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Biomedical subjects

T Kataoka

Publications and source records attributed to T Kataoka.

At least 91 records · Page 5Linked to original sources
PubMed1998

Cholesterol-lowering effects of psyllium seed associated with urea metabolism.

Twenty-eight mild hypercholesterolemic male and female adults were orally administered psyllium seed for 3 months. After psyllium treatment, the serum total cholesterol, low-density-lipoprotein-cholesterol and atherogenic index significantly decreased, but levels of high-density-lipoprotein-cholesterol, triglyceride and urea nitrogen did not. To determine the parameters associated with the cholesterol-lowering effect in the subjects' backgrounds, both biochemical and hematological parameters, we statistically examined the correlation between pretreatment parameters and the absolute change of total cholesterol level. The absolute change of total cholesterol level showed a direct correlation with the triglyceride level at pretreatment (r=0.41, P=0.03) and had an inverse correlation with urea nitrogen level (r=-0.46, P=0.01) but not with the total cholesterol level (r=-0.18). The change in urea nitrogen level had an inverse correlation with the urea nitrogen level itself at pretreatment (r=-0.82, P=7 x 10[-8]) and had a direct correlation with the triglyceride level (r=0.43, P=0.02). The change in triglyceride level had an inverse correlation with the urea nitrogen level (r=-0.48, P=0.008). Furthermore, the change in total cholesterol level had direct correlations with changes in the triglyceride level (r=0.56, P=0.002) and the urea nitrogen level (r=0.51, P=0.006), but these changes in triglyceride and urea nitrogen level did not correlate significantly. These findings suggest the close association of urea nitrogen and lipid metabolism in hyperlipidemia and psyllium seed treatment.

Adult↗
PubMed1998

Serotonin 5-HT4 receptor agonistic activity of the optical isomers of (+/-)-4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide.

The enantiomers, (R)-(-)-1 and (S)-(+)-1, of (+/-)-4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide [(+/-)-1] were prepared from optically active benzyl 4-acetylamino-2,3-dihydro-2-methylbenzo[b]furan-7-carboxylate [(R)-(+)-6, (S)-(-)-6], respectively. The requisite (R)-(+)-6 and (S)-(-)-6 were prepared by large-scale preparative HPLC on chiral stationary phases (CSPs). The absolute configuration of (S)-(+)-1 was determined by single crystal X-ray analysis. The serotonin 5-HT4 receptor agonistic activity of (S)-(-)-1 hemifumarate (SK-951) which was hemifumarate of (S)-(+)-1 was about twice that of the other enantiomer (R)-(+)-1 hemifumarate which was hemifumarate of (R)-(-)-1.

Animals↗
PubMed1998

Synthesis and muscarinic activity of a series of quinolines and naphthalenes with a 1-azabicyclo[3.3.0]octane moiety.

In order to discover a medicine effective against Alzheimer's disease, we synthesized a series of quinoline derivatives having a characteristic 1-azabicyclo[3.3.0]octane amine ring, and performed pharmacological evaluation of them. Acetylcholine esterase inhibitory activities of these derivatives were unexpectedly weak. Tests for central nervous muscarinic cholinergic receptor binding affinity indicated that these compounds had higher affinities to muscarinic M1 receptors than to M2 receptors. A series of naphthalene derivatives substituted with the 1-azabicyclo[3.3.0]octane ring were also synthesized and muscarinic M1 and M2 receptor binding affinity determined. These compounds had much higher affinity for M1 receptors than the quinoline derivatives, and 1-[N-(1-azabicyclo[3.3.0]octan-5-yl)methyl-N-methylamino]-4-nitronaph tha lene showed the highest affinity and selectivity. The ability of this compound to improve cognitive function was assessed using the passive avoidance test in scopolamine-induced mice.

Animals↗
PubMed1998

Synthesis and structure-activity relationship of 3-Substituted benzamide, benzo [b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-77-carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5-HT4 receptor agonists.

The title compounds (6-9) were prepared and evaluated for serotonin 5-HT4 agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b]furan skeleton and 2,3-dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2-methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dimethylbenzo[b]furan-7-carboxamide (8d) hemifumarate were more potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D1, D2, serotonin 5-HT1, 5-HT2 and muscarine M1, M2 receptor binding activity in the in in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.

