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Y Uehara

Publications and source records attributed to Y Uehara.

At least 55 records · Page 3Linked to original sources
PubMed1999

Long-term inhibition of renin-angiotensin system sustains memory function in aged Dahl rats.

The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 microg/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 microg/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CA1 regions compared with those in the untreated DS. Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.

Aging↗
PubMed1999

Tracheal barrier and the permeability of hydrophilic drugs and dipeptides.

The permeability of model hydrophilic compounds with different molecular weights and model dipeptides were examined to characterize the tracheal epithelial barrier in in vitro experiments using excised rabbit trachea. 6-Carboxyfluorescein (6-CF; 376 Da) and fluorescein isothiocyanate (FITC)-dextrans (FDs) with varying molecular weights (4 to 70 kDa) were used as model hydrophilic and macromolecular compounds, and glycyl-D-phenylalanine (Gly-D-Phe) and glycyl-L-phenylalanine (Gly-L-Phe) were used as model dipeptides in this experiment. The apparent permeability coefficients (Papp) of 6-CF and FDs with Mw 376 Da to 70 kDa ranged from 2.35x10(-7) to 4.05x10(-10)cm/s and exhibited a good inverse correlation with their molecular weights. The tracheal permeability of 6-CF, FD-4 (4 kDa) and FD-10 (10 kDa) were increased over three fold by 10 mM glycocholate, which is an absorption enhancer. The Papp of Gly-D-Phe was 1.03x10(-6)cm/s and there was no metabolism during tracheal permeation. Gly-L-Phe was immediately degraded in the mucosal fluid and its intact form was not detected in serosal fluid during the 150 min experimental period. These results suggest that absorption of some peptide drugs via the respiratory tract may contribute to their systemic delivery following pulmonary administration by intratracheal insufflation and instillation.

Animals↗
PubMed1999

Effect of thiazinotrienomycin B, an ansamycin antibiotic, on the function of epidermal growth factor receptor in human stomach tumor cells.

Thiazinotrienomycin B (TT-B), an ansamycin isolated from fermentation broths of Streptomyces sp. MJ672-m3, inhibited the growth in vitro of human stomach tumor SC-6 cells over 10 times more strongly than the growth of other human tumor cells, such as HeLa (cervix), T24 (bladder) and LX-1 (lung). The extent of growth inhibition by TT-B of SC-6, but not of LX-1 nor T24, was lowered in a competitive manner by raising serum concentrations in the culture medium. TT-B inhibited the cell cycle progression of SC-6 at an early stage of the progression from G0/G1 to S. The inhibition was again competitive with serum concentrations in the culture medium. No direct inhibition of DNA synthesis was observed at the concentration range which caused the cell cycle arrest. TT-B and anti-epidermal growth factor receptor (anti-EGFR) were antagonistic to each other in inhibiting the cell cycle progression of SC-6 from G0/G1 to S, suggesting that the two compounds share the same target, EGFR. The kinase activity of EGFR was little inhibited by TT-B in a cell-free system.

Anti-Bacterial Agents↗
PubMed1998

CD27/CD70 interaction augments IgE secretion by promoting the differentiation of memory B cells into plasma cells.

The induction of IgE switching in B cells requires several signals given by cytokines and cell contact-delivered signals. Here, we investigated the role of CD27/CD70 interaction in B cell IgE synthesis. The addition of CD27 ligand (CD70) transfectants to B cell cultures increased the IgE synthesis synergistically in the presence of IL-4 plus anti-CD40 mAb (anti-CD40). The effect of CD70 transfectants was dose dependent and was completely blocked by anti-CD70 mAb. CD27+ B cells had the ability to produce IgE, which was increased by contact with CD70 transfectants, whereas CD27- B cells did not produce IgE. CD27/CD70 interaction enhanced B cell proliferation in the presence of IL-4 or IL-4 plus anti-CD40. The augmentation of B cell proliferation by CD70 transfectants was apparent in CD27+ B cells, but was mild in CD27- B cells. The helper activity for IgE synthesis by the CD27/CD70 interaction did not contribute to the enhancement of germline epsilon transcripts. Flow cytometric and morphological analyses demonstrated that the addition of CD70 transfectants to B cell cultures remarkably promoted differentiation into plasma cells in the presence of IL-4 and CD40 signaling. Finally, CD27 cross-linking resulted in the up-regulation of positive regulatory domain I-binding factor-1. Taken together, our findings indicate that signaling via CD27 on B cells induces IgE synthesis, in cooperation with IL-4 and CD40 signaling, by promoting the generation of plasma cells through up-regulation of positive regulatory domain I-binding factor-1.

