effects.

Animals↗
PubMed1999

Effect of diesel exhaust on guinea pig nasal mucosa.

In this study using guinea pigs, we investigated the effects of diesel exhaust (DE) containing diesel exhaust particulate (DEP) on 1) vascular permeability induced by histamine, 2) nasal mucosal permeability to horseradish peroxidase (HRP), and 3) eosinophilic epithelial infiltration. The vascular permeability induced by histamine was enhanced significantly and dose-dependently in DE-exposed guinea pigs. The HRP reaction products in epithelial cells and intercellular spaces were significantly and dose-dependently increased in those guinea pigs. Eosinophil infiltration into the epithelial layer was significantly increased in guinea pigs exposed to DE containing 3.2 mg/m3 DEP, and the reactivity of the nasal mucosa to histamine solution applied on the nasal mucosa was significantly enhanced in those guinea pigs. These findings suggest that DE may play an important role not only in promoting nasal hyperreactivity induced by the enhancement of absorption of antigen through the nasal epithelium, but also in inducing eosinophil infiltration in nasal mucosa and enhancing nasal mucosal reactivity.

Animals↗
PubMed1999

Effects of beta-blockers and nicardipine on oxotremorine-induced tremor in common marmosets.

Effects of beta-blockers (propranolol, arotinolol and nipradilol) and a Ca2+ channel blocker (nicardipine) on oxotremorine-induced tremor were studied in common marmosets. Generalized tremor was elicited by an intraperitoneal administration of 0.25 mg/kg oxotremorine. Intensity of the tremor was classified into 7 degrees, and it was evaluated every 10 min. The total intensity of oxotremorine-induced tremor for each drug was expressed as "points", which were the sum of tremor intensity scores evaluated every 10 min up to 190 min following the administration of oxotremorine. Beta-blockers significantly suppressed the tremor. On the other hand, the Ca2+ channel blocker exacerbated the tremor.

Adrenergic beta-Antagonists↗
PubMed1999

Adenosine and neopterin levels in cerebrospinal fluid of patients with neurological disorders.

We determined the cerebrospinal fluid (CSF) levels of adenosine, a mediator of cerebral blood flow regulation, and neopterin, a macrophage-producing compound, in patients with neurological disorders. Compared to control subjects, the adenosine levels were significantly increased in the patients with acute-stage cerebral infarction (n=12, p<0.0001), acute meningitis (n=10, p<0.0001), or amyotrophic lateral sclerosis (ALS, n=12, p<0.05) (Mann-Whitney U-test). The neopterin levels were significantly increased in the 41 patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP, p<0.0001), acute meningitis (p<0.0001), ALS (p<0.05) (Mann-Whitney U-test), or acute-stage cerebral infarction (p<0.005, Student's t-test). In the analysis of 41 HAM/TSP patients, the neopterin levels were significantly correlated with the cell number and glucose levels in the CSF, and were a sensitive marker of inflammation. Several of the HAM/TSP patients with increased adenosine levels were probably complicated with other diseases. The increased neopterin levels in the HAM/TSP group persisted, suggesting that the mononuclear cellular infiltration remained for a long time.

Adenosine↗
PubMed1999

Structural and functional analysis of the control region of the human DNA topoisomerase II alpha gene in drug-resistant cells.

We have previously shown that the DNA topoisomerase II alpha (topo II alpha) gene is down-regulated in VP16/VM26-resistant cells at the transcriptional level. To determine the DNA elements responsible for down-regulation, the transcriptional activities of luciferase reporter constructs containing various lengths of the promoter sequences were investigated by transient transfection of two resistant cell lines, KB/VP2 and KB/VM4. The transcriptional activities of the full-length promoter (-295 to +85) and of three deletion constructs (-197, -154 and -74 to +85) were significantly down-regulated in resistant cells. In contrast, the transcriptional activity of the minimal promoter (-20 to +85) in resistant cells was similar to that in parental KB cells. Furthermore, introduction of a mutation in ICE1 abolished the down-regulation of the topo II alpha promoter activity in drug-resistant cells. In vivo footprinting analysis of topo II alpha gene promoter revealed several specific protein-binding sites, a GC box, ICE1, ICE2 and ICE3. In vivo footprinting analysis also identified a cluster of hypersensitive sites. However, there was no marked difference in protein-binding sites between parental and resistant cells. To confirm our previous results, we have established the VP16-resistant cell lines T12-VP1 and T12-VP2 from T12 cells derived from human bladder cancer T24 cells stably transfected with the chloramphenicol acetyltransferase reporter gene driven by the topo II alpha gene promoter. The expression to topo II alpha was down-regulated in both cell lines. We also found that CAT gene expression was significantly decreased to one-fifth of that in T12 parental cells. These results suggest that the expression of the topo II alpha gene requires the binding of multiple factors to the core promoter and is down-regulated at the transcriptional level, probably through binding of a negative factor to ICE1 in drug-resistant cells.

