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Biomedical subjects

N Nakai

Publications and source records attributed to N Nakai.

At least 19 recordsLinked to original sources
PubMed2000

The alpha-ketoisocaproate catabolism in human and rat livers.

Catabolism of alpha-ketoisocaproate in liver is mediated by cytosolic alpha-ketoisocaproate dioxygenase (KICD) and mitochondrial branched-chain alpha-keto acid dehydrogenase complex (BCKDC). The latter is believed to be involved in the main pathway of the KIC catabolism. In the present study, we measured the activities of KICD and BCKDC in human and rat livers. The KICD activity in human liver was 0.9 mU/g tissue, which was 14.2% of the total activity of BCKDC, and that in rat liver was 4.2 mU/g tissue, which was only 1.0% of the total activity, suggesting that KICD in human liver plays a relatively important role in the alpha-ketoisocaproate catabolism. The KICD activity in human liver was significantly increased by cirrhosis. In rat liver, the enzyme activity was markedly increased by physical training and streptozotocin-induced diabetes, but not by feeding of a diet rich in branched-chain amino acids, although BCKDC activity was increased by feeding of the diet.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2000

Additive effects of estrogen deficiency and diabetes on bone mineral density in rats.

We investigated the combined effects of estrogen deficiency and diabetes on bone mineral density (BMD) and bone metabolism in rats. Ten-week-old, female rats were randomly divided into four groups: controls (C), an ovariectomized group (O), a streptozotocin-induced diabetic group (S), and a combined ovariectomy and streptozotocin-induced diabetic group (OS). The BMD of the lumbar spine and the femur were measured before grouping and at 23 weeks old. At the end of the experiment, blood samples were obtained via cardiac puncture, and bone gla protein (BGP), tartrate-resistant acid phosphatase (TRAP) and 1,25-dihydroxyvitamin D levels were measured. The rats in the C, O, S, and OS groups, in that order, had higher levels of BMD of the lumbar spine and femur at 23 weeks of age. The BGP levels in the S and OS groups were significantly lower than in C and O groups. Significantly higher 1,25-dihydroxyvitamin D was observed in the O group compared with the C, S and OS groups. No differences were obtained in TRAP among four groups. Our data suggest that the combined effects of estrogen deficiency and diabetes on BMD are not synergistic or counteractive but additive.

Alkaline Phosphatase↗
PubMed2000

Exercise training prevents maturation-induced decreases in insulin receptor substrate-1 and phosphatidylinositol 3-kinase in rat skeletal muscle.

We have previously reported that exercise training prevents a maturation-induced decrease in insulin sensitivity and suggested that an improvement of insulin sensitivity by exercise training was attributable, in part, to an increase in insulin-sensitive GLUT-4 on the skeletal muscle plasma membrane. In this study, we examined the effects of maturation and exercise training on the gene expression and protein content of the components of post-insulin receptor signal transduction in rat skeletal muscle. Rats aged 3 weeks were sedentary or trained by voluntary running through 4 or 27 weeks of age, and then the rats in both the sedentary and trained groups were killed and the gastrocnemius muscle was immediately removed for analysis of mRNA and protein content. The concentration of mRNA and protein for insulin receptor substrate-1 (IRS-1) in sedentary rats significantly decreased with maturation (49% and 63%, respectively, at age 27 weeks v age 4 weeks), but in trained rats they did not decrease with maturation. Although the level of phosphatidylinositol 3-kinase (PI 3-kinase) mRNA in sedentary rats was not altered with maturation, PI 3-kinase protein in sedentary rats significantly decreased with maturation (73% at 27 weeks v 4 weeks). However, PI 3-kinase protein in trained rats did not decrease with maturation. These results suggest that the prevention of maturation-induced decreases in the protein content of IRS-1 and PI 3-kinase is involved in the mechanisms responsible for the improvement of insulin sensitivity by exercise training, and exercise training may affect transcriptional regulation of the IRS-1 gene and posttranscriptional regulation of PI 3-kinase expression.

Animals↗
PubMed2000

Suppression of glycogen consumption during acute exercise by dietary branched-chain amino acids in rats.