Adult↗
PubMed1998

1a-docosahexaenoyl mitomycin C: a novel inhibitor of protein tyrosine kinase.

A series of derivatives of mitomycin C conjugated with various fatty acids at position 1a was synthesized and the effect of these compounds on protein kinase activities was evaluated. 1a-Docosahexaenoyl mitomycin C (DMMC) selectively inhibited protein tyrosine kinase (PTK) activity in the postnuclear fraction of v-src-transformed NIH 3T3 cells although neither derivatives conjugated with other fatty acids or docosahexaenoic acid or mitomycin C did not. DMMC inhibited the activity of calmodulin-dependent kinase III and protein kinase A very weakly, and only barely affected protein kinase C activity. DMMC also attenuated autophosphorylation of immunoprecipitated p60v-src irreversibly. The addition of thiol compounds to the reaction mixture reversed the inhibition by DMMC, suggesting that some thiol moiety of PTK protein might be involved. DMMC also inhibited kinase activity of p210bcr-abl immunoprecipitated from the lysate of K562 cells. These results indicate that DMMC is a novel inhibitor of PTK.

3T3 Cells↗
PubMed1998

Increased expression of CD44v6 mRNA significantly correlates with distant metastasis and poor prognosis in gastric cancer.

Expression of CD44 and its variants is associated with clinically aggressive behavior of some human cancers. The present study was undertaken to determine the expression level of these CD44 mRNAs in relation to the clinicopathologic features and prognosis of gastric cancer. Using reverse transcription polymerase chain reaction followed by Southern blotting, we examined the expression of the standard and variant (v6 and v9) forms of CD44 mRNA in 73 cases of gastric cancer. We determined the ratio of mRNA expression in cancer tissue to normal tissue (T/N ratio) and evaluated the correlations of the ratio with clinico-pathologic features, tumor progression and prognosis. The expression level of the standard form of CD44 (CD44s) mRNA correlated with peritoneal dissemination only, and that of CD44v9 mRNA did not significantly correlate with any clinicopathologic factor. The expression level of CD44v6 mRNA was significantly higher in patients with lymph node metastasis and liver metastasis. In 48 curatively resected patients, the expression level of CD44v6 mRNA correlated with the site of recurrence. Furthermore, there was a significant survival advantage in patients with low expression of CD44v6 mRNA compared with those with high expression. The level of CD44v6 mRNA expression may be a potential prognostic indicator and may be useful as a predictor for distant metastasis and recurrence in patients with gastric cancer.

Adult↗
PubMed1998

Design of new inhibitors for cdc2 kinase based on a multiple pseudosubstrate structure.

New inhibitors have been designed for cdc2 kinase based on a multiple pseudosubstrate structure. The new inhibitors have three different structural components: 3,4-bis(indol-3-yl)maleimide, Ac-Cys-(Ser)-Pro-Lys-Lys-NHMe, and ethyloxy group between the two components. Inhibitory activities toward cdc2 and other protein kinases were investigated, and the compound (21) with Ac-Cys-Pro-Lys-Lys-NHMe connected with the triethylene glycol spacer exhibited the most potent inhibition with relatively high selectivity.

Binding Sites↗
PubMed1998

X-ray absorption beamline at the Mitsubishi compact storage ring.