Antigens, Neoplasm↗
PubMed1999

Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in japanese patients with chronic hepatitis B.

Lamivudine is effective in suppressing replication of hepatitis B virus (HBV). However, the emergence of HBV variants resistant to lamivudine is a concern. Lamivudine resistance has been attributed mainly to a substitution of isoleucine or valine for methionine at residue 550 (M550I or M550V) in the catalytic site of the virus polymerase. A substitution of methionine for leucine at residue 526 (L526M) has also been identified. To examine such virus genotypic mutations in Japanese patients, we studied five patients with chronic hepatitis B, who showed HBV breakthrough while on a 1-year lamivudine treatment. The entire nucleotide and deduced amino acid sequences of the proposed reverse transcriptase domain of the polymerase gene were determined on HBV DNA amplified by polymerase chain reaction from patient sera collected at the start and at the end of therapy. The HBV sequences from all five patients were of genotype C. In four patients, a substitution of valine or isoleucine for leucine at residue 426, which has not been reported previously, emerged in combination with M550I. One also harbored L526M. In the remaining patient, an alteration of leucine to methionine at residue 428 co-occurred with M550V. Longitudinal study of the mutations showed that the two or three mutations in each patient emerged almost simultaneously 4 weeks before or at the time of breakthrough and were replaced by wild-type virus after completing the therapy. Our results indicate that occurrence of HBV polymerase mutations at residue 426 in combination with M550I is frequent in Japanese or genotype C virus-in- fected patients who develop resistance to lamivudine.

Adult↗
PubMed1999

Quantification of neuromodulin (GAP-43, B-50) and synapsin I in rat striata.

We reported previously that phosphorylated neuromodulin and phosphorylated synapsin I content increased in the striata of amphetamine-sensitized rats; however, the neuronal pathways responsible for the increase were unclear. In the present study, changes in neuromodulin and synapsin I content resulting from the manipulation of lesions were quantified to elucidate the responsible pathways. Nerve terminals originating in the corticostriatal pathway, those from the nigrostriatal pathway and those from interneurons in the striatum, were impaired by unilateral cortical ablation, 6-hydroxydopamine (6-OHDA) treatment and kainic acid injection into the striatum, respectively. Neuromodulin and synapsin I content in the ipsilateral striatum after unilateral ablation of the frontal cortex decreased by 51 and 31%, respectively. The impairment of dopaminergic terminals by 6-OHDA reduced the neuromodulin content by 22%; however, no significant alteration was observed in the synapsin I content as the result of 6-OHDA treatment. The injection of kainic acid did not cause the content of either protein to decrease. These results suggest that corticostriatal nerve terminals possess a large part of the total neuromodulin and almost all the synapsin I in the striatum. Therefore, the increase in phosphorylated neuromodulin induced by repeated treatment with amphetamine may occur in corticostriatal glutamatergic terminas and/or nigrostriatal dopaminergic terminals. On the other hand, the increase in phosphorylated synapsin I may preferentially occur in the corticostriatal glutamatergic terminals.

Animals↗
PubMed1998

Structural analysis of peptide substrates for mucin-type O-glycosylation.

The structures of three nine-residue peptide substrates that show differential kinetics of O-linked glycosylation catalyzed by distinct recombinant uridine diphosphate-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc transferases) were investigated by NMR spectroscopy. A combined use of NMR data, molecular modeling techniques, and kinetic data may explain some structural features required for O-glycosylation of these substrates by two GalNAc transferases, GalNAc-T1 and GalNAc-T3. In the proposed model, the formation of an extended backbone structure at the threonine residue to be glycosylated is likely to enhance the O-glycosylation process. The segment of extended structure includes the reactive residue in a beta-like or an inverse gamma-turn conformation and flanking residues in a beta-strand conformation. The hydroxyl group of the threonine to be glycosylated is exposed to solvent, and both the amide proton and carbonyl oxygen of the peptide backbone are exposed to solvent. The exchange rate of the amide proton for the reactive threonine correlated well with substrate efficiency, leading us to hypothesize that this proton may serve as a donor for hydrogen bonding with the active site of the enzyme. The oxygens of the residue to be glycosylated and several flanking residues may also be involved in a set of hydrogen bonds with the GalNAc-T1 and -T3 transferases.