Animals↗
PubMed1998

Selective induction of interleukin-1 production and tumor killing activity of macrophages through apoptosis by the inhibition of oxidative respiration.

Suppression of mitochondrial respiration and increased glycolysis are characteristic features of activated macrophages. We show here that antimycin A, a respiratory inhibitor, induced interleukin-1 synthesis and tumoricidal activity without inducing tumor necrosis factor or nitric oxide. The induction of tumoricidal activity was resistant to inhibitors of tyrosine-specific protein kinases and intracellular glycoprotein transport. The cognate interaction between macrophages and target cells was not a prerequisite for the tumoricidal activity. In contrast, lipopolysaccharide induced the production of interleukin-1, tumor necrosis factor and nitric oxide, the induction of tumoricidal activity being sensitive to genistein and brefeldin A. Antimycin A, like lipopolysaccharide, induced the release of a cytoplasmic enzyme and apoptosis of macrophages. Antimycin A showed anti-metastatic activity in vivo. These results suggest that the inhibition of oxidative respiration would induce apoptosis and the resultant release of soluble effector molecules of macrophages which inhibit tumor metastasis in vivo.

Animals↗
PubMed1997

Membrane recruitment of Raf-1 is not the only function of Ras in Raf-1 activation.

Ras interacts with Raf-1 and stimulates its kinase activity, which results in activation of the mitogen-activated protein (MAP) kinase cascade. It has been proposed that the main function of Ras in Raf-1 activation is to recruit Raf-1 to the plasma membrane, where a separate activation event such as phosphorylation takes place. Here, we examined the activities of various mutants of human Ha-Ras to induce membrane translocation of Raf-1 and to activate Raf-1 in vivo. Overexpression of an activator region mutant Ha-Ras(V45E) in COS7 cells induced membrane translocation of Raf-1 as effectively as wild-type Ha-Ras. However, the activity of this mutant to activate Raf-1 and extracellular signal-regulated kinase-2 (ERK2) was attenuated by approximately 70% compared to that of wild-type Ha-Ras. The decrease in the specific activity was further demonstrated by measuring the activity of the Ha-Ras(V45E)-associated Raf-1 purified from the membrane fraction. These results imply that the association of Ras with Raf-1 has another important consequence, presumably dependent on the interaction between its activator region and Raf-1, than the simple recruitment of Raf-1 to the plasma membrane.

Animals↗
PubMed1997

Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with ras-dependent activation of Raf-1.

Raf-1 is a major downstream effector of mammalian Ras. Binding of the effector domain of Ras to the Ras-binding domain of Raf-1 is essential for Ras-dependent Raf-1 activation. However, Rap1A, which has an identical effector domain to that of Ras, cannot activate Raf-1 and even antagonizes several Ras functions in vivo. Recently, we identified the cysteine-rich region (CRR) of Raf-1 as another Ras-binding domain. Ha-Ras proteins carrying mutations N26G and V45E, which failed to bind to CRR, also failed to activate Raf-1. Since these mutations replace Ras residues with those of Rap1A, we examined if Rap1A lacks the ability to bind to CRR. Contrary to the expectation, Rap1A exhibited a greatly enhanced binding to CRR compared with Ha-Ras. Enhanced CRR binding was also found with Ha-Ras carrying another Rap1A-type mutation E31K. Both Rap1A and Ha-Ras(E31K) mutant failed to activate Raf-1 and interfered with Ha-Ras-dependent activation of Raf-1 in Sf9 cells. Enhanced binding of Rap1A to CRR led to co-association of Rap1A and Ha-Ras with Raf-1 N-terminal region through binding to CRR and Ras-binding domain, respectively. These results suggest that Rap1A interferes with Ras-dependent Raf-1 activation by inhibiting binding of Ras to Raf-1 CRR.

Amino Acid Sequence↗
PubMed1997

Association of elongation factor 1 alpha and ribosomal protein L3 with the proline-rich region of yeast adenylyl cyclase-associated protein CAP.

