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T Inoue

Publications and source records attributed to T Inoue.

At least 793 records · Page 44Linked to original sources
PubMed1998

A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a] pyridine moiety.

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (FR167344). With this potent new lead compound in hand, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-a]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization of these new heteroaromatic derivatives revealed the detailed structure-activity relationships (SAR) around the imidazo[1, 2-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50's of 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on the pyridine moiety led to a novel pharmacophore and resulted in the identification of 99 (FR184280), whose IC50 value for human B2 receptors (0.51 nM) was comparable to that of the second-generation peptide B2 antagonist Icatibant.

Administration, Oral↗
PubMed1998

Dehydration of Hydrated Bilayer of Dipalmitoylphosphatidylcholine Caused by Beryllium Ion: Evidence from a Differential Scanning Calorimetry of Bilayer Phase Transition.

The effect of polyvalent metal ions Be2+, Mg2+, Ca2+, Sr2+, Ba2+, and La3+ on the phase transition behavior of hydrated bilayer of dipalmitoylphosphatidylcholine (DPPC) was investigated by differential scanning calorimetry (DSC) in relation to their ability to induce the aggregation of DPPC vesicles. The addition of the metal ions other than Be2+ provided DSC thermograms characteristic to a fully hydrated DPPC bilayer. By the addition of Be2+, the endothermic peak associated with the bilayer phase transition was shifted to that corresponding to partially dehydrated DPPC bilayer, which was reported by Kodama et al. (Biochem. Biophys. Acta 689, 567, 1982). This demonstrates that Be2+ causes dehydration of DPPC head group in hydrated bilayer and supports the speculation that the unusual property of Be2+ to induce the aggregation of PC vesicles is attributed to the destruction of repulsive hydration force due to the partial dehydration of vesicular surface. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Solid-Liquid Phase Behavior of Binary Mixture of Tetraethylene Glycol Decyl Ether and Water.

Solid-liquid phase behavior of binary mixture of nonionic surfactant, tetraethylene glycol decyl ether (C10E4), and water was examined by means of differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), polarized optical microscopy (POM), and visual observation in the temperature range -40-70 degreesC. The DSC experiments allowed us to determine many phase boundaries among various phases appearing in this mixture system, including mesomorphic phases. The T-X phase diagram for fluid phases of C10E4/H2O mixture constructed from the results of DSC and visual observation was in good agreement with that previously reported by Lang and Morgan for the same mixture system except for the occurrence of a dilute lamellar phase (Lang, J. C. and Morgan, R. D., J. Chem. Phys., 73, 5849 (1980). The FT-IR spectra obtained for the mixture in a solid state demonstrated that the phase compound expressed by C10E4 . 6H2O is formed in the solid phase, which indicates that there is a strong interaction in the solid state between water and the hydrophilic polyoxyethylene chain of the surfactant. The FT-IR results also suggested that the strength of the hydrogen bond between water and the polyoxyethylene chain of C10E4 differs among the phase states of the mixture, and increases in the order L2 < L1 < Lalpha approximately H1 < solid, where L2 refers to the inverted micellar phase, L1 the normal micellar phase, Lalpha the lamellar phase, and H1 the normal hexagonal phase. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Phase Behavior of Aqueous Mixtures of Some Polyethylene Glycol Decyl Ethers Revealed by DSC and FT-IR Measurements.

Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR) were used to investigate the phase behavior of aqueous binary mixtures of three polyoxyethylene type nonionic surfactants, penta-, hexa-, and octaethylene glycol decyl ethers (C10E5, C10E6, and C10E8, respectively) in the temperature range -40-70 degreesC. Many thermotropic transitions among various phases assumed by these mixture systems, including mesomorphic phases, were detected in DSC thermograms, from which the T-X phase diagrams were constructed with the aid of polarized optical microscopic observation to characterize the mesomorphic phases. It was revealed by FT-IR measurements that the phase compounds are formed in a solid phase between these surfactants and water molecules; the compositions of the compounds for the three surfactant species are expressed as C10E5 . 10H2O, C10E6 . 12H2O, and C10E8 . 16H2O, respectively. The stoichiometry of the phase compounds clearly demonstrates that just two water molecules are bound per oxyethylene unit of polyoxyethylene (POE) chain of the surfactants in the solid phase, probably due to the hydrogen bonding. It was also found that the phase state of the mixture is reflected in the wavenumber of the absorption maximum associated with the OH stretching vibration, nuOH, although no significant difference was appreciable in nuOH among mesomorphic phases. The nuOH decreased in the order L (liquid phase) > H1 (normal hexagonal phase) approximately V1 (normal cubic phase) approximately Lalpha (lamellar phase) > solid phase, which indicates that the hydrogen bonding between water and the POE chain of the surfactants becomes stronger in the sequence liquid < mesophase < solid. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Direct association of YY-1 with c-Myc and the E-box binding protein in regulation of glycophorin gene expression.

We previously reported that YY-1, a versatile transcription factor, regulates expression of glycophorin gene by binding to its locus control region-like region (Gp-LCR) in combination with E-box binding protein during murine erythroleukemia (MEL) cell differentiation. In the present work, we demonstrated that YY-1 and c-Myc, a nuclear oncoprotein, were physically associated in vivo and that down regulation of c-Myc liberated free YY-1 from its complex, resulting in the functional binding of YY-1 to the Gp-LCR. We also showed that the E-box binding protein (EBP) which bound to E-box was physically associated with YY-1, facilitated binding of YY-1 to the neighboring site and their combinatorial binding may stimulate the GpLCR mediated enhancement of erythroid-specific transcription of glycophorin gene in MEL cells.

Animals↗
PubMed1998

Inhibitory effect of pentachlorophenol on gap junctional intercellular communication in rat liver epithelial cells in vitro.

To understand the initiating/promoting actions of pentachlorophenol (PCP), a non-mutagenic hepatocarcinogen, and its metabolite, tetrachlorohydroquinone (TCHQ), we investigated the effects of each chemical on gap junctional intercellular communication (GJIC) in rat liver epithelial cells (WB cells) by the scrape-loading and dye transfer method. After treatment with PCP, the GJIC was initially inhibited at 4 h but was restored in 6-8 h, followed by a second phase of inhibition between 16 and 24 h. Both the first and second inhibitions were concentration-dependent and were restored by 2-4 h after removal of PCP. The phosphorylation state of connexin 43 (CX43) and its localization on the plasma membrane were unchanged up to 24 h after treatment; however, this was accompanied by a decrease in the CX43 protein level. No inhibitory effect was apparent on the GJIC of cells treated with TCHQ. These results suggest that PCP may play a critical role of promoting activity via non-mutagenic mechanisms.

Animals↗
PubMed1998

Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry.

Signaling molecules such as Activin, Sonic hedgehog, Nodal, Lefty, and Vg1 have been found to be involved in determination of left-right (L-R) asymmetry in the chick, mouse, or frog. However, a common signaling pathway has not yet been identified in vertebrates. We report that Pitx2, a bicoid-type homeobox gene expressed asymmetrically in the left lateral plate mesoderm, may be involved in determination of L-R asymmetry in both mouse and chick. Since Pitx2 appears to be downstream of lefty-1 in the mouse pathway, we examined whether mouse Lefty proteins could affect the expression of Pitx2 in the chick. Our results indicate that a common pathway from lefty-1 to Pitx2 likely exists for determination of L-R asymmetry in vertebrates.

Animals↗
PubMed1998

Reduced susceptibility to collagen-induced arthritis in mice deficient in IFN-gamma receptor.