The effects of a diet supplemented with branched-chain amino acids (BCAA; 4.8% or 6.2%) on BCAA catabolism and glycogen metabolism in rats were examined. Rats were fed a BCAA diet or control diet for 4 wk and part of the rats were subjected to exercise training during the experimental period. Feeding the BCAA diet increased serum BCAA concentrations and activity of the hepatic branched-chain alpha-keto acid dehydrogenase complex, the rate-limiting enzyme in the catabolism of BCAA, suggesting that dietary BCAA promotes BCAA catabolism. Although the serum glucose concentration and glycogen contents in the liver and gastrocnemius muscle of rested rats were not significantly affected by feeding of the BCAA diet, those in rats exhausted by acute exercise were 2-4-fold higher in rats fed the BCAA diet than in rats fed the control diet. The activity of pyruvate dehydrogenase complex in the liver and gastrocnemius muscle after acute exercise showed reverse trends; the complex activities (especially in liver) tended to be less in the BCAA diet group than in the control diet group. These results suggest that dietary BCAA spares glycogen stores in liver and skeletal muscle during exercise and that the decrease in pyruvate dehydrogenase complex activity in these tissues by dietary BCAA is involved in the mechanisms.

Amino Acids, Branched-Chain↗
PubMed1999

Insulin activation of pyruvate dehydrogenase complex is enhanced by exercise training.

We studied the effects of exercise training on the activity of the pyruvate dehydrogenase (PDH) complex in rat gastrocnemius muscle (experiment 1) and the response of the complex to glucose and insulin infusion (euglycemic clamp) in trained and sedentary rats (experiment 2). In experiment 1, half of the rats were randomly allocated as sedentary animals and the other half were trained by voluntary running exercise for 8 weeks. The total activity of the PDH complex was not affected by exercise training, and the activity state (proportion of the active form) of the PDH complex was decreased from 15.0%+/-2.4% to 7.5%+/-1.1% by exercise training. The activity of 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase ([3-HADH] an enzyme in beta-oxidation) was significantly higher in trained versus sedentary rats. In experiment 2, sedentary and trained rats were starved for 24 hours before performing the euglycemic clamp. Glucose and insulin infusion was performed by a euglycemic clamp (insulin infusion rate, 6 mU/kg/min) for 90 minutes. The PDH complex was inactivated to less than 1% in both sedentary and trained rats after 24 hours of starvation. The glucose infusion rate (GIR) during the euglycemic clamp was higher in trained versus sedentary rats. The euglycemic clamp resulted in activation of the PDH complex in both sedentary and trained rats, but the response of the PDH complex to the euglycemic clamp was significantly higher in trained rats (5.8%+/-0.5%) than in sedentary rats (2.9%+/-0.5%). These results suggest that exercise training promotes fatty acid oxidation in association with suppression of glucose oxidation in skeletal muscle under resting conditions, but increases the rate of carbohydrate oxidation when glucose flux into muscle cells is stimulated by insulin.

Animals↗
PubMed1999

Case report of lymphoepithelioma-like carcinoma of the lung--lymphoid population consisting of cytotoxic T cells in resting state.

The present report describes a case of lymphoepithelioma-like carcinoma (LELC) of the lung and presents immunohistochemical and in situ hybridization (ISH) studies of the tumor. A 39-year-old Chinese woman, who was born in China and emigrated to Japan at the age of 29, suffered from a cough for 2 years and received a middle and lower lobectomy with mediastinal lymph node dissection after induction chemotherapy. The tumor consisted of undifferentiated carcinoma and areas of more differentiated squamous cell carcinoma with an intense lymphoid infiltrate. Serological studies and ISH studies showed EBV infection of the tumor. The immunophenotype of tumor-infiltrating T-lymphocytes (TITL) of the present case was examined immunohistochemically and was compared with that of an LELC case reported previously. Most CD3-positive T cells of TITL in both cases were labeled with both CD8 and TIA-1 but not with granzyme-B, indicating the TITL to be cytotoxic T lymphocytes (CTL) in the resting state. The lack of CTL activation at the tumor site might have been due to local inhibition of EBV-specific CTL responses such as T-cell anergy. Because the EBV-specific CTL derived from peripheral blood lymphocytes, in contrast to the TITL, may not be influenced by either tumor-produced suppressor factors or negative regulatory T cells, they may inhibit the hematogenous metastasis of EBV-positive LELC, possibly resulting in a better prognosis. Because LELC of the lung responded to preoperative chemotherapy in the present study, it may be useful for reducing the local tumor burden and facilitate subsequent local therapy, although the mechanism of chemosensitivity of LELC remains unknown.

