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Biomedical subjects

J Nakamura

Publications and source records attributed to J Nakamura.

At least 271 records · Page 15Linked to original sources
PubMed1996

Effect of propionyl-L-carnitine on motor nerve conduction, autonomic cardiac function, and nerve blood flow in rats with streptozotocin-induced diabetes: comparison with an aldose reductase inhibitor.

The effects of propionyl-L-carnitine (PCAL) on caudal motor nerve conduction velocity, the coefficient of variation of the R-R interval on the electrocardiogram, and sciatic nerve blood flow were compared with those of [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate, an aldose reductase inhibitor, in rats with streptozotocin-induced diabetes. Diabetic control rats showed significantly delayed nerve conduction (P < .05), decreased R-R variability (P < .05) and reduced sciatic nerve blood flow (P < .05). Oral administration of PCAL (0.5 g/kg/day) and [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (0.05% in the diet: 60 mg/kg/day) for 8 weeks significantly improved both nerve conduction (P < .05) and R-R variability (P < .05) in diabetic rats, along with the normalization of sciatic nerve blood flow. PCAL treatment increased the nerve tissue levels of carnitine and myo-inositol and reduced the serum triglyceride level in diabetic rats. Our results suggests that PCAL could have therapeutic potential for the treatment of diabetic neuropathy.

Aldehyde Reductase↗
PubMed1996

[Clinical effects of cortisol synthesis inhibition on treatment-resistant depression].

Clinical trial with a steroid suppressive agent, metyrapone, was carried out in 6 patients with treatment-resistant depression (3 patients with major depression and 3 with bipolar disorder). Up to 2,000 mg/day of metyrapone was administered for 4 weeks, and 10 trials of the therapy were done in these patients. Most patients completed the therapy without remarkable side effects. As a result, three patients (6 trials) showed remission within 4 weeks and one patient (one trial) showed a partial response. In the remitted patients, plasma cortisol levels were suppressed below 10 micrograms/dl during the therapy and plasma ACTH levels were elevated. These results indicate that "hypercortisolemia-induced depression" similar to Cushing's disease may be present in patients with treatment-resistant depression.

Adrenocortical Hyperfunction↗
PubMed1996

[Significance of high normal blood pressure in occupational health care].

In order to elucidate the significance of high normal blood pressure in occupational health care, a 5 year follow up survey was performed on 874 men with normal blood pressure and 225 men with high normal blood pressure. The major results of this survey were as follows. 1) Sixty-seven out of 874 with normal blood pressure (7.7%), and 78 out of 225 with high normal blood pressure (34.6%) became hypertensive in 5 years. 2) High normals started with a higher frequency of obesity, hypercholesterolemia, hyper gamma-Glutamyl transpeptidasemia compared with normal blood pressure at the start of the survey. 3) Logistic regression analysis showed that age, SBP, DBP were risk factors of developing hypertension from normal blood pressure, while only the amount of alcohol drinking applied for high normal blood pressure. 4) Logistic regression showed that high normal blood pressure, drinking, obesity and were significantly related to the development of hypertension. These results suggested that interventive activities for high normal blood pressure should be included in occupational health care because of a high tendency of underlying poor life style and a high risk of getting hypertension.

Adult↗
PubMed1995

Polyol pathway, 2,3-diphosphoglycerate in erythrocytes and diabetic neuropathy in rats.

The relationship between the 2,3-diphosphoglycerate concentration in red blood cells as a biological indicator of tissue hypoxia and diabetic neuropathy, and the effect of a potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2'5'-dioxospiro [chroman-4,4'-imidazolidine]-2-carboxamide (SNK-860), on both were investigated in streptozotocin-induced diabetic rats. Diabetic rats demonstrated significantly delayed motor nerve conduction velocity and reduced sciatic nerve blood flow. Altered biochemical features in the sciatic nerves, including a marked accumulation of sorbitol and fructose, myo-inositol depletion and decreased Na+/K(+)-ATPase activity were also detected in diabetic rats. These defects were accompanied by a decrease in the red blood cell 2,3-diphosphoglycerate concentration. Treatment with SNK-860 partially or completely ameliorated these abnormalities. These observations suggest that a decrease in the red blood cell 2,3-diphosphoglycerate concentration is one of the factors contributing to tissue hypoxia, which results in diabetic neuropathy, and that this decrease is mediated through an aldose reductase inhibitor-sensitive pathway.