Beamline #5 (BL#5) at the Mitsubishi compact storage ring (MELCO-SR) is a beamline designed to perform X-ray absorption experiments in the 1-5 keV energy range. MELCO-SR is a racetrack-type storage ring with compact superconducting magnets, which is operated at 600 MeV, mainly for X-ray lithography experiments. As the ring is set in a shield wall of 2 m thickness, a point just outside the shield wall of BL#5 is located at 6.8 m from the source point. A small toroidal mirror, located inside the shield wall at 3.4 m from the source, focuses the beam vertically and horizontally onto the 7.3 m point. This simple optical configuration allows us to bring the source point outside of the shield wall, and to collect about 10 mrad horizontally and maintain small footprints on the monochromator crystal. A new 'Cowan type' monochromator, located at 7.4 m from the source and selected for simplicity of design and for stability, will provide a bright high-resolution and stable X-ray beam for use in the X-ray spectroscopy of electronic materials in MELCO.

Journal Article↗
PubMed1998

Prostaglandin D2 inhibits inducible nitric oxide synthase expression in rat vascular smooth muscle cells.

Vascular smooth muscle cells (VSMCs) as well as macrophages have been shown to generate a substantial amount of NO in inflammatory vascular lesions. Prostaglandin (PG) D2 (PGD2) is produced by inflammatory cells, including mast cells and macrophages. We investigated whether PGD2 modulates NO metabolism in rat VSMCs. PGD2 at a concentration of 10(-7) mol/L or greater dose-dependently inhibited nitrite accumulation in the medium of cultured VSMCs stimulated with interleukin 1beta (IL-1beta). In a dose-response analysis of IL-1beta and nitrite accumulation, PGD2 was seen to decrease the maximal ability of VSMCs to generate NO, arguing against competition by PGD2 at cytokine receptors. Northern analysis showed that PGD2 suppresses induction of inducible NO synthase (iNOS) mRNA in IL-1beta-stimulated VSMCs, with consequent inhibition of iNOS protein expression in Western analysis. A thromboxane A2 (TXA2) analogue, U46619 (10(-5) mol/L), produced less inhibition of NO generation than did PGD2. Neither the PGI2 analog carbaprostacyclin nor PGE1 showed any inhibition. PGD2 dose-dependently inhibited NO generation despite the addition of the TXA2 antagonist SQ29548. PGJ2, delta12-PGJ2, and 15-deoxy-delta12,14-PGJ2, all metabolites of PGD2, were as potent as or slightly stronger than PGD2 in the inhibition of NO generation. These data suggest that PGD2 suppresses NO generation in VSMCs by inhibiting iNOS mRNA expression, most likely through the cascade of the PGJ2 series rather than through the TX receptor or cAMP upregulation. Such action makes it likely that PGD2 regulates NO metabolism in vascular lesions.

Animals↗
PubMed1998

Influence of absorption enhancers (bile salts) and the preservative (benzalkonium chloride) on mucociliary function and permeation barrier function in rabbit tracheas.

Effects of bile salts and benzalkonium chloride on the ciliary beat activity (frequency) and the mucociliary transport rate of tracheas, and permeabilities of 6-carboxyfluorescein (6-CF; Mw 376) and FITC-dextrans (FD-4; Mw 4300) as hydrophilic compounds through trachea were investigated for intratracheal delivery of drugs. Ciliary beat activity was measured by an in vitro photoelectric method by using excised rabbit tracheas. Transport rate was determined by an in vivo endoscopic method in rabbit tracheas. Permeation test was carried out by using excised rabbit tracheas. The ciliary beat activities and mucociliary transport rates were not significantly affected by 1, 10 and 20 mM sodium glycocholate, while they were significantly decreased by 1 and 10 mM sodium taurodeoxycholate and immediately halted after application of 20 mM taurodeoxycholate. They were not significantly affected by 0.02% of benzalkonium chloride, whereas they were completely halted by 0.05% of benzalkonium chloride. The apparent permeability coefficients (Papp) of 6-CF and FD-4 were 2.35x10(-7) and 2.22x10(-8) cm/s, respectively. One mmol of glycocholate did not significantly increase the Papp of 6-CF and FD-4, while, 10 mM of glycocholate and 1 and 10 mM of taurodeoxycholate significantly increased the Papp. Benzalkonium chloride (0.01%) did not significantly increase the Papp of 6-CF, whereas 0.03% significantly increased the Papp of 6-CF. Benzalkonium chloride (0.01 and 0.03%) slightly increased the Papp of FD-4. Therefore, sodium glycocholate may be a safe and useful absorption enhancer for intratracheal delivery of drugs.