Adult↗
PubMed1999

Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRgamma1 isoform.

BACKGROUND: Retinoid X receptors RXRalpha, beta and gamma exert multiple functions in the genetic regulation of mammalian signalling systems by forming heterodimeric complexes with several nuclear ligand receptors. In contrast to the widespread expression of RXRalpha and RXRbeta, the expression of RXRgamma is restricted to particular tissues in which RXRgamma1 is the major isoform expressed in the mouse corpus striatum. RESULTS: To investigate the function of this particular isoform RXRgamma1, we generated RXRgamma1 gene-knockout mice by homologous recombination in ES cells. Both heterozygous and homozygous mice showed severe runting after birth, which often resulted in the early death of mice of the 129/C57BL-6 genetic background. Independent of genetic background, however, the expression of choline acetyltransferase (ChAT) in the cholinergic interneurones in the striatum (caudal putamen) was markedly reduced in the RXRgamma1 gene-null mice. Furthermore, the mutant exhibited an altered response to the administration of dopamine receptor antagonists, haloperidol and chlorpromazine, which normally induce catalepsy in mice. CONCLUSIONS: These results strongly suggest that RXRgamma1 plays an important role in either the development or activation of cholinergic neurones in nigrostriatal extrapyramidal pathways.

Animals↗
PubMed1999

Troglitazone improves insulin-stimulated glucose utilization associated with an increased muscle glycogen content in obese Zucker rats.

Recent studies have demonstrated that troglitazone has the capacity to improve insulin resistance. The present study was undertaken to determine the effect of troglitazone on in vivo insulin action, the activities of the pyruvate dehydrogenase (PDH) complex and 3-hydroxyacyl-CoA dehydrogenase (3-HADH) in muscle, and muscle GLUT-4 and glycogen content in obese and lean Zucker rats. Rats were fed a normal chow diet with and without troglitazone as a food admixture (0.2%) for 3 weeks. In vivo insulin action was measured by the sequential euglycemic clamp technique at two different insulin infusion rates (6 and 30 mU/kg BW/min). At the basal (fasting) state and after the clamp studies, the activities of PDH complex and 3-HADH, and the amounts of GLUT-4 and glycogen contained in the red gastrocnemius muscles were determined. Troglitazone treatment produced a significant rise in the metabolic clearance rate of glucose (MCR) during the 6-mU/kg BW/min insulin clamp study (19.5+/-3.9 vs 9.9+/-1.5 ml/kg BW/min, mean+/-SE, P<0.05) in obese rats, but not in lean rats. Troglitazone significantly increased the muscle glycogen content after the clamp study, compared to non-treated rats, in obese rats (9.9+/-0.5 vs 6.5+/-0.4 mg/g tissue, P<0.05) and has the tendency to increase the activity state of PDH complex in obese and lean rats at the fasting state. However, no effect of the drug on muscle GLUT-4 content was found. These results indicate that troglitazone may improve insulin sensitivity associated with increased muscle glycogen content.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1999

Hepatic branched-chain alpha-keto acid dehydrogenase complex in female rats: activation by exercise and starvation.

The effects of acute exercise and starvation on hepatic branched-chain alpha-keto acid dehydrogenase (BCKDH) complex activity were examined in female rats fed high (30%)- or low (8%)-protein diets. The total activity of the complex was significantly higher in the high protein-fed rats than in the low protein-fed rats but was not affected by acute exercise and starvation in either diet group. The proportion of the active form of BCKDH complex was less than 10% in both diet groups. Acute exercise and starvation markedly increased the active form of the complex in both diet groups. The activity of BCKDH kinase, which is responsible for inactivation of the BCKDH complex by phosphorylation, tended to be decreased by acute exercise and starvation in both diet groups. These results suggest that the activity of the BCKDH kinase is an important factor determining the proportion of the active form of BCKDH complex in exercise and starvation, and that the female rat is a useful model for studying the regulation of hepatic BCKDH complex activity.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1999

[Lymphoepithelioma-like carcinoma of the lung].

