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Biomedical subjects

M Nishimura

Publications and source records attributed to M Nishimura.

At least 451 records · Page 25Linked to original sources
PubMed1998

Immunosuppressive effects of chloroquine: potential effectiveness for treatment of post-transfusion graft-versus-host disease.

Post-transfusion graft-versus-host disease (PT-GVHD) is a fatal adverse effect of blood transfusion. In spite of its severity, there is no effective treatment at present for PT-GVHD. Previously, we reported that chloroquine (CH) inhibited the cytotoxicity of cytotoxic T-cell (CTL) clones and tumour necrosis factor beta (TNF beta) production by TNF beta-producing clones in vitro, both the clones being derived from peripheral blood lymphocytes (PBMCs) of PT-GVHD patients. To explore the possibility of utilizing CH for the treatment of PT-GVHD, we extended our investigation of the immunosuppressive effects of CH in vitro to PBMCs derived from healthy donors. Our results show that CH inhibits the mixed lymphocyte reaction (MLR) between allogeneic PBMCs, production of inflammatory cytokines such as TNF alpha, interleukin-1 beta (IL-1 beta) and interferon gamma (IFN gamma) in mixed lymphocyte culture and natural killer cell activity, and, further, reduces the number of alloreactive CTL precursors.

Chloroquine↗
PubMed1998

Beneficial effect of long-term combined treatment with voglibose and pioglitazone on pancreatic islet function of genetically diabetic GK rats.

Effects of voglibose (an alpha-glucosidase inhibitor) and pioglitazone (an insulin sensitizer) on glycemic control and on the function of pancreatic islets were evaluated using Goto-Kakizaki (GK) rats with non-insulin-dependent diabetes mellitus (NIDDM). Five week administration (8-13 weeks of age in GK rats) of voglibose alone (added to the chow at a concentration of 10 ppm), pioglitazone alone (10 mg/kg daily p.o.), or both of the agents together significantly improved fasting plasma glucose levels and those at 120 min in oral glucose tolerance tests. Insulin secretory capacity in response to glucose of the isolated islets, assessed by batch incubation, was significantly improved in the voglibose and in the voglibose plus pioglitazone groups. Eight-week administration (5-13 weeks of age) of voglibose and voglibose plus pioglitazone successfully lowered the fasting levels of plasma glucose and triglyceride. The glucose-responsiveness in insulin release from the islets was also significantly recovered by the therapy. The treatment increased the insulin content of the islets to almost twice that in untreated controls. Thus, treatment by these drugs can not only effectively ameliorate the metabolic derangement of NIDDM in GK rats, but it can also restore the deteriorated islet function, possibly through protection from glucose toxicity.

Animals↗
PubMed1998

Presenilin-1 mRNA and beta-amyloid precursor protein mRNA are expressed in the developing rat olfactory and vestibulocochlear systems.

The mRNA expression of presenilin-1 (PS1) and beta-amyloid precursor protein (betaAPP) was investigated in the embryonic day 20 rat olfactory bulb, nasal cavity, and inner ear using in situ hybridization histochemistry. In the olfactory bulb, PS1 mRNA was strongly expressed in both olfactory bulb neuroepithelium and the differentiating olfactory bulb. In contrast, betaAPP mRNA was preferentially expressed in differentiating fields. In the nasal cavity, PS1 mRNA was strongly expressed throughout the olfactory epithelium, while betaAPP mRNA expression was concentrated in the middle part of the epithelium. In the membrane labyrinth of the inner ear, although PS1 mRNA was evenly distributed in both sensory epithelium and supporting cells, betaAPP mRNA was exclusively expressed in the sensory epithelium. These data suggest that PS1 is expressed earlier than betaAPP, and that PS1 and betaAPP co-operatively play pivotal roles in the development of the olfactory and vestibulocochlear systems.

Alzheimer Disease↗
PubMed1998

Analysis of the butyrylcholinesterase gene and nearby chromosome 3 markers in Alzheimer disease.

