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Biomedical subjects

J Nakamura

Publications and source records attributed to J Nakamura.

At least 307 records · Page 17Linked to original sources
PubMed1995

An aldose reductase inhibitor, TAT, reduces ADP-induced platelet hyperaggregation in streptozotocin-induced diabetic rats with neuropathy.

To investigate the relationship between metabolic and vascular factors, especially polyol pathway and platelet aggregation, in the pathogenesis of diabetic neuropathy, the effects of a novel potent aldose reductase inhibitor, TAT ((5-(3-thienyl) tetrazol-1-yl) acetic acid monohydrate) on adenosine diphosphate-induced platelet aggregation, polyol contents in platelets, motor nerve conduction velocity (MNCV), and sciatic nerve blood flow (SNBF) were examined in streptozotocin-induced diabetic rats. Diabetic rats demonstrated hyperaggregation in response to adenosine diphosphate, accompanied by sorbitol and fructose accumulation and myoinositol depletion in platelets. Treatment with TAT improved these abnormalities in diabetic rats. A delayed MNCV and a reduced SNBF in diabetic rats were normalized by the administration of TAT. These observations suggest that increased polyol pathway activity plays an important role in platelet aggregation in the development of diabetic neuropathy and that aldose reductase inhibitor is useful for the treatment of diabetic neuropathy from the viewpoint not only of metabolic factors but also of vascular factors.

Adenosine Diphosphate↗
PubMed1995

[A case of bilateral partial anomalous pulmonary venous connections with the right upper pulmonary vein draining to the high superior vena cava].

A 10-year-old girl with bilateral partial anomalous pulmonary venous connections (PAPVC) was referred to us. The right upper pulmonary vein (PV) drained to the high superior vena cava (SVC) and the left upper PV to the left innominate vein. The left upper PV was directly anastomosed to the right atrial appendage. The SVC was divided distal to the orifice of the right upper PV and anastomosed to the right atrial appendage. A Xenomedica patch was placed within the right atrium to divert the pulmonary venous blood from the SVC orifice across the surgically enlarged ASD to the left atrium. The postoperative course was satisfactory without arrhythmia, and cineangiography revealed no obstruction at the SVC and the right upper PV pathways. We thought that this method is advantageous in preserving the sinus node and its feeding artery, as well as being applicable to the PAPVC to the high SVC.

Anastomosis, Surgical↗
PubMed1994

Two types of proton-modulated calcium binding in the sarcoplasmic reticulum Ca(2+)-ATPase. I. A model of two different conformations of chemically equivalent ATPase molecules.

Two pools of calcium binding sites of the sarcoplasmic reticulum Ca(2+)-ATPase have been found at 0 degrees C: Half of the calcium sites are in a slow (t1/2 > or = 2 s)/rapid (t1/2 < 2 s) binding site dependent on pH, and the other half are in a slow binding state independent of pH (Nakamura, J. (1989) J. Biol. Chem. 264, 17029-17031). Herein, to clarify the molecular basis of the two calcium sites, the relation between calcium binding to the enzyme and phosphorylation of the enzyme was examined at pH 7.40, where the calcium sites are split into rapid and slow binding states. The enzyme was slowly or rapidly phosphorylated with ATP, accompanied by slow or rapid calcium binding with a stoichiometry of about 1:2. Analysis of the amino acid sequence of lysyl endopeptidase peptides of the ATPase preparation confirmed the homogeneity of the preparation, which was of fast twitch muscle type. These results suggest that each of the two pools of calcium sites belongs to one of the two different conformations of chemically equivalent ATPase molecules, which are in pH-dependent equilibrium between E1 (high affinity state for calcium) and E2 (low affinity state for calcium) and predominantly in E2 independent of pH, respectively, before calcium binding.

Amino Acid Sequence↗
PubMed1994

Two types of proton-modulated calcium binding in the sarcoplasmic reticulum Ca(2+)-ATPase. II. Characteristics of their calcium bindings.