2,3-Diphosphoglycerate↗
PubMed1995

The glutamine hydrolysis function of human GMP synthetase. Identification of an essential active site cysteine.

GMP synthetase (EC 6.3.5.2) is an amidotransferase that catalyzes the amination of xanthosine 5'-monophosphate to form GMP in the presence of glutamine and ATP. Glutamine hydrolysis produces the necessary amino group while ATP hydrolysis drives the reaction. Ammonia can also serve as an amino group donor. GMP synthetase contains two functional domains, which are well coordinated. The "glutamine amide transfer" or glutaminase domain is responsible for glutamine hydrolysis. The synthetase domain is responsible for ATP hydrolysis and GMP formation. Inorganic pyrophosphate inhibits the synthetase and uncouples the two domain functions by allowing glutamine hydrolysis to take place in the absence of ATP hydrolysis or GMP formation. Acivicin, a glutamine analog, selectively abolishes the glutaminase activity. It inhibits the synthetase activity only when glutamine is the amino donor. When ammonia is used in place of glutamine, acivicin has no effect on the synthetase activity. Acivicin inhibits GMP synthetase irreversibly by covalent modification. Enzyme inactivation is greatly facilitated by the presence of substrates. Acivicin labels GMP synthetase at a single site, and a tryptic peptide containing the modified residue was isolated. Mass spectrometry and Edman sequence analysis show that Cys104 is the site of modification. This residue is conserved among GMP synthetases and is located within a predicted glutamine amide transfer domain. These data suggest that Cys104 is an essential residue involved in the hydrolysis of glutamine to produce an amino group and is not needed for the hydrolysis of ATP or amination of xanthosine 5'-monophosphate to produce GMP.

Adenosine Triphosphate↗
PubMed1995

Negative or positive cooperation in calcium binding to detergent-solubilized ATPase of the sarcoplasmic reticulum. Its modulation by a high concentration of ATP.

Two different conformations of chemically equivalent Ca(2+)-ATPase molecules in the sarcoplasmic reticulum have been shown to non- and positive cooperatively bind two calcium ions, respectively (Nakamura, J. (1994) J. Biol. Chem. 269, 30822-30827). At pH 7.40, these ATPase molecules split into E1 (high affinity state for calcium), and E2 (low affinity state for calcium), respectively, before calcium binding. At this pH, calcium binding to the monomeric ATPase, solubilized with dodecyloctaethylenglycol monoether, was studied by examining 45Ca2+ binding to the ATPase and calcium dependence of its phosphorylation, fluorescence intensity, ATP-hydrolysis at a low (5 microM) concentration of ATP, and acetyl phosphate hydrolysis. The results suggest that the solubilized ATPase molecules predominantly preexist in E2 and negative cooperatively (the Hill value (nH) = 0.5-0.6) bind 2 mol of calcium/mol of the ATPase with an apparent calcium affinity (K0.5) of 3-5 microM. The nonequivalences of calcium bindings at the membranous ATPase molecules seem to result from the intermolecular interaction of the molecules. A high concentration (5 mM) of ATP modulated the binding manner so that it became positively cooperative (nH approximately 2) and increased the K0.5 to 0.1 microM.

Adenosine Triphosphate↗
PubMed1995

Effect of chronic L-dopa administration on serum luteinizing hormone levels in male rats.