Amino Acid Sequence↗
PubMed1998

A family of human beta3-galactosyltransferases. Characterization of four members of a UDP-galactose:beta-N-acetyl-glucosamine/beta-nacetyl-galactosamine beta-1,3-galactosyltransferase family.

BLAST analysis of expressed sequence tags (ESTs) using the coding sequence of a human UDP-galactose:beta-N-acetyl-glucosamine beta-1, 3-galactosyltransferase, designated beta3Gal-T1, revealed no ESTs with identical sequences but a large number with similarity. Three different sets of overlapping ESTs with sequence similarities to beta3Gal-T1 were compiled, and complete coding regions of these genes were obtained. Expression of two of these genes in the Baculo virus system showed that one represented a UDP-galactose:beta-N-acetyl-glucosamine beta-1, 3-galactosyltransferase (beta3Gal-T2) with similar kinetic properties as beta3Gal-T1. Another gene represented a UDP-galactose:beta-N-acetyl-galactosamine beta-1, 3-galactosyltransferase (beta3Gal-T4) involved in GM1/GD1 ganglioside synthesis, and this gene was highly similar to a recently reported rat GD1 synthase (Miyazaki, H., Fukumoto, S., Okada, M., Hasegawa, T., and Furukawa, K. (1997) J. Biol. Chem. 272, 24794-24799). Northern analysis of mRNA from human organs with the four homologous cDNA revealed different expression patterns. beta3Gal-T1 mRNA was expressed in brain, beta3Gal-T2 was expressed in brain and heart, and beta3Gal-T3 and -T4 were more widely expressed. The coding regions for each of the four genes were contained in single exons. beta3Gal-T2, -T3, and -T4 were localized to 1q31, 3q25, and 6p21.3, respectively, by EST mapping. The results demonstrate the existence of a family of homologous beta3-galactosyltransferase genes.

Amino Acid Sequence↗
PubMed1998

The role of an inverted CCAAT element in transcriptional activation of the human DNA topoisomerase IIalpha gene by heat shock.

Expression of the DNA topoisomerase IIalpha (topoIIalpha) gene is highly sensitive to various environmental stimuli including heat shock. The amount of topoIIalpha mRNA was increased 1.5-3-fold 6-24 h after exposure of T24 human urinary bladder cancer cells to heat shock stress at 43 degreesC for 1 h. The effect of heat shock on the transcriptional activity of the human topoIIalpha gene promoter was investigated by transient transfection of T24 cells with luciferase reporter plasmids containing various lengths of the promoter sequence. The transcriptional activity of the full-length promoter (nucleotides (nt) -295 to +85) and of three deletion constructs (nt -197 to +85, -154 to +85, and -74 to +85) was increased approximately 3-fold 24 h after heat shock stress. In contrast, the transcriptional activity of the minimal promoter (nt -20 to +85), which lacks the first inverted CCAAT element (ICE1), the GC box, and the heat shock element located between nt -74 and -21, was not increased by heat shock. Furthermore, the transcriptional activity of promoter constructs containing mutations in the GC box or heat shock element, but not that of a construct containing mutations in ICE1, was significantly increased by heat shock. Electrophoretic mobility shift assays revealed reduced binding of a nuclear factor to an oligonucleotide containing ICE1 when nuclear extracts were derived from cells cultured for 3-24 h after heat shock. No such change in factor binding was apparent with an oligonucleotide containing the heat shock element of the topoIIalpha gene promoter. Finally, in vivo footprint analysis of the topoIIalpha gene promoter revealed that two G residues of ICE1 that were protected in control cells became sensitive to dimethyl sulfate modification after heat shock. These results suggest that transcriptional activation of the topoIIalpha gene by heat shock requires the release of a negative regulatory factor from ICE1.

Antigens, Neoplasm↗