The first part of this study reported the existence of two different conformations of chemically equivalent Ca(2+)-ATPase molecules from the sarcoplasmic reticulum, which were in pH-dependent equilibrium between E1 (high affinity state for calcium) and E2 (low affinity state for calcium) and predominantly in E2 independent of pH, respectively, before calcium binding (Nakamura, J., and Furokohri, T. (1994) J. Biol. Chem, 269, 30818-30821). Here, calcium bindings at the ATPase molecules were further studied by varying [Ca2+] and pH at 0 degree C. The molecule, which pre-existed in equilibrium between E1 and E2, noncooperatively (the Hill value (nH) approximately 1) bound calcium with an apparent calcium affinity (K0.5) of 2-6 microM independent of pH. nH of the pH profile of the pre-existing equilibrium was about 2, suggesting participation of two protons in the equilibrium. On the other hand, the molecule, which predominantly pre-existed in E2, cooperatively (nH approximately 2) bound calcium with K0.5, which was increased from about 7 microM to about 0.2 microM by increasing pH from 6.23 to 7.40. Analysis of pH dependency of the K0.5 showed participation of 1 proton/calcium in competition for the binding sites. Calcium bindings at the two ATPase molecules seem to be differently modulated by the proton(s).

Animals↗
PubMed1994

Ethanol-induced reduction of the amount of stimulatory GTP-binding regulatory protein, Gs, in wild-type S49 murine lymphoma cells: effect of cycloheximide and puromycin.

The activity and the amount of Gs in wild-type S49 murine lymphoma cells decreased by 16-18% and by 29%, respectively, after 24 h treatment of the cells with 50 mM ethanol, through a transient increase of the Gs activity with no alteration in its content after 4 and 8 h treatment. No decrease of the Gs activity was noted when membranes from S49 cells were treated with 50-500 mM ethanol. To study the role of protein metabolism in the ethanol-induced reduction in the amount of Gs, S49 cells were treated with ethanol for 24 h in the presence of inhibitor of protein synthesis. Cycloheximide at concentrations of 0.05-0.15 micrograms/ml and puromycin at 0.15-0.60 micrograms/ml caused a dose-dependent inhibition of cell division in S49 cells to a similar degree. The ethanol-induced reduction of the activity and the amount of Gs was completely abolished by those concentrations of cycloheximide, but not by puromycin. Cycloheximide itself caused no alteration in the Gs activity of S49 cell membranes. These results indicate that the process of the ethanol-induced event of Gs involves cycloheximide-sensitive protein synthesis.

Animals↗
PubMed1994

Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA.

GMP synthetase is a key enzyme in the de novo synthesis of guanine nucleotides. Human GMP synthetase has been purified to homogeneity, and a cDNA encoding the enzyme has been isolated from the T-lymphoblastoma cell line, A3.01. The open reading frame encodes a protein of 693 amino acids with a predicted molecular weight of 76,725. The cDNA complements a guaA mutant of Escherichia coli, which lacks a functional GMP synthetase and extracts from the transformed E. coli exhibit GMP synthetase activity, which is absent in the parental strain. RNA hybridization analysis shows that human GMP synthetase is encoded by a single 2.4-kilobase message. DNA hybridization analysis suggests that the human GMP synthetase is encoded by one gene. In several human cell lines, the level of mRNA expression is substantially higher in proliferating, transformed cells than in nontransformed cells. In two transformed cell lines, treatment with phorbol ester inhibits proliferation and results in a dramatic down-regulation in the levels of GMP synthetase mRNA and protein.

Amino Acid Sequence↗
PubMed1994

KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity.