The K-variant of butyrylcholinesterase (BCHE-K) recently has been reported to be associated with Alzheimer disease (AD) in carriers of the epsilon4 allele of the apolipoprotein E (APOE) gene. We have re-examined the frequency of the BCHE-K allele in a large data set of both sporadic and familial cases of AD disease, and we have also examined the segregation of three genetic markers on chromosome 3 near BCHE . Our data neither support an association of BCHE-K with sporadic or familial AD, nor do they suggest the existence of another gene nearby on chromosome 3 as a common cause of familial AD.

Aged↗
PubMed1998

Purification and characterization of a puromycin-hydrolyzing enzyme from blasticidin S-producing Streptomyces morookaensis.

Blasticidin S-producing Streptomyces morookaensis JCM4673 produces an enzyme which inactivates puromycin (PM) by hydrolyzing an amide linkage between its aminonucleoside and O-methyl-L-tyrosine moieties [Nishimura et al. (1995) FEMS Microbiol. Lett. 132, 95-100]. In this study, we purified to homogeneity the enzyme from the cell-free extracts of S. morookaensis. The molecular weight of PM-hydrolyzing enzyme, estimated by SDS-PAGE and gel filtration, was 68 and 66 kDa, respectively, suggesting that this protein is monomeric. The PM-hydrolyzing activity was strongly inhibited by Zn2+, Fe2+, Cu2+, Hg2+, and N-bromosuccinimide, but was stimulated by DTT. The optimum pH and temperature for PM-hydrolyzing activity were 8.0 and 45 degrees C, respectively. Several L-aminoacyl-beta-naphthylamides were good substrates for the enzyme, suggesting that the PM-inactivating enzyme has an aminopeptidase activity. The N-terminal sequence of the first 14 amino acids (Val-Ser-Thr-Ala-Pro-Tyr-Gly-Ala-Trp-Gln-Ser-Pro-Ile-Asp) of the enzyme showed no significant homology with any published hydrolase sequences.

Aminopeptidases↗
PubMed1998

Glyoxysomal malate dehydrogenase in pumpkin: cloning of a cDNA and functional analysis of its presequence.

Glyoxysomal malate dehydrogenase (gMDH) is an enzyme of the glyoxylate cycle that participates in degradation of storage oil. We have cloned a cDNA for gMDH from etiolated pumpkin cotyledons that encodes a polypeptide consisting of 356 amino acid residues. The nucleotide and N-terminal amino acid sequences revealed that gMDH is synthesized as a precursor with an N-terminal extrapeptide. The N-terminal presequence of 36 amino acid residues contains two regions homologous to those of other microbody proteins, which are also synthesized as large precursors. To investigate the functions of the N-terminal presequence of gMDH, we generated transgenic Arabidopsis that expressed a chimeric protein consisting of beta-glucuronidase and the N-terminal region of gMDH. Immunological and immunocytochemical studies revealed that the chimeric protein was imported into microbodies such as glyoxysomes and leaf peroxisomes and was then subsequently processed. Site-directed mutagenesis studies showed that the conserved amino acids in the N-terminal presequence, Arg-10 and His-17, function as recognition sites for the targeting to plant microbodies, and Cys-36 in the presequence is responsible for its processing. These results correspond to those from the analyses of glyoxysomal citrate synthase (gCS), which was also synthesized as a large precursor, suggesting that common mechanisms that can recognize the targeting or the processing of gMDH and gCS function in higher plant cells.

Amino Acid Sequence↗
PubMed1998

Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells.

BACKGROUND: Ketamine has been characterized as having psychotomimetic and sympathomimetic effects. These symptoms have raised the possibility that ketamine affects monoaminergic neurotransmission. To elucidate the relation between ketamine and monoamine transporters, the authors constructed three cell lines that stably express the norepinephrine, dopamine, and serotonin transporters and investigated the effects of ketamine on these transporters. METHODS: Human embryonic kidney cells were transfected using the Chen-Okayama method with the human norepinephrine, rat dopamine, and rat serotonin transporter cDNA subcloned into the eukaryotic expression vector. Using cells stably expressing these transporters, the authors investigated the effects of ketamine on the uptake of these compounds and compared them with those of pentobarbital. RESULTS: Inhibition analysis showed that ketamine significantly inhibited the uptake of all three monoamine transporters in a dose-dependent manner. The Ki (inhibition constant) values of ketamine on the norepinephrine, dopamine, and serotonin transporters were 66.8 microM, 62.9 microM, and 162 microM, respectively. Pentobarbital, a typical general anesthetic agent with no psychotic symptoms, did not affect the uptake of monoamines, however. Further, neither the glycine transporter 1 nor the glutamate/aspartate transporter was affected by ketamine, indicating that ketamine preferentially inhibits monoamine transporters. CONCLUSIONS: Ketamine inhibited monoamine transporters expressed in human embryonic kidney cells in a dose-dependent manner. This result suggests that the ketamine-induced inhibition of monoamine transporters might contribute to its psychotomimetic and sympathomimetic effects through potentiating monoaminergic neurotransmission.