Collagen-induced arthritis (CIA) is an arthritic model that was developed after immunization with type II collagen (CII). Apparently, contradictory results have been reported regarding the role of IFN-gamma in the development of CIA. Therefore, we employed IFN-gamma R-deficient mice to study the role of IFN-gamma. To introduce the CIA susceptibility gene (H-2q), IFN-gamma R-deficient (H-2b/b/IFN-gamma R-/-) mice were mated with DBA/1 (H-2q/q/IFN-gamma R+/+) mice; next, the F1 mice were interbred to yield F2 offspring bearing different combinations of H-2 (H-2q/q, H-2q/b, and H-2b/b) and IFN-gamma R (IFN-gamma R+/+, IFN-gamma R+/-, and IFN-gamma R-/-) genes. Although the H-2q allele appeared to confer susceptibility to CIA, mice that were homozygous for the IFN-gamma R mutation showed a substantially decreased incidence and severity of CIA. The CII-specific IgG levels of serum samples, which are known to be involved in the development of CIA, were remarkably reduced in IFN-gamma R-/- mice. Furthermore, the anti-CII IgG2a levels controlled by IFN-gamma R were significantly reduced in IFN-gamma R-/- F2 mice compared with those seen in IFN-gamma R+/+ and IFN-gamma R+/- mice, although the levels of all IgG subclass Abs examined were lower in IFN-gamma R-/- mice than in IFN-gamma R+/+ mice. No clear evidence of the imbalance of Th1/Th2 cytokines was observed in CII-immunized, IFN-gamma R-deficient mice. Taken together, these results suggest that IFN-gamma exacerbates CIA by affecting, at least, levels of CII-specific IgG Ab rather than the imbalance of Th1/Th2 cells.

Animals↗
PubMed1998

Crystallization in Polyamide 6/Polysulfone Blends: Effect of Polysulfone Particle Size.

By reactive blending of polyamide 6 (PA) with polysulfone (PSU) using a gram-scale mixer (Mini-Max Molder), we prepared a series of PA/PSU (80/20 wt.ratio) with various diameters of PSU particles: 90 nm by using phthalic anhydride-terminated PSU (PSU-PhAH), 0.2 µm by carboxylic acid-grafted PSU (PSU-COOH), and 1.0 µm by nonreactive PSU (nf-PSU). Isothermal crystallization was carried out at 200 degreesC. Light scattering studies showed that spherulites in the blends can grow to more than 10 µm in diameter, as in the case of neat PA. It suggests that crystal growth in the radial direction can be achieved by circumventing the PSU obstacles; i.e., it does not matter how big or small they are in the range of 90 nm to 1 µm. The smaller the PSU particles, the slower was the overall rate of crystallization. The slower rate may be caused by the higher population of brush PA chains attached to PSU particles as block or graft chains, since the brushes may be hard to organize into crystal lamellae, compared with free chains. The blends showed rather broad wide-angle X-ray diffraction profiles. The smaller the PSU particles, the broader was the profile. The scattering from the particles themselves should appear only at extremely low angles (<0.1 degrees) and hardly affects the wide-angle X-ray profiles so that the results may imply that the presence of smaller PSU particles renders the less perfection of the PA crystal. This may be caused also by the higher population of brush chains. Note that the brush chains are formed only in the reactive systems and the population may be higher in the smaller particle systems. Even for the blend with smallest particle size, a small-angle X-ray scattering peak appeared at a magnitude of scattering vector of approximately 0.8 nm-1, suggesting the evolution of interlamellar spacing of 8.7 nm. However, the scattering profile was much broader than that of neat PA. It implies a less ordered lamellar stacking in the blend.

Journal Article↗
PubMed1998

Type 1 inositol 1,4,5-trisphosphate receptor is required for induction of long-term depression in cerebellar Purkinje neurons.

The inositol 1,4,5-trisphosphate receptor (InsP3R) is an intracellular Ca2+ channel that releases Ca2+ from internal Ca2+ stores in response to InsP3. Although InsP3R is highly expressed in various regions of the mammalian brain, the functional role of this receptor has not been clarified. We show here that cerebellar slices prepared from mice with a disrupted InsP3R type 1 gene, which is predominantly expressed in Purkinje cells, completely lack long-term depression (LTD), a model of synaptic plasticity in the cerebellum. Moreover, a specific antibody against InsP3R1, introduced into wild-type Purkinje cells through patch pipettes, blocked the induction of LTD. These data indicate that, in addition to Ca2+ influx through Ca2+ channels on the plasma membrane, Ca2+ release from InsP3R plays an essential role in the induction of LTD, suggesting a physiological importance for InsP3R in Purkinje cells.