KF17837 is a novel selective adenosine A2A receptor antagonist. Oral administration of KF17837 (2.5, 10.0 and 30.0 mg/kg) significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680 (10 micrograms), in a dose-dependent manner. KF17837 also reduced the catalepsy induced by haloperidol (1 mg/kg i.p.) and by reserpine (5 mg/kg i.p.). These anticataleptic effects were exhibited dose dependently at doses from 0.625 and 2.5 mg/kg p.o., respectively. Moreover, KF17837 (0.625 mg/kg p.o.) potentiated the anticataleptic effects of a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 25 mg/kg i.p.) plus benserazide (6.25 mg/kg i.p.). These results suggested that KF17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists. Furthermore, KF17837 may be a useful drug in the treatment of parkinsonism.

Adenosine↗
PubMed1994

Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice.

The effects of topiramate, a novel antiepileptic drug, on tonic and absence-like seizures in spontaneously epileptic rats (SER; zi/zi, tm/tm) and on sound-induced seizures in DBA/2 mice were investigated. Topiramate (20 and 40 mg/kg i.p.) inhibited both tonic and absence-like seizures in a dose-dependent manner, whereas phenytoin (20 mg/kg i.p.) and zonisamide (40 mg/kg i.p.) inhibited only the tonic seizures. The inhibitory effects of topiramate on absence-like seizures were antagonized by pretreatment with haloperidol (0.5 mg/kg i.p.), but those on the tonic seizures remained unaffected. Topiramate inhibited sound-induced seizures in DBA/2 mice (ED50 = 8.6 mg/kg p.o.). These findings suggest that topiramate may be effective for treatment of both convulsive and absence seizures of human epilepsy. The inhibitory effect of topiramate on absence-like seizures in SER may be mediated through the central dopaminergic system.

Acoustic Stimulation↗
PubMed1994

Inhibitory effects of botulinum toxin on 5-HT1C receptor-induced Cl- current in Xenopus oocytes.

Several low molecular weight G proteins have been identified, but their functional roles remain unclear. To clarify the involvement of low molecular weight G protein in receptor-stimulated turnover of polyphosphoinositide (PI) turnover, influences of botulinum toxins on serotonin (5-HT)-stimulated Cl- current mediated by PI turnover were investigated using Xenopus oocytes injected with rat brain mRNA. Treatment with botulinum toxin C, D or purified ADP-ribosyltransferase of botulinum toxin (botulinum toxin C3 enzyme) inhibited the 5-HT-induced Cl- current in oocytes, and ADP-ribosylated 23 kDa proteins. Both botulinum toxin C3 enzyme-induced inhibition of the current and ADP-ribosylation were suppressed by pretreatment with antibotulinum toxin C3 enzyme antibody. Botulinum toxin D treatment of oocytes was ineffective in the response of Cl- current induced by injection of 50 pmol inositol 1,4,5-trisphosphate and 50 pmol Ca2+. It is suggested that low molecular weight G proteins ADP-ribosylated by botulinum toxin C3 enzyme are involved in phospholipase C activation in Xenopus oocytes.

ADP Ribose Transferases↗
PubMed1994

Intestinal permeability of ophthalmic beta-blockers for predicting ocular permeability.

The purpose of this study was to investigate the intestinal permeability of ophthalmic beta-blockers and evaluate the utility of intestinal membrane for predicting the ocular permeability. The penetrations of beta-blockers were measured across the isolated jejunum and colon of the albino rabbit using a two-chamber glass diffusion cell. beta-Blockers tested include atenolol, carteolol, tilisolol, timolol, and befunolol. Colonic membrane showed lower permeability of hydrophilic drugs than jejunal membrane. Scraping the entire cell monolayer of jejunum increased the drug permeability. There was a significant correlation between colonic permeability coefficients and lipophilicities of beta-blockers. The permeability coefficients through jejunum and scraped jejunum were not susceptible to drug lipophilicities. Jejunum, scraped jejunum, and colon showed permeability coefficients almost equal to those of sclera, conjunctiva, and cornea, respectively. There was a significant correlation between permeability coefficients through colon and cornea. These results indicate that the steady-state permeability of ophthalmic beta-blockers through ocular membranes may be predicted by measuring the permeability through certain intestinal membranes. However, the analyses of intestinal permeability using Fick's equation showed the functional difference of intestinal permeability from ocular permeability of ophthalmic beta-blockers.

