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T Ichida

Publications and source records attributed to T Ichida.

At least 91 records · Page 5Linked to original sources
PubMed1995

Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats.

Heptic fibrosis/cirrhosis is a common hepatic disease characterized by the hyper-accumulation of connective tissue components, and hepatic necrosis. Chronic alcohol ingestion, viral infection, and metabolic disorders are contributing factors and there has been no effective treatment. Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is a long-sought hepatotrophic factor for liver regeneration. Administration of human recombinant HGF into rats with hepatic fibrosis/cirrhosis caused by dimethylnitrosamine (DMN) elicited mitogenic action for hepatocytes, stimulated hepatic collagenase activity, and prevented the onset and progression of hepatic fibrosis/cirrhosis. Accumulation of fibrous tissue components in the liver due to DMN-treatment were markedly decreased in HGF-injected rats. Moreover, HGF completely abrogated death caused by severe hepatic cirrhosis and dysfunction. We postulate that HGF may prove to be an effective treatment for human liver fibrosis/cirrhosis and for chronic hepatic failure.

Animals↗
PubMed1995

Functional alteration of the GABAB receptor in the brain of spontaneously hypertensive rats.

1. We studied the ontogenetic development of GABAB receptors and their coupling to cyclic AMP formation in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rat brains. GABAB receptor binding to various brain regions was compared in age-matched SHR and WKY rats. 2. The specific [3H]-GABA binding to the posterior hypothalamus (PH) was significantly lower in not only 4 week old (normotensive) but also 11 week old (hypertensive) SHR, when compared with age-matched WKY. 3. Moreover, GABAB receptor agonists (baclofen and DN-2327)-induced suppression of adenylate cyclase activity also showed a decrease in 4 week old and 11 week old SHR PH. 4. We concluded that the number and the functional responsiveness of GABAB receptors in rat brains decrease in SHR, preceding blood pressure elevation. The activity of GABABergic mechanisms may be different in the brains of SHR and WKY rats.

Adenylyl Cyclase Inhibitors↗
PubMed1995

[Effects of temperature and humidity on the stability of nitric oxide, and efficacy of soda lime as a selective absorber of nitrogen dioxide].

Although inhaled nitric oxide (NO) has attracted attention as a pulmonary vasodilator, little heed has been given to its potential toxicity. Nitric oxide is known to be rapidly oxidized to nitrogen dioxide (NO2), which may damage pulmonary tissue. We examined the effects of temperature and humidity on the production of NO2 from NO. We also evaluated the amount of NO2 absorbed by soda lime, which is usually placed in the inspiratory line. For this purpose, we measured changes over time in the concentrations of NO and NO2 in mixtures that included NO, oxygen, and nitrogen in various concentrations, and at different temperatures and humidities. We confirmed that the formation of NO2 from NO follows the equation: -d[NO]/dt = 2 k[NO]2 [O2], where k is the rate constant. We found that k was significantly smaller at 37 degrees C than at 25 degrees C but was not influenced by humidity (0%, 40% or 90%). Although soda lime was very effective in absorbing NO2 from the inspiratory line, NO was simultaneously absorbed at the same molar ratio when the two gases existed together in the line. We thus conclude that inhalation of NO at 37 degrees C is more desirable than inhalation at room temperature, to suppress the production of NO2. When soda lime is used in the inspiratory line, attention should be paid to the reduction in the concentration of NO in the line.

Absorption↗
PubMed1994

Catalytic subunit of protein kinase A induces amylase release from streptolysin O-permeabilized parotid acini.

Amylase release from parotid acinar cells is a typical model of cAMP-mediated exocytosis. To obtain unequivocal data concerning the role of cAMP-dependent protein kinase (PKA) in amylase exocytosis, we undertook the direct introduction of the PKA catalytic subunit into the parotid acini by permeabilization with streptolysin O (SLO). In the presence of 100 hemolytic units/ml SLO, cAMP increased amylase release in a time- and dose-dependent manner. PKI-(5-24)-peptide, a specific PKA inhibitor, markedly inhibited amylase release, but the extent of inhibition was approximately 50%. On the other hand, the PKA catalytic subunit highly purified from bovine hearts significantly induced amylase release. The release was strictly dependent on the presence of SLO and the catalytic activity of PKA added. The catalytic subunit dose dependently induced amylase release, but the heat-inactivated subunit had no stimulatory effect. PKI-(5-24)-peptide completely blocked amylase release evoked by the subunit. These results clearly demonstrate that the catalytic subunit of PKA regulates cAMP-mediated amylase release through phosphorylation of unidentified protein(s) directly or indirectly involved in the process of exocytosis.