Animals↗
PubMed1998

Orchiectomy and response to testosterone in the development of obesity in young Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats.

OBJECTIVE: Withdrawal of testosterone prevents the development of hyperglycaemia in male Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus (NIDDM), but the exact mechanism has not been established. The present studies were undertaken to examine a possible role of testosterone in the development of obesity in young OLETF rats who have not shown marked hyperphagia. METHODS: Body weight, food intake and circulating concentrations of metabolic factors including immunoreactive leptin (IRL) were measured at five weeks of age in young male OLETF rats and their lean controls, Long-Evans-Tokushima-Otsuka (LETO) rats. At six weeks of age, both LETO and OLETF rats were bilaterally orchiectomized (Orchx) and half of each group implanted with a silastic tube containing testosterone. After a three week observation period, all animals were killed and circulating concentrations of metabolic factors and the ob gene expression in retroperitoneal white adipose tissues were measured. RESULTS: Body weight and 24h food intake were already increased in OLETF rats at five weeks of age. Serum testosterone concentrations were significantly lower in OLETF rats than in LETO rats. Expression of the ob gene was significantly decreased in the retroperitoneal white adipose tissue of OLETF rats, and their serum IRL concentrations were lower. Food intake and body weight gain for three weeks after the operation were significantly lower in the Orchx group of OLETF rats than in the sham-operated group. Hyperglycaemia, accompanied by hyperinsulinaemia, was attenuated by orchiectomy in OLETF rats. Circulating IRL concentrations were significantly higher in OLETF rats than in LETO rats and decreased by orchiectomy. Testosterone supplement reversed all of the changes caused by orchiectomy in OLETF rats. In contrast, the changes, which were observed after orchiectomy in OLETF rats, were not obvious in LETO rats. CONCLUSION: The present data indicate that testosterone plays a role in the development of obesity and NIDDM in young OLETF rats, but that changes of leptin production in white adipose tissue may not be important in the development of obesity in young OLETF rats.

Animals↗
PubMed1998

A hypertensive father, but not hypertensive mother, determines blood pressure in normotensive male offspring through body mass index.

This investigation was to assess the role of genetic loading of hypertensive parents in the determination of blood pressure (BP) in their normotensive offspring. The medical check-up data from 7279 Japanese university students aged 19.22 +/- 0.01 years were analysed of which 641 students had only one hypertensive parent with or without hypertensive grandparents, and from this number 609 cases were available for the present analysis. The BP in the students having only one hypertensive parent were in the normotensive range, but was significantly higher than in those students without hypertensive relatives. Analyses of the data from the students having only one hypertensive parent revealed that systolic BP (SBP) and body mass index (BMI) were higher in the male than in the female students. In addition, there were no differences in BP and BMI between the male students with a hypertensive father and the male students having a normotensive father. However, multivariate analyses revealed that BMI was an independent predictor of SBP solely in the male students having a hypertensive father, but not in the male students having a normotensive father. Such a relationship between BMI and BP determination was not observed in the female students with one hypertensive parent. It is suggested that there are different mechanisms for the determination of BP in normotensive offspring of hypertensive parents, and genetic loading of a hypertensive father plays a critical role in the determination of BP through BMI.

Adolescent↗
PubMed1998

Genetic analysis of the epithelial sodium channel in Liddle's syndrome.