Lymphoepithelioma-like carcinoma of the lung was diagnosed in a 39-year-old Chinese woman. In situ hybridization of Epstein Barr virus-encoded small nuclear RNA 1 (EBER 1) detected strong EBER 1 signals in the nuclei of tumor cell specimens from the patient. After polymerase chain reaction (PCR) amplification, electrophoresis identified the IR-1 region in this tumor as a positive sharp band, closely resembling Raji cells (Burkitt's cell line). The uniform and intense presence of EBER 1 in the tumor nuclei and the PCR products of EBV DNA in the tumor demonstrated that a high copy number of EB virus genome existed in the tumor, and indicated involvement of the EB virus in the pathogenesis of lymphoepithelioma-like carcinoma of the lung.

Adult↗
PubMed1998

The effects of anti-asthma drugs on mediator release from cultured human mast cells.

BACKGROUND: A method for generating human mast cells in vitro was recently established. Little is known about the pharmacological profiles of allergic mediator release from cultured mast cells. OBJECTIVE: The main objective was to investigate the nature of cultured mast cells from a pharmacological point of view. We examined the effect of anti-asthma drugs on the release of histamine, sulfidoleukotrienes (LTs) and prostaglandin D2 (PGD2) from the cultured mast cells. METHODS: Using the method established by Saito et al. we cultured cord blood mononuclear cells in the presence of 80 ng/mL stem cell factor (SCF), 50 ng/mL interleukin-6 (IL-6) and 300 nmol/L prostaglandin E2 (PGE2), and obtained almost pure (> 99%) mast cells. We sensitized cultured mast cells with immunoglobulin E (IgE)-rich serum, and then treated them with some anti-asthma drugs before challenge with anti-human IgE. Released histamine, LTs and PGD2 were measured by high-performance liquid chromatography, commercial enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA) systems, respectively. RESULTS: The cultured mast cells released histamine, LTs and PGD2 following immunological stimulation through IgE. The mast cell stabilizing agents disodium cromoglycate (DSCG, 1 mmol/L) and azelastine (100 micromol/L) significantly inhibited the release of these three mediators. The beta-adrenoceptor agonists isoproterenol, salbutamol, and clenbuterol also inhibited all three mediators' release in a concentration-dependent manner. The non-selective and selective phosphodiesterase (PDE) inhibitors theophylline, rolipram, and cilostazol had no significant effect on mediator release at clinically useful concentrations. BAY x 1005 (a 5-lipoxygenase-activating protein inhibitor) inhibited the LTs release, whereas indomethacin (a cyclo-oxygenase I and II inhibitor) and NS-398 (a cyclo-oxygenase II inhibitor) inhibited PGD2 release. CONCLUSIONS: The present results indicate that cultured mast cells release histamine, LTs and PGD2 following IgE crosslinking. Anti-asthma drugs showed a characteristic suppression of the release of each mediator. The suppressive actions of these drugs are similar to their pharmacological actions on human lung mast cells. These results suggest that cultured mast cells are useful for the analysis of function and pharmacological profiles of lung mast cells.

Anti-Asthmatic Agents↗
PubMed1998

Comparison of the most comfortable mandibular position with the intercuspal position using cephalometric analysis.

For evaluation of the most comfortable position (MCP) in edentulous subjects, as decided by mandibular position sense, the MCP was recorded in ten edentulous subjects and compared with the intercuspal position (ICP) of normal dentate persons. It was found that the MCP was at a lower mandibular position than the ICP; the facial height was markedly reduced in the former by a front-upward rotation of the mandible centering around the condyles. Thus, it has been suggested that the occlusal vertical dimension (OVD) of the MCP in the restored dentition is less than that of the original ICP.

Age Factors↗
PubMed1998

Branched-chain alpha-keto acid dehydrogenase kinase content in rat skeletal muscle is decreased by endurance training.

The activity state of branched-chain alpha-keto acid dehydrogenase complex in skeletal muscle was elevated by running exercise in trained and untrained rats, but level of this elevation was significantly greater in the former than in the latter. To elucidate the mechanism of the training effect on the exercise-induced activation of the complex, a protein amount of branched-chain alpha-keto acid dehydrogenase kinase, which is responsible for inactivation of the complex by phosphorylation, in the muscle was measured by the Western blot analysis. Endurance training decreased the content of the kinase protein in the muscle by approximately 30%, suggesting that this decrease is involved in the mechanisms for greater activation of the complex by exercise in trained rats.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1998

Dietary maltitol decreases the incidence of 1,2-dimethylhydrazine-induced cecum and proximal colon tumors in rats.

