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N Kubota

Publications and source records attributed to N Kubota.

At least 55 records · Page 3Linked to original sources
PubMed2000

The role of PPARgamma as a thrifty gene both in mice and humans.

The biological role of peroxisome proliferator-activated receptor gamma (PPARgamma) was investigated by gene targeting and case-control study of the Pro12Ala PPARgamma2 polymorphism. Homozygous PPARgamma-deficient embryos died at 10.5-11.5 days post conception (dpc) due to placental dysfunction. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARgamma agonist treatment. Heterozygous PPARgamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARgamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARgamma. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against type 2 diabetes. These results revealed that in both mice and humans, PPARgamma is a thrifty gene mediating type 2 diabetes.

Adipose Tissue↗
PubMed2000

Mitogenic activity of gelatin to murine spleen cells.

We reported previously that gelatin stimulates the growth of spleen cells in vitro. Tritium thymidine (3H-TdR) uptake into phytohemagglutinin (PHA)-stimulated spleen cells as well as intact spleen cells was augmented by gelatin. These findings suggest that gelatin serves as a mitogen for lymphoid cells. In this study, the target of action of gelatin was investigated. Tritium thymidine uptake into T cell-rich fraction was enhanced by incubation with 7.5 mg/ml of gelatin for 48 hours. The level of 3H-TdR uptake into B cell-rich fraction was not definitely increased by gelatin. Flow cytometric analysis confirmed these findings. Namely, it showed that treatment of spleen cells with 7.5 mg/ml gelatin increased a ratio of CD3-positive cells and decreased that of CD19-positive cells. Tritium thymidine uptake into natural killer cell-rich fraction was augmented by gelatin in a similar fashion to T cell-rich fraction. Tritium thymidine uptake into macrophages was very low and not affected by gelatin. Tritium thymidine uptake into macrophage-precursors was very low but was enhanced by gelatin. These findings suggest that gelatin could be used as an agent of cancer biotherapy.

Animals↗
PubMed2000

Effect of hemostatics used during operations for digestive organ on cancer cells present in the peritoneal cavity.

We investigated effects of hemostatics used during operations for digestive organ on cancer cells present in the peritoneal cavity using BALB/c mice inoculated with Meth A tumor cells (fibrosarcoma) intraperitoneally (i.p.) and C3H/He mice inoculated with MH134 tumor cell (hepatic cell carcinoma) i.p. Microfibrillar collagen hemostat (Avitene) or fibrinogen preparation (Beriplast P) did not affect survivals of those tumor-bearing mice. Gelatin sponge (Spongel)prolonged survivals of MH134 tumor-bearing mice. Liquid form gelatin used instead of Spongel displayed in vitro antitumor effect on MH134 tumor cells at the concentration of 15 mg/ml. Radioactive sodium chromate-labeled MH134 and Meth A tumor cells were not lysed when they were incubated with 15 mg/ml of liquid form gelatin for 24 hours. On the other hand, the tritium thymidine (3H-TdR) uptake by MH134 or RL male 1 tumor cells was suppressed when they were incubated with 15 mg/ml of liquid form gelatin for 24 hours. Proliferation of Meth A tumor cells were not affected by the treatment. Effect of liquid form gelatin on phytohemagglutinin (PHA)-stimulated spleen cells as a benign counter-part of RL male 1 tumor cells (T cell lymphoma) was examined. Liquid form gelatin (15 mg/ml) did not suppress 3H-TdR uptake by PHA-stimulated spleen cells.

Animals↗
PubMed2000

Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover.

Insulin receptor substrates (IRS-1 and -2) are essential for intracellular signaling by insulin and IGF-I, anabolic regulators of bone metabolism. Mice lacking the IRS-1 gene IRS-1(-/-) showed severe osteopenia with low bone turnover. IRS-1 was expressed in osteoblasts, but not in osteoclasts, of wild-type (WT) mice. IRS-1(-/-) osteoblasts treated with insulin or IGF-I failed to induce tyrosine phosphorylation of cellular proteins, and they showed reduced proliferation and differentiation. Osteoclastogenesis in the coculture of hemopoietic cells and osteoblasts depended on IRS-1 expression in osteoblasts and could not be rescued by IRS-1 expression in hemopoietic cells in the presence of not only IGF-I but also 1,25(OH)(2)D(3). In addition, osteoclast differentiation factor (RANKL/ODF) was not induced by these factors in IRS-1(-/-) osteoblasts. We conclude that IRS-1 deficiency in osteoblasts impairs osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia. Osteoblastic IRS-1 is essential for maintaining bone turnover, because it mediates signaling by IGF-I and insulin and, we propose, also by other factors, such as 1,25(OH)(2)D(3).