Animals↗
PubMed1998

Cell density-dependent regulation of fibronectin splicing at the EDA region in fibroblasts: cell density also modulates the responses of fibroblasts to TGF-beta and cancer cell-conditioned medium.

Recently we reported that cancer cell-fibroblast interactions can modulate the expression of fibronectin (FN) isoforms in vitro, i.e. conditioned medium of human rectal adenocarcinoma cell line RCM-1 (RCM-1 CM) stimulated the expression of EDA-containing FN (EDA(+)FN) mRNA by fibroblasts and this stimulation was partly mediated by transforming growth factor-beta (TGF-beta) included in RCM-1 CM. In the present study, cell density was shown to regulate FN splicing at the EDA region in fibroblasts. Fibroblasts plated at a low cell density expressed a significantly higher percentage of EDA(+)FN mRNA than those plated at a high cell density. Moreover, fibroblast cell density modulated the effects of TGF-beta and RCM-1 CM on FN splicing at the EDA region differently. The time courses of their effects were similar to each other at a high cell density. At a low cell density, however, they were different. TGF-beta showed a relatively short-lived stimulation of EDA(+)FN mRNA, with the peak response 24 h after treatment, followed by a decline to the base line by 72 h. On the other hand, RCM-1 CM caused a prolonged stimulation, maintaining almost the maximum responses from 24 to 72 h. Thus, these results at a low cell density indicated the presence of a factor(s) other than TGF-beta in RCM-1 CM that stimulates the expression of EDA(+)FN mRNA directly or modulates the effect of TGF-beta. The use of several different cell densities might help in the search for new factors affecting FN splicing.

Adenocarcinoma↗
PubMed1998

Factors affecting mandibular complications in low dose rate brachytherapy for oral tongue carcinoma with special reference to spacer.

PURPOSE: To evaluate the efficacy of a spacer in the prevention of mandibular complications in low dose rate (LDR) brachytherapy (BRT) for oral tongue carcinoma. METHODS AND MATERIALS: A retrospective analysis was conducted using 103 patients with T1 or T2 tongue carcinoma treated by a single plane implantation of iridium (192Ir) pins between 1979-1994. Of these patients, 60 were treated by BRT alone, and the rest were combined with external irradiation (Ext) and/or chemotherapy (CHT). Forty-eight and 55 patients were given BRT with and without a spacer, respectively. Spacers were individually made of acrylic resin according to a prosthetic technique so as to obtain the thickness of 7-10 mm at the lingual part of the implanted side. Variables, including a spacer, which may be associated with the development of osteoradionecrosis (ORN) of the mandible, were analyzed by the Cox proportional hazards regression analysis. RESULTS: Our spacer reduced about 50% of the absorbed dose at the lingual side surface of the lower gingiva (LSG) to that in the absence of a spacer. Absolute incidence of ORN was 2.1% (1 of 48) and 40.0% (22 of 55), with and without a spacer, respectively, and the difference was statistically significant by univariate analysis (p = 0.0004). It was revealed by the Cox analysis that the spacer (p = 0.0247), combined CHT (p = 0.0295), and combined Ext (p = 0.0279) were significant independent factors associated with the development of ORN. The spacer was shown to be a significant factor by univariate analysis (p = 0.0037), but not by multivariate analysis when analysis was restricted to the patients who did not receive CHT. The absorbed dose, dose rate, and biological effective dose (BED) reflecting early or late response were estimated at the LSG, and prognosticators associated with the incidence of ORN were also determined by the Cox analysis. Particularly, BED for late response by BRT, the total absorbed dose, and any BED by Ext plus BRT were highly significant factors in the whole population. Essentially similar results were obtained in the patients without receiving CHT. CONCLUSIONS: It was clarified that our spacer effectively prevents mandibular complications in LDR BRT by 192Ir for oral tongue carcinoma. Furthermore, introduction of a spacer provided novel information concerning the development of ORN, where BED particularly for late response given by BRT, the total absorbed dose, and any BED by Ext plus BRT could be good prognostic factors only when estimated at the LSG.