Adrenergic beta-Antagonists↗
PubMed1994

The correlation of serum luteinizing hormone levels with the induction of Leydig cell tumors in rats by oxolinic acid.

Studies were performed to examine the mechanism by which testicular Leydig cell tumors are induced in rats by administration of the antimicrobial agent oxolinic acid (1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinolinecarboxylic acid). In these studies, the effects of oxolinic acid on serum levels of luteinizing hormone (LH), testosterone, and prolactin and the binding of testosterone to prostatic androgen receptors were examined. In a long-term hormonal study, male Wistar rats were fed a diet containing oxolinic acid at 0, 100, 1000, or 3000 ppm for 104 weeks. A statistically significant increase in serum LH levels was observed at 1000 and 3000 ppm, but no dose of oxolinic acid had a significant effect on serum testosterone levels. Serum LH levels were no longer elevated above control levels within 2 weeks of cessation of the administration of oxolinic acid. Oxolinic acid was found to have no effect on the rate of clearance of exogenous LH from the circulation. Serum prolactin levels were decreased by the administration of oxolinic acid. The increase in serum LH induced by oxolinic acid was completely blocked by the intraperitoneal injection of the dopamine antagonist haloperidol (2 mg/kg). In addition, no significant affinity of oxolinic acid for androgen receptors was found in an in vitro study. These findings suggest that: (1) oxolinic acid induces Leydig cell tumors in rats by chronically stimulating the release of LH from the pituitary, (2) the mechanism of stimulating the release of LH involves facilitation of the dopaminergic systems in the hypothalamus-pituitary axis, and (3) oxolinic acid has no effect on androgen-mediated feedback inhibition.

Administration, Oral↗
PubMed1994

Transphosphatidylation of sugar alcohols and its implications for the pathogenesis of diabetic complications.

Glucose-induced sorbitol accumulation and attendant alterations in cellular myo-inositol and phosphoinositide metabolism have been invoked in the pathogenesis of diabetic complications; however, direct effects of sorbitol on membrane phospholipid composition or metabolism have never been evaluated. Phospholipase D catalyses the transphosphatidylation of ethanol into phosphatidylcholine to yield phosphatidylethanol, an "abnormal" phospholipid whose content in rat brain is increased by chronic ethanol ingestion. Analogous transphosphatidylation of sorbitol or other polyols whose concentration is elevated in diabetes was explored in vitro and in glucose-exposed cultured human retinal pigment epithelial cells. Phosphatidylcholine and varying concentrations of sorbitol, galactitol, mannitol and glucose were incubated with peanut phospholipase D in sodium acetate buffer for varying time periods. Thin layer chromatography revealed new phospholipid bands whose hydrolysis by phospholipase D liberated a water-soluble compound that cochromatographed with sorbitol on gas-liquid chromatography, and whose concentration increased in a time- and concentration-dependent fashion. Identical transphosphatidylation activity was demonstrated in a rat brain synaptosomal fraction. Phospholipase D hydrolysis of lipids from human retinal pigment epithelial cells constitutively overexpressing the aldose reductase gene yielded a sorbitol-like compound whose appearance was increased by glucose exposure and was decreased by an aldose reductase inhibitor. Thus, glucose-induced aldose reductase inhibitor sensitive sorbitol accumulation might induce the formation of "phosphatidylsorbitol" through a transphosphatidyl mechanism that may contribute to altered membrane phospholipid metabolism in diabetes.

Aldehyde Reductase↗
PubMed1994

The recognition of cancer-associated fucosylated antigens in colorectal cancer by a novel monoclonal antibody, YB-2.