Animals↗
PubMed2000

Insulin effect during embryogenesis determines fetal growth: a possible molecular link between birth weight and susceptibility to type 2 diabetes.

Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic beta-cell type glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [n = 30] vs. 1.63+/-0.03 [n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes.

Animals↗
PubMed2000

Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.

To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2-/- mice) had a body weight similar to wild-type mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2-/- mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta-cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta-cells in IRS-1-deficient mice (IRS-1-/- mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta-cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2-/- mice compared with wild-type mice but was decreased in IRS-1-/- mice. These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells.

Animals↗
PubMed2000

Esotropia surgery in children: long term outcome regarding changes in binocular alignment; a study of 956 cases.

PURPOSE: To study the correlation between the outcome at 1 month (when the postoperative eye position is at the earliest stabilized), and 4 years after surgery. METHOD: Retrospective review of medical records. CASES: The authors reviewed 956 patients under 15 years of age who underwent unilateral or bilateral recession of the medial rectus muscle during a 22 year period representing the entire practice period of the senior author since the department was founded in 1977. The series comprised 521 cases of congenital/infantile esotropia (manifest before 6 months of age with no accommodative component) and 435 cases of acquired esotropia (manifest after 6 months of age with no accommodative component or with an accommodative component but excluding those with a high AC/A ratio). A consistent surgical plan was employed throughout this period for each condition. RESULTS: Both types of esotropia showed a slight tendency to become exotropic during the 4 years after surgery. There was no difference in general success with regard to the reconstructive restoration of normal appearance or improvement of appearance between 1 month and 4 years after surgery. Patients with normal retinal correspondence or simultaneous perception achieved better binocular alignments at the 4 year followup than those who did not have such sensory binocular cooperation. CONCLUSIONS: In infantile and acquired esotropia, it is essential that orthotropia or minimal esotropia be present at 1 month of surgery in order to obtain a binocular alignment within +/- 4 PD of orthotropia 4 years after surgery. It is strongly recommended to avoid overcorrection (consecutive exotropia) at 1 month after surgery for both congenital/infantile and acquired esotropia.

Accommodation, Ocular↗
PubMed2000

[Binocular function of intermittent exotropia before and after surgery].

PURPOSE: We examined the binocular function of intermittent exotropia before and after surgery, and studied the effect of the surgery and the factor that might be involved in its result. MATERIALS AND METHODS: 402 intermittent exotropic patients, who underwent their first surgical correction for the strabismus at Teikyo University Hospital, were examined for retinal correspondence and stereo acuity before and after surgery. RESULTS: 367 patients (91.3%) had already had good stereo acuity before surgery when their eyes were straight. Regarding retinal correspondence, though 192 patients (47.8%) were abnormal (dual) before surgery, 301 patients (74.9%) were normal after surgery. The eye deviation of 101 patients who could not get normal retinal correspondence after surgery was significantly larger than normal (p < 0.001), and 77.2% of them had also vertical strabismus which was mainly composed of dissociated vertical deviation. CONCLUSION: Normal binocular function could be recovered by surgical treatment in most intermittent exotropic patients. When patients could not get normal retinal correspondence after surgery, we supposed that dissociated vertical deviation might exert an important effect upon their binocular function.

Adolescent↗
PubMed2000

[18q-syndrome].

Explore the source record for details and available documents.

Abnormalities, Multiple↗
PubMed1999

Beta(2)-microglobulin identified as an apoptosis-inducing factor and its characterization.