ATP-Binding Cassette Transporters↗
PubMed1998

Effects of pressure-support ventilation on recovery from acute diaphragmatic fatigue in rabbits.

OBJECTIVES: To examine the effects of pressure-support ventilation on recovery from acute diaphragmatic fatigue. DESIGN: Prospective laboratory trial. SETTING: Experimental laboratory. SUBJECTS: Twenty-one healthy, adult New Zealand white rabbits. INTERVENTIONS: Diaphragmatic fatigue was induced with 50-Hz phrenic nerve stimulation for 30 mins. Recovery was compared between pressure-support ventilation 0 cm H2O (SB), 10 cm H2O (P10), and 20 cm H2O (P20) for 90 mins immediately after the end of the fatigue inducing procedure. MEASUREMENTS AND MAIN RESULTS: After the fatigue-inducing procedure, pressure-support ventilation reduced transdiaphragmatic pressure and integrated diaphragmatic electromyogram both at P20 and P10, but not in SB. Recovery was assessed by airway occlusion pressure (Poccl) generated by high- (100 Hz) and low- (20 Hz) frequency phrenic nerve stimulation. Poccl at 100 Hz was lower in P10 and P20 than in SB (74.6 +/- 6.2 [SEM] %, 66.9 +/- 3.3%, and 94.8 +/- 3.6% of the baseline at 90 mins for P10, P20, and SB, respectively), while those at 20 Hz showed no differences between the three groups. CONCLUSION: Recovery from acute diaphragmatic fatigue might be disturbed with pressure-support ventilation.

Animals↗
PubMed1998

Lower than normal expression of brain nitric oxide synthase gene in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats.

OBJECTIVE: To elucidate the role of brain nitric oxide produced by neuronal constitutive nitric oxide synthase in sodium-induced hypertension. DESIGN AND METHODS: Diets containing a high (8% NaCl), a medium (2% NaCl), and a low (0.2% NaCl) sodium content were administered to Wistar rats aged 12 weeks for 10 days or 8 weeks until they were killed. Male Wistar rats administered either deoxycorticosterone acetate, 1% NaCl or both and the respective controls were killed 2 weeks (during prehypertensive stage) or 6 weeks (during hypertensive stage) after the start of treatment. The hypothalamus and lower brainstem were excised for extraction of total RNA. Reverse transcription polymerase chain reactions of constitutive nitric oxide synthase messenger RNA and glyceraldehyde-3-phosphate dehydrogenase messenger RNA were performed, and constitutive nitric oxide synthase messenger RNA levels were expressed relative to glyceraldehyde-3-phosphate dehydrogenase messenger RNA levels. RESULTS: A high sodium intake for 10 days tended to decrease constitutive nitric oxide synthase messenger RNA levels in the hypothalamus, compared with effect of a low sodium intake. Constitutive nitric oxide synthase messenger RNA levels in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats were lower than those in the control sham-operated rats. Neither alteration of sodium intake nor administration of deoxycorticosterone with and without sodium affected constitutive nitric oxide synthase gene expression in the lower brainstem. CONCLUSIONS: Expression of neuronal constitutive nitric oxide synthase gene is downregulated in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. This lower than normal expression of neuronal constitutive nitric oxide synthase gene in the hypothalamus could be an adaptive response to sodium-induced hypertension, and suggests that nitric oxide produced by hypothalamic constitutive nitric oxide synthase plays a role in maintenance of blood pressure in relation to sodium balance in rats.