We examined whether the repeated oral administration with a high dose of L-3-(3,4-dihydroxyphenyl)-alanine (L-DOPA) in 0.5% carboxymethyl cellulose increases serum luteinizing hormone (LH) levels in male rats. Serum LH levels were increased 4 h after a single administration of 1000 mg/kg L-DOPA to male rats, and returned to control levels within 8 h after administration. Four hours after a single administration, serum LH levels were significantly increased by L-DOPA at 1000 mg/kg, but not at 20, 100 or 200 mg/kg. Decreases in body weight and relative weight of the prostate were observed after 7 and 14 days of administration of 1000 mg/kg per day L-DOPA, but no changes were observed in weight of the testis, epididymis or seminal vesicle. The administration of L-DOPA at 500 or 1000 mg/kg per day for 7 or 14 days resulted in increased basal serum LH levels and decreased basal serum prolactin levels 24 h after the last administration. Serum testosterone levels tended to be higher in treated than in control rats. The levels of two metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in rats treated with 500 mg/kg per day tended to be slightly higher than those in control rats after 7 days of administration. Levels of DA, DOPAC and HVA were significantly increased after 7 and 14 days of administration of 1000 mg/kg per day and after 14 days of administration of 5000 mg/kg per day. The level of norepinephrine, but not its metabolite 3-methoxy-4-hydroxyphenylglycol, was significantly increased after only 7 days of administration of 1000 mg/kg per day. No significant changes were observed in levels of 5-hydroxytryptamine or its metabolite 5-hydroxyindole-3-acetic acid with administration of 500 or 1000 mg/kg per day. These findings suggest that a prolonged treatment with a high dose of L-DOPA in male rats induces release of LH from the pituitary, resulting in sustained elevation of LH levels in peripheral circulation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Biochemical characterization of human GMP synthetase.

GMP synthetase (EC 6.3.5.2) plays a key role in the de novo synthesis of guanine nucleotides. It is a potential target for immunosuppressive therapy. Recently, the human enzyme was purified to homogeneity (Hirst, M., Haliday, E., Nakamura, J., and Lou, L. (1994) J. Biol. Chem. 269, 23830-23837). We now report the characterization of this enzyme in terms of its biochemical and kinetic properties. We found that there are distinct features of the human enzyme that has not been reported for GMP synthetase from other sources. There are two variant forms of human GMP synthetase. Their catalytic properties are very similar, although their isoelectric points are different. They most likely represent post-translational modification variants. Magnesium ion is required for enzyme activity, and the requirement is beyond levels needed for ATP chelation. Magnesium appears to be an essential activator and there may be more than one binding site. Interaction of GMP synthetase with xanthosine 5'-monophosphate (XMP), a substrate, exhibits sigmoidal kinetics with a Hill coefficient of 1.48 +/- 0.07. This positive cooperativity is not due to ligand-induced oligomerization, since GMP synthetase remains a monomer in the presence of XMP and other substrates. Decoyinine, a selective inhibitor of GMP synthetase, inhibits the human enzyme reversibly with uncompetitive inhibition kinetics toward glutamine and XMP and non-competitive kinetics toward ATP.

Adenosine Triphosphate↗
PubMed1995

Analysis of molluscum contagiosum virus genomes isolated in Japan.

The genomes of 477 Japanese strains of molluscum contagiosum virus (MCV) were analyzed using an in-gel digestion method with the restriction enzyme BamHI, and classified into four types, including a newly detected type (MCV type 4). All type 1 (MCV-1) genomes examined so far in Japan showed a common difference from the genome of the MCV-1 prototype (MCV-1p), the type reported to be most prevalent in Europe. The common markers of the variants of MCV-1 were 24-kbp fusion fragments generated by the loss of a BamHI site between the D2 and F fragments of MCV-1p. These variants of MCV-1 were classified into three groups (MCV-1va, MCV-1vb, MCV-1vc), with the variability among them being due to additions and losses of BamHI sites located in the right terminus and around the E and I fragments of MCV-1va. The restriction map of MCV-4 was generated and lined up with those of the other types. Cross-hybridization analysis revealed that the organization of all types of MCV genomes were essentially colinear. Considerable numbers of BamHI restriction sites were conserved between MCV-2 and 4, indicating a close analogy between them. The overall prevalence of MCV, as shown by the ratios of MCV-1 (MCV-1p):MCV-2:MCV-3:MCV-4, was 436(0):13:24:4. Thus, the molecular epidemiology of MCV in Japan is characterized by the absence of the European prototype of MCV-1, the exclusive occurrence and abundance of variants of MCV-1, a greater prevalence of MCV-3 over MCV-2, and the presence of MCV-4.

Genetic Variation↗
PubMed1995

High-level production from a baculovirus expression system and biochemical characterization of human GMP synthetase.