CAP is a multifunctional protein; the N-terminal region binds adenylyl cyclase and controls its response to Ras while the C-terminal region is involved in cytoskeletal regulation. In between the two regions, CAP possesses two proline-rich segments, P1 and P2, resembling a consensus sequence for binding SH3 domains. We have identified two yeast proteins with molecular sizes of 48 and 46 kDa associated specifically with P2. Determination of partial protein sequences demonstrated that the 48-kDa and 46-kDa proteins correspond to EF1 alpha and rL3, respectively, neither of which contains any SH3-domain-like sequence. Deletion of P2 from CAP resulted in loss of the activity to bind the two proteins either in vivo or in vitro. Yeast cells whose chromosomal CAP was replaced by the P2-deletion mutant displayed an abnormal phenotype represented by dissociated localizations of CAP and F-actin, which were colocalized in wild-type cells. These results suggest that these associations may have functional significance.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Synergistic activation of c-fos promoter activity by Raf and Ral GDP dissociation stimulator.

Ral, a member of small GTP-binding protein (G protein) superfamily, has been suggested to act downstream of Ras, since Ral GDP dissociation stimulator (RalGDS) has been found to be an effector protein of Ras. In this study, we examined the effects of RalGDS and Ral on gene expression using c-fos promoter linked to the luciferase reporter gene (c-fos-luciferase). RalGDS interacted with RasG12V/E37G (in which Gly-12 and Glu-37 were changed to Val and Gly, respectively) which failed to bind to Raf in COS cells. RafCAAX is an active Raf kinase targeted to the plasma membranes by virtue of the addition of a C-terminal localization signal from K-Ras. Transfection of either RalGDS or RafCAAX into NIH3T3 cells slightly stimulated c-fos-luciferase expression and cotransfection of both proteins greatly enhanced the expression. RalGDS and an activated Rac (RacG12V) did not act synergistically to stimulate c-fos-luciferase expression. Transfection of an activated Ral (RalG23V) stimulated c-fos-luciferase expression. Furthermore, cotransfection of RalG23V and an activated Ras (RasG12V) enhanced RasG12V-dependent c-fos-luciferase expression. However, RalG23V did not synergize with RafCAAX, RacG12V or RalGDS to stimulate the expression. These results show that RalGDS and Ral regulate c-fos promoter activity and suggest that RalGDS may activate c-fos promoter synergistically with the signal from Raf by transmitting the signal to a target other than Ral.

3T3 Cells↗
PubMed1997

Characterization of a series of vacuolar type H(+)-ATPase inhibitors on CTL-mediated cytotoxicity.

Four vacuolar type H(+)-ATPase (V-ATPase) inhibitors, i.e. concanamycin A (CMA), bafilomycin A1 (BMA), destruxin E (DRE) and prodigiosin 25-C (PRG) profoundly blocked the perforin-dependent cytotoxicity mediated by CD8+ CTL clone. Cytoplasmic acidic compartments were not detected under fluorescent microscopy after treatment of the cells with these V-ATPase inhibitors. In the lytic granule fractions, BMA, CMA, DRE and PRG completely abrogated the perforin activity, although these drugs slightly decreased the granzyme A activity. Under the same conditions, BMA and CMA markedly reduced the perforin content, while DRE and PRG had no significant effects as assayed by immunoblotting using anti-perforin antibody. These data suggest that perforin is predominantly inactivated even without proteolysis in DRE- or PRG-treated cells. We propose that acidic pH is essential to maintain not only quantity but also quality of perform in the lytic granules.

Animals↗
PubMed1997

TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB.

TRAIL induces apoptosis through two closely related receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Here we show that TRAIL-R1 can associate with TRAIL-R2, suggesting that TRAIL may signal through heteroreceptor signaling complexes. Both TRAIL receptors bind the adaptor molecules FADD and TRADD, and both death signals are interrupted by a dominant negative form of FADD and by the FLICE-inhibitory protein FLIP. The recruitment of TRADD may explain the potent activation of NF-kappaB observed by TRAIL receptors. Thus, TRAIL receptors can signal both death and gene transcription, functions reminiscent of those of TNFR1 and TRAMP, two other members of the death receptor family.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Inactivation and proteolytic degradation of perforin within lytic granules upon neutralization of acidic pH.