Animals↗
PubMed1998

Changes in the circadian rhythm of blood pressure in primary aldosteronism in response to dietary sodium restriction and adrenalectomy.

OBJECTIVE: Recently, we found that sodium restriction restored the circadian rhythm of blood pressure from non-dippers to dippers in patients with a sodium-sensitive type of essential hypertension. In the present study, we investigated the effects of sodium restriction on the circadian blood pressure rhythm in patients with primary aldosteronism, a typical sodium-sensitive form of secondary hypertension. DESIGN AND METHODS: We performed 24 h blood pressure monitoring in eight patients with primary aldosteronism due to unilateral adenoma (Conn's syndrome) during normal-sodium (7-12 g/day of NaCl) and low-sodium (1-3 g/day) diets, and after adrenalectomy. RESULTS: Sodium restriction lowered the 24 h mean arterial pressure from 116+/-14 to 109+/-12 mmHg (P< 0.01). During a normal-sodium diet, there was no change in systolic, diastolic and mean arterial pressures during the night-time compared with the daytime. In contrast, during a low-sodium diet, all night-time pressure values were significantly lower than those in the daytime. After adrenalectomy, the night-time pressures in patients on a normal-sodium diet were lower than those of the daytime. The nocturnal mean arterial pressure fall was increased by sodium restriction and adrenalectomy. CONCLUSIONS: These results indicate that the circadian rhythm of blood pressure was disturbed in patients with primary aldosteronism who maintained a relatively high sodium intake. Both adrenalectomy and sodium restriction restored a nocturnal dip in blood pressure in primary aldosteronism. Therefore, sodium restriction affects the circadian blood pressure rhythm in sodium-sensitive types of hypertension, not only in primary hypertension, but also in secondary hypertension.

Adult↗
PubMed1998

Concentration-dependent block of sodium current in guinea pig ventricular myocytes by a class III antiarrhythmic agent, MS-551.

Although MS-551 is classified as a class III antiarrhythmic agent (K+ channel blocker), its effect on the Na+ channel has not been fully characterized. We investigated the effect of MS-551 on the Na+ current (I(Na)) in isolated guinea pig ventricular myocytes. MS-551 blocked I(Na) in a concentration-dependent manner at a holding potential of -140 mV. The concentration-response curve revealed that the median inhibitory concentration (IC50) for the block of resting channel was 292 +/- 20 microM with a Hill coefficient of 1 (n = 11). Although MS-551, 300 microM, did not show a use-dependent block, it shifted the steady-state inactivation curve in a hyperpolarizing direction by 6.3 +/- 0.8 mV and delayed the recovery process from long depolarization. This delay was considered to be related to the drug unbinding and was expressed by a triple exponential function. The slowest component had a time constant of 409 +/- 35 ms, and the proportion of the amplitude of this component to the total current amplitude was 14 +/- 3% (n = 6). The IC50 for the inactivated Na+ channel was thus estimated to be 169 microM at maximum. These results suggest that MS-551 has a low affinity for both the resting and inactivated Na+ channel.

Animals↗
PubMed1998

2,4-Dichlorophenoxybutyric acid-resistant mutants of Arabidopsis have defects in glyoxysomal fatty acid beta-oxidation.

It has been demonstrated previously that 2,4-dichlorophenoxybutyric acid (2,4-DB) is metabolized to produce a herbicide, 2,4-D, by the action of peroxisomal fatty acid beta-oxidation in higher plants. To isolate mutants that have defects in peroxisomal fatty acid beta-oxidation, we screened mutant lines of Arabidopsis seedlings for growth in the presence of toxic levels of 2,4-DB. Twelve of the mutants survived; of these, four required sucrose for postgerminative growth. This result suggests that these mutants have defects in peroxisomal fatty acid beta-oxidation, because peroxisomal fatty acid beta-oxidation plays an important role in producing sucrose from storage lipids during germination. Genetic analysis revealed that these mutants can be classified as carrying alleles at three independent loci, which we designated ped1, ped2, and ped3, respectively (where ped stands for peroxisome defective). The ped1 mutant lacks the thiolase protein, an enzyme involved in fatty acid beta-oxidation during germination and subsequent seedling growth, whereas the ped2 mutant has a defect in the intracellular transport of thiolase from the cytosol to glyoxysomes. Etiolated cotyledons of both ped1 and ped2 mutants have glyoxysomes with abnormal morphology.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1998