GMP synthetase, a key enzyme in the de novo synthesis of guanine nucleotides, is a potential target for immunosuppression and anticancer chemotherapy. In order to closely examine the catalytic mechanism and active-site topography of this enzyme, large amounts of pure protein are needed. Catalytically active human GMP synthetase was expressed in a baculovirus system. A high-level production system has been established from which the yield of pure protein is routinely more than 50 mg/10 liters of cell culture. The recombinant enzyme was purified to homogeneity and characterized. Like native GMP synthetase, the recombinant enzyme was resolved into two forms by ion-exchange chromatography. The two forms are both monomers and they differ in their isoelectric points. There is no evidence that these forms are in equilibrium or interconvertible. Protein sequence analysis reveals that both forms are blocked at the amino-terminus and they are essentially identical in sequence. Since they can be produced by a cDNA with a single open reading frame, we believe that they represent post-translational modification variants. The recombinant GMP synthetase is not distinguishable from the native enzyme in terms of chromatographic profiles, subunit composition, molecular weight, and kinetic properties. The inhibition constants and the modes of inhibition toward decoyinine, a selective inhibitor of GMP synthetase, are also the same as the native enzyme. The high-level production of active enzyme is invaluable to the determination of the three-dimensional structure and the discovery of potent and selective drug candidates.

Animals↗
PubMed1995

A possible mechanism for the increase in serum luteinizing hormone levels in male rats by oxolinic acid.

Oxolinic acid (1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-3- quinolinecarboxylic acid), an antimicrobial agent, raises the serum levels of luteinizing hormone (LH) and increases the incidence of testicular Leydig cell tumors in male rats. In the present study the mechanism by which serum LH levels are raised in male rats receiving oxolinic acid was investigated. Aged Wistar rats were fed a diet containing oxolinic acid at 0 or 3000 ppm for more than 4 weeks. There was no effect of oxolinic acid on either the maximal levels of serum LH after castration nor on the serum levels of LH stimulated with 1 microgram/rat of luteinizing hormone-releasing hormone (LHRH). The concentrations of testosterone in serum and testis were not changed by the treatment of oxolinic acid. In the in vitro organ culture, the testes of rats receiving oxolinic acid released testosterone in the same manner as the controls, in the presence or the absence of human chorionic gonadotropin (100 mIU/ml). The oxolinic acid-stimulated serum LH was not increased further by the daily administration of L-dopa (500 mg/kg/day, po, 7 days) and was blocked by the injection of a dopamine antagonist, haloperidol (2 mg/kg, ip). In a microdialysis study, oxolinic acid increased the extracellular concentration of dopamine in the preoptic area of hypothalamus. These findings suggest that a high dietary level of oxolinic acid elevates LH release from the anterior pituitary with an increase in LHRH, in part, by the excitatory input of a dopaminergic system in the preoptic area of rat hypothalamus.

Animals↗
PubMed1995

Neurotropin prevents neurophysiological abnormalities and ADP-induced hyperaggregability in rats with streptozotocin-induced diabetes.

Neurotropin, a non-proteinaceous extract from the inflamed dermis of rabbits inoculated with vaccinia virus, was administered for 8 weeks to rats with streptozotocin-induced diabetes. The physiological and biochemical changes of the nerves were studied as well as ADP-induced platelet aggregation. Neurotropin improved the caudal motor nerve conduction velocity, R-R variability, sciatic nerve blood flow, and platelet hyperaggregability in diabetic rats, despite having no effect on sorbitol and fructose accumulation or myoinositol depletion in the sciatic nerve. The correlation between nerve conduction velocity, R-R variability, nerve blood flow, and platelet aggregation were significant between each two parameters (p < 0.0001). Thus, the mechanism of action of neurotropin differed from that of aldose reductase inhibitors. These findings suggest that vascular factors may play an important role in the development of diabetic neuropathy, and that neurotropin may be useful for the treatment of this condition.

Adenosine Diphosphate↗
PubMed1995

Gamma knife surgery for Cushing's disease.