In our recent studies, an inhibitor of vacuolar-type H(+)-ATPase, concanamycin A (CMA) has been shown to neutralize acidic pH in vacuolar organelles, including lytic granules, and to decrease the perforin content markedly. In the present paper, we have further investigated the role of acidification in perforin storage by using CMA. In CD8+ cytotoxic T-lymphocyte (CTL) clones, the amount of perforin decreased rapidly at 30-90 min but no more decrease occurred at 90-120 min after the addition of CMA. Since exposure to actinomycin D, cycloheximide, or brefeldin A failed to reduce the perforin content, the perforin decrease in CMA-treated cells seems to be largely due to a reduction in the perforin already stored in lytic granules, rather than to the inhibition of the de novo synthesis or the intracellular glycoprotein transport of perforin. Diisopropylfluorophosphoridate (DFP) markedly antagonized the decrease in the perforin content in CMA-treated cells, while other protease inhibitors, i.e. antipain, E-64, leupeptin, pepstatin A and phenylmethylsulphonyl fluoride, did not. Nevertheless, DFP hardly reversed the abrogation of the killing activity by CMA. Indeed, the lytic granules prepared from DFP plus CMA-treated cells showed only a marginal level of haemolytic activity. In cell-free experiments using perforin-enriched granule fractions, acidic pH completely blocked the perforin activity. Under the acidic conditions, perforin was more resistant to an inactivation by calcium when exposed to calcium prior to the haemolysis test. Thus, these data suggest that perforin is primarily inactivated, possibly in a calcium-dependent manner, and is subsequently hydrolysed by DFP-sensitive proteases in the lytic granules at neutral pH. We conclude that acidic pH plays an essential role to maintain the integrity of perforin within the lytic granules.

Animals↗
PubMed1997

Effect of association with adenylyl cyclase-associated protein on the interaction of yeast adenylyl cyclase with Ras protein.

Posttranslational modification of Ras protein has been shown to be critical for interaction with its effector molecules, including Saccharomyces cerevisiae adenylyl cyclase. However, the mechanism of its action was unknown. In this study, we used a reconstituted system with purified adenylyl cyclase and Ras proteins carrying various degrees of the modification to show that the posttranslational modification, especially the farnesylation step, is responsible for 5- to 10-fold increase in Ras-dependent activation of adenylyl cyclase activity even though it has no significant effect on their binding affinity. The stimulatory effect of farnesylation is found to depend on the association of adenylyl cyclase with 70-kDa adenylyl cyclase-associated protein (CAP), which was known to be required for proper in vivo response of adenylyl cyclase to Ras protein, by comparing the levels of Ras-dependent activation of purified adenylyl cyclase with and without bound CAP. The region of CAP required for this effect is mapped to its N-terminal segment of 168 amino acid residues, which coincides with the region required for the in vivo effect. Furthermore, the stimulatory effect is successfully reconstituted by in vitro association of CAP with the purified adenylyl cyclase molecule lacking the bound CAP. These results indicate that the association of adenylyl cyclase with CAP is responsible for the stimulatory effect of posttranslational modification of Ras on its activity and that this may be the mechanism underlying its requirement for the proper in vivo cyclic AMP response.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Characterization of the carrot beta-tubulin gene coding a divergent isotype, beta-2.

Four different beta-tubulin clones were isolated from carrot genomic and cDNA libraries. Their nucleotide sequences were determined 1 and their predicted amino acids were compared with each other. The predicted amino acid composition of the C-terminal region of three of them (beta-1, 3, 4) resembled one another, but that of one isotype (beta-2) was divergent. The beta-2 tubulin included two hydroxyl amino acids, serine and threonine, and consisted of a lower number of negatively charged amino acids than the others in the C-terminal region. The predicted hydrophobicity profile of the beta-2 tubulin around the residue 200 is less hydrophobic than beta-1, but it is still more hydrophobic than those of animal and fungal beta-tubulins. The beta-2 gene was transcribed in cultured cells and flowers, while the beta-1 gene was ubiquitously transcribed in cultured cells, roots, shoots and flowers. When the predicted amino acids of plant tubulin were compared with those of other organisms, substitutions from non-polar amino acids to those with hydroxyl group were conspicuous in the region corresponding to the third exon in the plant genes.

Amino Acid Sequence↗
PubMed1997

Immunosuppressive effects of gallic acid and chebulagic acid on CTL-mediated cytotoxicity.

Gallic acid (GA) and chebulagic acid (CA) were isolated from the extract of a herbal medicine, kashi (myrobalans: the fruit of Terminalia chebula) as active principles that blocked the cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. GA and CA inhibited the killing activity of CD8+ CTL clone at IC50 values of 30 microM and 50 microM, respectively. Granule exocytosis in response to anti-CD3 stimulation was also blocked by GA and CA at the equivalent concentrations.

Animals↗