Major histocompatibility complex (MHC) molecules play an important role in antigen presentation for induction of tumor as well as cellular and humoral immunities. Recent studies using anti-MHC antibodies demonstrated that antibodies specific for HLA class I molecules induced cellular activation and a type of apoptosis that may be distinct from Fas-dependent or TNFR (tumor necrosis factor-alpha receptor)-dependent processes. We purified a previously untested apoptosis-inducing factor from HL-60 human leukemic cell-conditioned media to homogeneity and sequenced it. It was identified as beta(2)-microglobulin (beta(2)m), which has been previously known as thymotaxin and is a part of the HLA class I antigen complex. beta(2)m acts on both T-leukemic cells and myeloid leukemic cells to induce apoptosis, which then activates caspase 1 and 3. Cross-linking studies showed that biotinilated beta(2)m recognized an epitope distinct from those recognized by the anti-HLA class I antibody, as reported previously. We demonstrated that beta(2)m plays a previously unrecognized and important role in regulating the elimination of tumor cells, which occurs as a result of the action of beta(2)m as an apoptosis-inducing factor.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion.

Glucose metabolism in glycolysis and in mitochondria is pivotal to glucose-induced insulin secretion from pancreatic beta cells. One or more factors derived from glycolysis other than pyruvate appear to be required for the generation of mitochondrial signals that lead to insulin secretion. The electrons of the glycolysis-derived reduced form of nicotinamide adenine dinucleotide (NADH) are transferred to mitochondria through the NADH shuttle system. By abolishing the NADH shuttle function, glucose-induced increases in NADH autofluorescence, mitochondrial membrane potential, and adenosine triphosphate content were reduced and glucose-induced insulin secretion was abrogated. The NADH shuttle evidently couples glycolysis with activation of mitochondrial energy metabolism to trigger insulin secretion.

Adenosine Triphosphate↗
PubMed1999

Proposed standard for human blood vitamin B1 value using HPLC. The Committee for Vitamin Laboratory Standards, Japan.

Standard reference ranges for all laboratory test values are mandatory. This study was designed to establish a reference range for blood vitamin B1 levels, since the normal range has not been determined in the Japanese population. We founded the Japan Committee for Vitamin Laboratory Standards, which was incorporated with the Vitamin Society of Japan and the Japanese Society of Nutrition and Food Science. We standardized whole blood vitamin B1 levels using three HPLC techniques (post-column reverse-phase HPLC, pre-column reverse-phase HPLC, and precolumn GP-HPLC). The reference range was obtained in 54 volunteers administered a 1,800 kcal diet with 2 mg of vitamin B1 (1.74 mg measured) daily to avoid marginal vitamin B1 deficiency in the population. The range for each assay was 26-47, 28-51, and 28-56 ng/ml, respectively. Our data suggest that 26-28 ng/ml is the lower limit of normal for whole blood vitamin B1, but further studies in a larger population are needed in order to obtain more definitive results.

Chromatography, High Pressure Liquid↗
PubMed1999

Pharmacological characterization of dopamine transport in cultured rat astrocytes.

The effects of GBR-12909 (selective DA uptake inhibitor), zimelidine (selective 5-HT uptake inhibitor) and nisoxetine (selective NE uptake inhibitor) on the uptake of 30 nM [3H]DA into cultured rat astrocytes were examined. [3H]DA uptake was inhibited by approximately 50% by GBR-12909 or zimelidine in a concentration-dependent manner (100 nM to approximately 10 microM). Furthermore, the inhibition curves of GBR-12909 were biphasic, and uptake was completely inhibited by a high concentration of GBR-12909 (100 microM). [3H]DA uptake was also inhibited by approximately 50% by nisoxetine in a concentration-dependent manner (0.1 to approximately 100 nM), and nisoxetine was more potent than GBR-12909 or zimelidine. The inhibitory potencies were in the order nisoxetine > GBR-12909 > zimelidine. The uptake of [3H]DA under Na+-free conditions was approximately 50% of that under normal conditions. Thus, DA was taken up by both Na+-dependent and Na+-independent mechanisms. Nisoxetine (100 nM), zimelidine (100 microM) and GBR-12909 (10 microM) inhibited [3H]DA uptake into astrocytes only in the presence of Na+. On the other hand, this uptake was completely inhibited by a high concentration of GBR-12909 (100 microM) in the absence of Na+. The present data suggest that the Na+-dependent uptake of [3H]DA in cultured rat astrocytes may occur in the NE uptake system. Furthermore, astrocytes express the extraneuronal monoamine transporter (uptake2), which is an Na+-independent system, and this transporter is involved in the inactivation of centrally released DA.

Animals↗
PubMed1999

Regulation of dopamine uptake by basic fibroblast growth factor and epidermal growth factor in cultured rat astrocytes.