BACKGROUND: The efficacy of gamma knife surgery on Cushing's disease is not well known to date. In most reported cases of Cushing's disease treated with gamma knife, the area to be irradiated was determined with computed tomography or pneumoencephalography. We report two cases of recurrent pituitary-dependent Cushing's disease treated with gamma knife using stereotactic magnetic resonance imaging (MRI). MATERIALS AND METHODS: Recurrent microadenomas were visualized as hypointense areas using gadolinium-enhanced MRI after two transsphenoidal surgeries in both cases. The doses of irradiation given were 35 Gy and 20 Gy to the margin of the tumors, and less than 8 Gy and 21 Gy to the optic apparatus and cranial nerves in the cavernous sinus, respectively. RESULTS: Both patients had clinical remission with normal serum cortisol and adrenocorticotrophic hormone levels, during 2-year follow-up after radiosurgery, without endocrinologic deficiency or neurologic deterioration. CONCLUSIONS: Gamma knife surgery can be an alternative therapy for Cushing's disease when pituitary adenomas are apart from the optic apparatus and can be visualized clearly by MRI, even if tumors are recurrent after microsurgery.

Adenoma↗
PubMed1995

Prevention of abnormalities in motor nerve conduction and nerve blood-flow by a prostacyclin analog, beraprost sodium, in streptozotocin-induced diabetic rats.

The effects of the prostacyclin analog beraprost sodium on motor nerve function and nerve blood-flow were examined in streptozotocin-induced diabetic rats. Oral administration of beraprost sodium 0.1 mg/kg/day for 8 wks significantly (P < 0.001) improved caudal motor nerve conduction velocity and sciatic nerve blood-flow, both of which are impaired in diabetic rats. Beraprost sodium did not affect glucose, sorbitol, or fructose levels in the sciatic nerve. However, a decreased content of cyclic AMP in the sciatic nerve and higher level of thromboxane B2 in the thoracic aorta of diabetic rats, as compared with those in normal rats, were reversed by the treatment with beraprost sodium (P < 0.01). Results suggest that beraprost sodium may have value in treating diabetic neuropathy, mainly by improving endoneurial blood-flow.

Animals↗
PubMed1995

Effect of a potent new aldose reductase inhibitor, (5-(3-thienyltetrazol-1-yl)acetic acid (TAT), on diabetic neuropathy in rats.

(5-(3-Thienyl)tetrazol-1-yl)acetic acid (TAT), a novel potent aldose reductase inhibitor, was administered for 4 weeks to rats with streptozotocin-induced diabetes. Physiological and biochemical studies were subsequently conducted on rat nerve tissue and erythrocyte sorbitol content was estimated. Sciatic nerve blood flow (SNBF) was markedly lower (about 43.4%) in untreated diabetic (DC) rats than in non-diabetic controls (NC). A significant delay in caudal motor nerve conduction velocity (MNCV) and significantly higher glucose, sorbitol and fructose values were observed in the sciatic nerve, accompanied by a markedly higher sorbitol concentration in erythrocytes. In contrast, TAT-treated diabetic groups (DT-10, DT-40 and DT-200) had significantly higher SNBF, MNCV and sciatic nerve myo-inositol values and lower sciatic nerve sorbitol and fructose levels and erythrocyte sorbitol concentration than the DC group. There were good correlations between SNBF and MNCV (r = 0.672, P < 0.001) and between SNBF and erythrocyte sorbitol (r = 0.455, P < 0.003). These findings suggest that both vascular and metabolic factors play an important role in diabetic neuropathy and the effect of aldose reductase inhibitors on diabetic neuropathy may be mediated by at least these two factors.

Aldehyde Reductase↗
PubMed1995

Interference by gliclazide in the glucose oxidase/peroxidase method for glucose assay.

Gliclazide interferes with the glucose determination using the glucose oxidase/peroxidase (EC 1.1.3.4/1.11.1.7) (GOD-PERID) method utilizing 2,2-azino-di-(3-ethyl-benzothiazoline-6-sulphonic acid) (ABTS) as the oxygen acceptor chromogen. There was an essentially linear relationship between the concentrations of gliclazide and decreasing glucose readings. One mu mol/1 of gliclazide in samples leads to an apparent loss of about 2.5 mu mol/l of glucose. However, gliclazide did not interfere with the glucose determination using the hexokinase/glucose-6-phosphate dehydrogenase method. This interference in the GOD-PERID method for glucose assay can occur in the in vitro experimental samples and cause underestimation of the glucose values. It is suggested that careful attention should be paid to the limited applicability of the GOD-PERID method for glucose assay.

Animals↗