BACKGROUND: Liddle's syndrome is an autosomal inheritable disorder that causes hypertension due to excess function of sodium channel. OBJECTIVE: To analyze the DNA sequence of the amiloride-sensitive epithelial sodium channel (ENaC) in three patients who had low-renin hypertension with hypokalemia. The patients included a 24-year-old woman and her 20-year-old brother whose mother was hypertensive. The third patient was a 15-year-old girl with no family history of hypertension. METHODS: The DNA sequence of the ENaC was analyzed as follows. Venous blood samples were collected from the patients and total genomic DNA was prepared by standard methods. Specific primers were used for direct polymerase chain reaction; one set of primers for amplifying the C terminus (codon 523-638) of the , subunit of ENaC, and two sets of primers for amplifying the C terminus (codons 525-587 and 568-650) of the y subunit of ENaC. Polymerase chain reaction products were purified and subjected to direct DNA sequence analysis. RESULTS: Direct sequence analysis demonstrated the presence of a single-base substitution in one segment of the 0 subunit of ENaC, a C-T transition that changed the encoded Pro (CCC) at codon 616 to Ser (TCC) in the siblings (cases 1 and 2). In case 3, we found a missense mutation of Pro (CCC) to Leu (CTC) at codon 616. Case 3 is considered to be sporadic, since DNA sequencing of the PY motif of her parents gave normal results. CONCLUSIONS: The DNA sequences of the ENaC in three patients with Liddle's syndrome were analyzed. In one family case, we found a new missense mutation of Pro (CCC) to Ser (TCC) at codon 616 in the 0 subunit of ENaC. A genetic analysis of the amiloride-sensitive epithelial sodium channel is recommended in assessing patients with low-renin, salt-sensitive hypertension whose blood pressure is not responsive to spironolactone treatment.

Adolescent↗
PubMed1998

Up-regulation of p27Kip1 correlates inversely with anchorage-independent growth of human cancer cell lines.

We examined the correlation between anchorage-independent growth and cell cycle-related molecules using 39 human cancer cell lines. They consisted of lung-, colon-, stomach-, breast-, ovarian-, brain-, renal- and melanoma-derived cell lines. Their anchorage-independent growth ability varied, but was not clearly related to the tissue of origin. There was a tendency for the levels of cyclin D1, cyclin E, cyclin A, p27, and p21 to show a tissue-dependent expression pattern. Statistical analysis revealed an inverse correlation of the p27 level with anchorage-independent growth (r=-0.456, P<0.01). Thus, the regulation of p27 is suggested to be linked to the anchorage independence of human cancer cells.

Cell Adhesion↗
PubMed1998

Protective Effects of Iganidipine on Morphological and Functional Changes of Arteries in Hypertensive Dahl Rats.

BACKGROUND: This study was performed to examine the protective effects of iganidipine, a new water-soluble calcium antagonist, on the morphological and functional changes of arteries in Dahl salt-sensitive (Dahl-S) rats. METHODS AND RESULTS: Vehicle and iganidipine were administered orally to Dahl-S rats fed a high-salt diet (HSD) for 8 weeks. Aorta, superior mesenteric arteries (SMA), and peripheral mesenteric arteries (PMA) were examined light-microscopically or electon-microscopically. Relaxant responses of isolated aorta and SMA were recorded isometrically. In rats fed HSD, blood pressure was markedly increased. Light microscopy showed intimal and medial hypertrophy, periarteritis, and narrowed arterial lumen in the PMA. Transmission and scanning electron microscopy or light microscopy showed medical thickness in the aorta and SMA and hypertrophy of endothelial cells and dilatation of the subendothelial space only in the aorta. In the SMA, both endothelium-dependent relaxation (EDR) and endothelium-independent relaxations (EIR) were reduced to a similar extent. In the aorta, the EDR was more markedly attenuated than the EIR. Iganidipine at 3 mg/kg/day showed a 24-h sustained hypotensive effect and completely prevented the morphological and functional changes in both arteries. Iganidipine at 1 mg/kg/day, which lowered blood pressure only for several hours, decreased the injuries in PMA and aortic endothelium and moderately restored the EDR in the aorta. Iganidipine at 0.3 mg/kg/day had no effects. CONCLUSIONS: In Dahl-S rats fed an HSD, iganidipine completely prevented all the changes at a sustained-hypotensive dose and prevented the injuries of PMA and aortic endothelium and the reduction of EDR in the aorta at a nonsustained hypotensive dose. Nonhemodynamic effects of iganidipine may be partly involved in its protective effects against arterial injuries.

Journal Article↗
PubMed1998

Angiotensin-Converting Enzyme Inhibition Delays Onset of Glucosuria With Regression of Renal Injuries in Genetic Rat Model of Non-Insulin-Dependent Diabetes Mellitus.

BACKGROUND: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. METHODS AND RESULTS: Six-week-old OLETF rats were treated with the angiotensin-converting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pressure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glucosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. CONCLUSIONS: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reductions but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.

Journal Article↗