Adult↗
PubMed1998

Changes in tumor marker levels as a predictor of chemotherapeutic effect in patients with gastric carcinoma.

BACKGROUND: Evaluating chemotherapeutic effect in patients with gastric carcinoma sometimes is difficult. The authors investigated whether changes in the serum levels of three tumor markers can be used to predict the clinical outcome after chemotherapy. METHODS: Thirty patients with advanced and recurrent gastric carcinoma were treated with continuous 5-fluorouracil and low dose cisplatin for 4 weeks. Thirteen patients were treated neoadjuvantly prior to gastrectomy. The serum levels of carcinoembryonic antigen, carbohydrate antigen 19-9, and sialyl-Tn antigen were measured prior to and after chemotherapy. Responders were defined as those in whom abnormal serum levels of all three markers decreased to at least 50% of the pretreatment values and remained stable for at least 1 month. RESULTS: The tumor markers could be evaluated in 27 of 30 patients (90%). The median duration of survival for the 15 responders and 12 nonresponders was 17 months and 6 months, respectively. There was a significant difference in the median duration of survival between the responders and nonresponders using the log rank test (P=0.0005). In the patients who received neoadjuvant therapy, the eight responders had a significantly longer survival period than did the three nonresponders (P=0.018). Seven of the eight responders showed evidence of tumor destruction histologically whereas none of the three nonresponders did. CONCLUSIONS: Changes in the serum levels of these tumor markers after chemotherapy may be an excellent prognostic indicator for patients with gastric carcinoma.

Adult↗
PubMed1998

Lower expression of neutrophil adhesion molecule indicates less vessel wall injury and might explain lower restenosis rate after cutting balloon angioplasty.

BACKGROUND: The Cutting Balloon is a novel dilatation catheter for coronary angioplasty (InterVentional Technologies Inc). It produces longitudinal, microsurgical incisions in the vessel wall before the actual dilatation. It is assumed that these controlled surgical incisions relieve hoop stress and reduce vessel wall injury and eventually restenosis. However, no clinical indicator to support the theory of reduced injury has been described. Certain clusters of differentiation (eg, CD11, CD18 on the leukocytes) are implicated in leukocyte adhesion, increased permeability, and opsonization. Therefore, they might serve as clinical indicators of the injury level of the vessels after angioplasty. METHODS AND RESULTS: We randomly selected 64 patients with isolated left anterior descending coronary artery disease for either Cutting Balloon angioplasty or conventional balloon angioplasty. The expression of CD18 and CD11b on the surface of neutrophils was determined by flow cytometric analysis. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) were also measured. The expression of both the CD18 and CD11b in the coronary sinus blood gradually increased and reached its maximum at 48 hours after angioplasty. The sICAM-1 levels in the coronary sinus serum also increased after angioplasty. Percentage increases of CD18 and CD11b expression and the increase of the sICAM-1 levels at 48 hours after angioplasty (as ratios to baseline values before angioplasty) were less in the Cutting Balloon angioplasty group than in the conventional balloon angioplasty group (CD18, 1.10+/-0.05 versus 1.31+/-0.05, P<0.05; CD11b, 1.23+/-0.06 versus 1.72+/-0.10, P<0.001; sICAM-1, 1.12+/-0.05 versus 1.25+/-0.02, P<0.05). In all patients, the late lumen loss at follow-up angiogram positively correlated with the increased levels of CD11b (R=0.59, P<0.001) and sICAM-1 (R=0.38, P<0.05) at 48 hours after angioplasty. CONCLUSIONS: Balloon angioplasty upregulated Mac-1 (CD11b/CD18) on the surface of the neutrophils and increased sICAM-1 levels in association with late loss increase. These changes were significantly smaller in the Cutting Balloon angioplasty group than in the conventional balloon angioplasty group. This suggests that Cutting Balloon angioplasty may produce less vessel wall injury and, consequently, less neutrophil activation, which may account for the lower rate of restenosis.