Transport of storage proteins to protein storage vacuoles is mediated by large precursor-accumulating vesicles

Novel vesicles that accumulate large amounts of proprotein precursors of storage proteins were purified from maturing pumpkin seeds. These vesicles were designated precursor-accumulating (PAC) vesicles and had diameters of 200 to 400 nm. They contained an electron-dense core of storage proteins surrounded by an electron-translucent layer, and some vesicles also contained small vesicle-like structures. Immunocytochemical analysis revealed numerous electron-dense aggregates of storage proteins within the endoplasmic reticulum. It is likely that these aggregates develop into the electron-dense cores of the PAC vesicles and then leave the endoplasmic reticulum. Immunocytochemical analysis also showed that complex glycans are associated with the peripheral region of PAC vesicles but not the electron-dense cores, indicating that Golgi-derived glycoproteins are incorporated into the PAC vesicles. These results suggest that the unique PAC vesicles might mediate a transport pathway for insoluble aggregates of storage proteins directly to protein storage vacuoles.

Journal Article↗
PubMed1998

Piroxicam and acarbose as chemopreventive agents for spontaneous intestinal adenomas in APC gene 1309 knockout mice.

The use of nonsteroidal anti-inflammatory drugs has been suggested to have a chemopreventive effect against colon carcinoma, through the inhibition of cyclooxygenases 1 and 2, in patients with familial adenomatous polyposis and in animal models. Acarbose, an alpha-glycosidase inhibitor, may also be chemopreventive. In order to examine the effects of these drugs we employed APC gene knockout mice randomized into 3 groups, one for treatment with piroxicam (0.05% concentration in drinking water), one for acarbose (0.04% concentration in food) and another for the control. After 14 weeks of treatment, mice were killed for quantitation of gastric and intestinal adenomas. Tumor multiplicity in the whole gastrointestinal tract decreased from 33.89 +/- 13.07 tumors/mouse in the control group to 17.05 +/- 7 tumors/mouse in the piroxicam-treated group (P < 0.001). The decrease in the acarbose-treated group (29.68 +/- 12.86 tumors/mouse) was not significant (P < 0.05). The number of tumors > or = 3 mm in diameter was also quantified in all gastrointestinal segments. The number of such tumors in the piroxicam group was decreased to 0.56 +/- 1.2 tumors/mouse from the control value of 3.78 +/- 1.17 tumors/mouse (P < 0.001), while in the acarbose-treated group the number decreased to 2.36 +/- 1.7 tumors/mouse (P < 0.01). Thus, piroxicam decreases the size and number of gastrointestinal adenomas in APC 1309 knockout mice, while acarbose decreases only the size.

Acarbose↗
PubMed1998

Low-grade B cell lymphoma of mucosa-associated lymphoid tissue in the thymus of a patient with rheumatoid arthritis.

The majority of thymic lymphomas are either lymphoblastic lymphoma, large B cell lymphoma or Hodgkin's disease, and other types of non-Hodgkin lymphoma are rare. A case of low-grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT) in the thymus is reported. A 55-year-old Japanese female with a history of rheumatoid arthritis (RA) complained of back pain. A mediastinal tumor was identified by computerized tomography and magnetic resonance imaging, and the thymus was resected through median sternotomy. The solid and nodular tumor had several small satellite extensions and was completely confined to within the thymus. Histologically, monotonous medium-sized centrocyte-like cells occupied the medulla of the thymus and infiltrated Hassall's corpuscles (lymphoepithelial lesions). Immunohistochemically, tumor cells were positive for CD20 and CD79a. IgA and kappa light chain restriction were also found in plasmacytoid cells in the tumor. Clonal rearrangement of the immunoglobulin heavy chain gene was demonstrated by polymerase chain reaction. This case was diagnosed as MALT-type low-grade B cell lymphoma in the thymus. This is the first report of low-grade B cell lymphoma in the thymus associated with RA. As autoimmune diseases are known to be associated with lymphoid neoplasms, it is suggested that the RA played an important role in the development of malignant lymphoma in this case.