Maltitol is fermented in the colon due to only partial hydrolysis in the small intestine. In the present study, we examined effects of dietary maltitol on dimethylhydrazine-induced intestinal tumor in rats. In experiment 1, rats were fed a fiber-free diet or diets supplemented with 1 or 5 g/100 g maltitol for 27 wk. Each group of rats was injected with dimethylhydrazine or vehicle alone for the first 14 wk of the experimental period. Maltitol supplementation at 1 g/100 g of the diet significantly reduced tumor incidence in the cecum and the 5% supplement reduced tumor incidence in both the cecum and proximal colon in dimethylhydrazine-treated rats. In experiment 2, we investigated the effect of the 1 g/100 g maltitol diet on the short chain fatty acid concentrations in cecal contents of placebo and dimethylhydrazine-treated rats. Intake of the 1 g/100 g maltitol diet doubled (P < 0.05) the concentration of butyrate but did not affect acetate or propionate in the cecal contents. These results suggest that dietary maltitol has a protective effect against dimethylhydrazine-induced tumors in rat cecum and proximal colon and that butyrate produced by bacterial fermentation of maltitol in the cecum may be involved in the protection.

1,2-Dimethylhydrazine↗
PubMed1998

Intramuscular 3-hydroxybutyrate levels after 60 tetani/min contraction in diabetic and non-diabetic rats.

Post-exercise hyperketonemia in poorly-controlled diabetic patients is a well recognized phenomenon, but because studies concerning changes in ketone body metabolism in muscle during and/or after exercise are scarce, we measured the intramuscular 3-hydroxybutyrate (3-OHBA) and lactate concentrations in 12 diabetic (streptozotocin-induced; 60 mg/kg, ip) and 13 non-diabetic control rats before and after a 1-h muscle contraction. One thigh tetanic contraction was elicited at a tetanic frequency of 60 tetani/min and the other thigh was kept resting. We used a microdialysis technique in both quadriceps muscles, vastus lateralis, and the right jugular vein. Blood flow in both femoral muscles was also monitored before and after contraction. Dialysate 3-OHBA and lactate levels in contracting and non-contracting muscles and in blood showed a significant increase after contraction (P<0.05) in diabetic rats. In control rats there was no significant change in dialysate 3-OHBA or the lactate concentration in contracting and non-contracting muscles or in blood before and after contraction. A significant increase in contracting muscle blood flow was observed only for the first 5 min after contraction in diabetic and control rats. These results suggest that 3-OHBA uptake in contracting muscle is reduced, and that this phenomenon may play a role in post-exercise ketosis in diabetes.

3-Hydroxybutyric Acid↗
PubMed1997

Gender difference in regulation of branched-chain amino acid catabolism.

Regulation of the activity state of the hepatic branched-chain 2-oxo acid dehydrogenase (BCODH) complex during the light-dark cycle differs markedly in male and female rats. Female rats exhibit a profound diurnal rhythm in the activity state of the complex that is not observed in male rats. Regardless of gender, most of the complex was dephosphorylated and active in the middle of the dark period and early in the light period, and this form of the complex predominated in male rats at the end of the light period. In contrast, most of the complex in female rats became phosphorylated and inactive by the end of the light period. Gonadectomy prevented the diurnal rhythm in females but was without effect in males, indicating that female sex hormones are required for this gender difference in regulation of the BCODH complex. Changes in levels of branched-chain 2-oxo acids, known regulators of BCODH kinase, do not seem to be involved; rather, an increase in BCODH kinase activity occurring between morning and evening is responsible for inactivation of the BCODH complex in female rats. The increase in kinase activity is due to an increase in the amount of kinase protein associated with the BCODH complex. Thus a marked diurnal variation in the amount of BCODH kinase and therefore its activity results in large swings in the activity state of the liver BCODH complex in female rats. This study provides the first evidence for a gender-specific difference in the regulation of branched-chain amino acid catabolism.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