CD18 Antigens↗
PubMed1998

Prepulse facilitation of auditory startle response in hamsters.

A visual prepulse was applied just before a burst of white noise with various lead intervals ranging from 50 to 400 ms in hamsters. After habituation each hamster received 120 trials of the auditory noise with or without the prepulse. Amplitude of startle response increased significantly at 100 ms and 200 ms (n = 10). This enhancement disappeared in blind controls (n = 6). The amplitude of startle response decreased during exploratory behavior, grooming, sniffing or other movements. However, the facilitatory effects of the visual prepulse were consistent, regardless of the animal's behavioral states, except sniffing. The authors conclude that visual prepulse task is useful for studying the ability to detect visual signals in hamsters, and that further study is necessary to elucidate the factors affecting the enhancement of startle response in hamsters.

Acoustic Stimulation↗
PubMed1998

Spontaneous regeneration of the pyramidal tract after transection in young rats.

Spontaneous regeneration of the pyramidal tract after transection of the medullary pyramid was examined in young rats by the anterograde tracing method with wheat germ agglutinin-conjugated horseradish peroxidase. Care was taken to cut the tract as sharply as possible to minimize traumatic injuries. A very sharp cut produced edema-free lesions without subsequent formation of either cysts or scars, whereas a relatively blunt cut produced edema and later scars and/or cysts in the lesion. Regenerated projections in the latter cases were sparse, short, dispersed and largely aberrant as described in previous reports. By contrast, regenerated projections in the former cases were very much similar to normal in various respects: the amount, extension, path, formation of a compact bundle and termination. There was, however, a decisive difference from normal, that is, the additional aberrant projections.

Age Factors↗
PubMed1998

Rapid development of nitric oxide-induced hyperalgesia depends on an alternate to the cGMP-mediated pathway in the rat neuropathic pain model.

Intrathecal injection of a nitric oxide releasing compound, NOC-18, was used to define the role of nitric oxide (NO) in the spinal mechanism of neuropathic pain caused by unilateral chronic constriction injury to rat sciatic nerves. Paw withdrawal latency was used to evaluate nociception induced by thermal stimuli before surgery and afterwards at 1, 3, and 6 h, and on days 1, 2, 3, 4, 5, 8, and 12 after the nerve ligature. In the sham-surgery control groups, intrathecal injection of 10 or 100 microg of NOC-18 did not produce any change in withdrawal latencies. In rats with unilateral nerve ligation, however, administration of 1 or 10 microg, but not 0.1 microg, of NOC-18 significantly shortened the time in which thermal hyperalgesia developed after nerve injury. Injection of 1 microg of NOC-18 decreased the onset time of thermal hyperalgesia from 2 days to 3 h and with 10 microg hyperalgesia developed within 1 h after the nerve injury. The effects of intrathecal injection of MK-801, a N-methyl-D-aspartate (NMDA) receptor antagonist, N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, methylene blue (MB), a soluble guanylate cyclase inhibitor, and hemoglobin (Hb), a NO scavenger, on the development of thermal hyperalgesia after the sciatic nerve ligature were examined in the presence and absence of 1 and 10 microg of NOC-18. Acceleration of the development of thermal hyperalgesia induced by 1 and 10 microg NOC-18 was completely inhibited by Hb, but was not affected by either MK-801, L-NAME or MB. These findings indicate that NO plays an important role in the rapid development of thermal hyperalgesia after the nerve injury, but that facilitation of nociceptive processing in the spinal cord may entail an alternate to the NO-cyclic guanosine 3',5'-monophosphate (cGMP) pathway.

Animals↗