Antigens, CD20↗
PubMed1998

Peroxisome targeting signal type 1 (PTS1) receptor is involved in import of both PTS1 and PTS2: studies with PEX5-defective CHO cell mutants.

To investigate the mechanisms of peroxisome assembly and the molecular basis of peroxisome assembly disorders, we isolated and characterized a peroxisome-deficient CHO cell mutant, ZP139, which was found to belong to human complementation group II, the same group as that of our earlier mutant, ZP105. These mutants had a phenotypic deficiency in the import of peroxisomal targeting signal type 1 (PTS1) proteins. Amino-terminal extension signal (PTS2)-mediated transport, including that of 3-ketoacyl coenzyme A thiolase, was also defective in ZP105 but not in ZP139. PEX5 cDNA, encoding the PTS1 receptor (PTS1R), was isolated from wild-type CHO-K1 cells. PTS1R's deduced primary sequence comprised 595 amino acids, 7 amino acids less than the human homolog, and contained seven tetratricopeptide repeat (TPR) motifs at the C-terminal region. Chinese hamster PTS1R showed 94, 28, and 24% amino acid identity with PTS1Rs from humans, Pichia pastoris, and Saccharomyces cerevisiae, respectively. A PTS1R isoform (PTS1RL) with 632 amino acid residues was identified in CHO cells; for PTS1R, 37 amino acids were inserted between residues at positions 215 and 216 of a shorter isoform (PTS1RS). Southern blot analysis of CHO cell genomic DNA suggested that these two isoforms are derived from a single gene. Both types of PEX5 complemented impaired import of PTS1 in mutants ZP105 and ZP139. PTS2 import in ZP105 was rescued only by PTS1RL. This finding strongly suggests that PTS1RL is also involved in the transport of PTS2. Mutations in PEX5 were determined by reverse transcription-PCR: a G-to-A transition resulted in one amino acid substitution: Gly298Glu of PTS1RS (G335E of PTS1RL) in ZP105 and Gly485Glu of PTS1RS (G522E of PTS1RL) in ZP139. Both mutations were in the TPR domains (TPR1 and TPR6), suggesting the functional consequence of these domains in protein translocation. The implications of these mutations are discussed.

Amino Acid Sequence↗
PubMed1998

Benzamil blockade of brain Na+ channels averts Na(+)-induced hypertension in rats.

To determine the possible involvement of brain amiloride-sensitive Na+ channels in Na(+)-induced hypertension, we investigated the effects of benzamil hydrochloride, a specific blocker of these Na+ channels, on the acute pressor mechanisms of intracerebroventricular infusion of hypertonic NaCl and the continuous pressor mechanisms of Na(+)-induced chronic hypertension, such as deoxycorticosterone acetate-salt hypertensive or stroke-prone spontaneous hypertensive rats, and of non-Na(+)-induced hypertension, such as renovascular hypertensive rats. Intracerebroventricular preinjection with benzamil (1 or 10 nmol/kg) abolished the increase in mean arterial pressure, heart rate, abdominal sympathetic discharge, and plasma vasopressin concentration induced by an acute increase in cerebrospinal Na+ concentrations at intracerebroventricular infusion of 1.5 M hypertonic NaCl. Continuous intracerebroventricular infusion of benzamil (1 or 10 nmol.kg-1.day-1) for 7 days attenuated Na(+)-induced chronic hypertension in both deoxycorticosterone acetate-salt and stroke-prone spontaneous hypertensive rats, accompanied by reduction of urinary excretion of vasopressin and norepinephrine but not in renovascular hypertensive rats. Intravenous infusion of benzamil (10 nmol.kg-1.day-1) for 7 days affected neither arterial pressure nor urinary excretion of vasopressin and norepinephrine in either model of hypertension. Benzamil-blockable brain amiloride-sensitive Na+ channels are expected to function as one of the Na+ receptors in the brain and to be involved in the pressor mechanism of Na(+)-induced hypertension.

Amiloride↗