We examined the characteristics of dopamine (DA) uptake and its regulation by neurotrophic factors such as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) in cultured rat astrocytes. In the presence of inhibitors of monoamine oxidase (MAO) and catechol-O-methyl-transferase (COMT), astrocytes took up DA by Na(+)-dependent and Na(+)-independent mechanisms that were sensitive to a reduction in temperature. The Na(+)-dependent and Na(+)-independent components increased linearly with increasing [3H]DA concentration (1-1000 microM), and showed no saturation. Na(+)-dependent DA uptake was significantly inhibited by ouabain, a Na(+)-K+ ATPase inhibitor. In bFGF-treated astrocytes, [3H]DA uptake increased in a time-dependent manner until 48 h, and declined after 72 h in both the presence and absence of Na+. In EGF-treated astrocytes, [3H]DA uptake increased in a time-dependent manner until 72 h in both the presence and absence of Na +. This enhancement of DA uptake induced by EGF or bFGF was significantly inhibited when the cells were cultured with actinomycin D, cycloheximide, or brefeldin A. Actinomycin D and brefeldin A also significantly inhibited the basal uptake of [3H]DA into astrocytes. These results suggest the existence of Na(+)-dependent and Na(+)-independent DA uptake in cultured rat astrocytes, and that EGF or bFGF might stimulate the expression and translocation of the extraneuronal DA transporter.

Animals↗
PubMed1999

PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance.

Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.

Adipocytes↗
PubMed1999

Mutation induction and RBE of low energy neutrons in V79 cells.

We have examined the neutron energy dependency of cell killing and mutation induction at the hprt locus in Chinese hamster V79 cells. Monoenergetic neutrons at 0.32, 0.57, and 1.2 MeV were generated at the Hiroshima University Radiobiological Research Accelerator (HIRRAC) Facility, and were used to irradiate cells. The variation in RBE with neutron energy for the end points of cell survival and hprt mutation induction was observed. When compared to 137Cs gamma-rays, all neutron energies were more effective at both cell killing and induction of mutation. Over the range of the neutron energies examined, we found that cytotoxicity increased as the energy decreased from 1.2 to 0.32 MeV. In comparison to gamma-rays, RBEs for cell lethality at 10% survival were 5.7, 6.7, and 7.6 for 1.2, 0.57, and 0.32 MeV, respectively. Mutation induction, on the other hand, was highest at 0.57 MeV with a gradual decrease at 1.2 and 0.32 MeV. RBEs for mutation induction were 9.7, 19.4, and 13.9 for 1.2, 0.57, and 0.32 MeV neutrons. We isolated independent V79 cell mutants at the hprt locus from untreated and neutron-exposed cells and determined the genetic changes underlying the mutation by multiplex polymerase chain reaction (PCR)-based exon deletion analysis. Preliminary results are suggestive of a specific relationship between deletion pattern and neutron energy.

Animals↗
PubMed1999

Computerized tomography nephroscopic images of renal pelvic carcinoma.

PURPOSE: Computerized tomography (CT) endoscopy is an interactive 3-dimensional image acquired by helical CT. We assess the usefulness of CT nephroscopy in the diagnosis of renal pelvic cancers. MATERIALS AND METHODS: Surface rendering CT nephroscopy was performed after intravenous administration of contrast agent and furosemide in 32 patients with suspected renal pelvic carcinoma. Retrospective review revealed that 23 patients later underwent nephroureterectomy. Two observers blinded to the pathology results independently reviewed the CT nephroscopic and axial CT images of the 23 patients to localize pelvic tumors and to determine the extent of the disease. The CT nephroscopic and axial CT images were correlated with the pathological findings. RESULTS: Pathological examination revealed 4 polypoid, 6 pedunculated, 7 sessile, 1 sessile with ulceration and 6 infiltrating renal pelvic carcinomas in the 23 patients. CT nephroscopy revealed 22 carcinomas (92%) and CT demonstrated 20 (83%). CT nephroscopy was superior to axial CT in detecting 4 pedunculated and 3 infiltrating carcinomas but failed to detect 1 sessile carcinoma which completely replaced the upper portion of a double renal pelvis and 1 polypoid tumor associated with infiltrating carcinoma. The CT nephroscopic images correlated well with pathological findings. CONCLUSIONS: CT nephroscopy is useful to visualize the complex morphology of renal pelvic carcinomas noninvasively and is superior to axial CT for the detection of infiltrating and pedunculated carcinomas.

Adult↗