A monoclonal antibody, YB-2, which has a novel epitope for fucosylated antigens and shows cross-reactivity with Y/Leb/H type 2 antigens, was used in an immunohistochemical study of human neoplastic and normal colorectal tissues. Of 64 colorectal cancers, 59 (92.2%) were stained by the YB-2 antibody; however, only 3 (12.0%) of 25 samples of normal colon mucosa and 13 (50.0%) of 26 adenomas expressed the antigens recognized by YB-2. Clinicopathologically, the YB-2-negative colon cancers were exclusively in Dukes stage A. These results indicate that the monoclonal antibody, YB-2, could detect cancer-associated antigens, and the degree of YB-2-reacted antigen expression might be correlated with the progression of colorectal carcinogenesis.

Adenoma↗
PubMed1994

Effectiveness of concomitant setiptiline maleate (Tecipul) on negative symptoms of schizophrenia.

1. Setiptiline maleate was administered to schizophrenic patients with the object of improving their negative symptoms. 2. Moderate improvements were observed in 58% of the treated patients, thus usefulness of this drug was demonstrated. 3. There was no aggravation of symptoms, and side effects were minor. 4. Measurements of plasma monoamine metabolites showed a tendency of MHPG to decrease and a significant decrease in 5-HIAA, but no change in the level of HVA was observed, suggesting a relationship between the negative symptoms and noradrenaline and/or serotonin systems.

Adult↗
PubMed1994

Carcinogenicity studies of oxolinic acid in rats and mice.

A chronic feeding study was conducted to determine the carcinogenic potential of oxolinic acid, an antimicrobial agent, in rats and mice. Oxolinic acid was administered in the diet to Wistar rats (0, 30, 100, 300 or 1000 ppm; 50 rats/dose/sex) for 104 wk and to ICR mice (0, 50, 150 or 500 ppm; 50 mice/dose/sex) for 78 wk. Clinical signs, body weight, food consumption, autopsy findings and histopathological data were noted. Mortality was unaffected by oxolinic acid administration in neither species. In rats, body weight gain was suppressed in both sexes at 1000 ppm. Histopathological examinations conducted after autopsy at 104 wk revealed a slight increase in benign Leydig cell tumours of the testis at 1000 ppm, which did not appear until late in the lifetime of rats. No other treatment-related neoplastic lesions were observed in rats. Non-neoplastic lesions in males at 1000 ppm included Leydig cell hyperplasia and tubular atrophy of the testes. In mice, decreased body weight gain was observed in both sexes at 500 ppm, but no non-neoplastic or neoplastic lesions attributable to the treatment with oxolinic acid occurred in either sex. In conclusion, oxolinic acid induced benign Leydig cell tumours of the testis in rats at the highest dose level tested (1000 ppm). The no-effect level for tumour induction was confirmed to be 300 ppm (10.9 mg/kg/day) in rats. None was induced in mice.

Animals↗
PubMed1994

Pharmacokinetic analysis of in vivo metabolism of amino acid or dipeptide conjugates of salicylic acid in rabbit intestinal microorganisms.

We analyzed the pharmacokinetics of salicylic acid (SA)-amino acid (alanine, glutamic acid, methionine, and tyrosine) or SA-dipeptide (glycylglycine) conjugates in rabbits, by using a model that takes into account the metabolism of prodrug to SA by intestinal microorganisms and, also, by model-independent analysis. The blood concentration profiles of these prodrugs and released SA following intracecal and oral administration to rabbits were obtained previously (Nakamura et al., J. Pharm. Pharmacol., 44, 295-299, 1992; Chem. Pharm. Bull., 40, 2164-2168, 1992; Int. J. Pharm., 87, 59-66, 1992; J. Pharm. Pharmacol., 44, 713-716, 1992). First, the overall in vivo behavior was evaluated by statistical moment analysis. Next, the blood concentration profiles of prodrug and SA following intracecal and oral administration were simultaneously fitted to the above model. In general, good agreement was observed between fitted lines and experimental data for every prodrug, suggesting the validity of this model. The obtained parameters characterized the difference in the rate of metabolism and absorption among the prodrugs. Lower absorbability and enhanced hydrolysis rate of the prodrug lead to prolonged blood concentration of SA.

Administration, Oral↗