Amylases↗
PubMed1994

Association and agonistic action of DN-2327, a novel isoindoline derivative, GABAB receptor in brain.

The association and action of DN-2327, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4-dioxa-8- azaspiro[4,5]dec-8-yl)carbonylmethyl]isoindolin-1-one, on the gamma-aminobutyric acid (GABA)B receptor in rat brain have been examined. DN-2327 inhibited the binding of [3H]GABA to GABAB receptor in crude synaptic membrane obtained from rat brain. The Scatchard analysis of [3H]GABA binding to GABAB receptor indicated that DN-2327 induced the decrease in affinity of both high and low affinity binding sites without changing the Bmax values. The forskolin-stimulated adenylate cyclase activity in slices from rat cerebral cortex was significantly suppressed by the addition of DN-2327. Furthermore, this inhibition by DN-2327 was eliminated by the simultaneous additions of 2-hydroxy saclofen or CGP 55845A, GABAB receptor antagonists. These results suggest that DN-2327 may have not only a high association with GABAB receptor but also an agonistic action on the receptor.

Adenylyl Cyclases↗
PubMed1994

Evidence for the involvement of protein phosphorylation in cyclic AMP-mediated amylase exocytosis from parotid acinar cells.

We evaluated the role of protein phosphorylation in cAMP-mediated amylase exocytosis from parotid acinar cells by using H89, a new protein kinase A (PKA) inhibitor, which is more lipophilic and 25 times more potent than H8. In our previous studies, H8 markedly inhibited protein phosphorylation without decreasing amylase release [Takuma, T. (1988) Biochem. J. 256, 867-871]. These findings were completely reproduced even in the small acini that were prepared by trypsin treatment before collagenase digestion. In the present study, however, H89 strongly inhibited both amylase release and protein phosphorylation in a dose-dependent manner. The inhibitory effect was specific for PKA at least up to 33 microM, since 33 microM H89 did not block amylase release stimulated by PMA. H85, a closely related compound of H89 without inhibitory effect on PKA, did not prevent amylase release or protein phosphorylation at least up to 33 microM. These results suggest that protein phosphorylation by PKA is involved in cAMP-mediated amylase exocytosis. The inhibition of protein phosphorylation by H8 might be insufficient or inadequate for blocking of amylase release.

Amylases↗
PubMed1994

Therapeutic effect of a CDDP-epirubicin-Lipiodol emulsion on advanced hepatocellular carcinoma.

Prior injection of an anticancer agent and Lipiodol mixture is a key point for the treatment of hepatocellular carcinoma (HCC). We therefore prepared a new, improved emulsion of Lipiodol containing a high dose of cis-diamminedichloroplatinum (CDDP) and epirubicin by replacing the ionic contrast medium (Urografin 67) with a nonionic contrast medium (Iopamidol; Iopamiron 300) and adding phosphatidyl choline. This CDDP-epirubicin-Lipiodol emulsion (CELE) was examined pharmacologically and chemically with the following results. The size of these particles is less than 10 microns (diameter) for up to 24 h; the release of 28%-34% of the CDDP and 80%-90% of the epirubicin was estimated in the dissolution test, and 85% of the CDDP and 35% of the epirubicin was retained in the organs in the moment calculation. CELE was injected into 58 HCC patients via a celiac angiographic catheter. In 36 of these patients, the CELE injection was followed by transcatheter arterial embolization (TAE) therapy. Following the administration of CELE as one-shot injection therapy for stage IV HCC, the 1-year survival rate was 59% and the 2-year survival rate was 27%. Moreover, in patients (stage II, 12; stage III, 8; stage IV, 16) who received CELE and subsequently underwent TAE therapy, the 1-year survival rate was 90% and the 2-year survival rate was 67%. The nonionic contrast medium with Lipiodol forms finer emulsified particles, and these particles are more capable of penetrating into the tumor. In addition, the greater pharmacological stability of these particles provides a slow-release effect and prolonged stability of their shape. Finally, theoretically, the use of two major anticancer agents such as CDDP and epirubicin showed a greater clinical effect in the treatment of HCC than either our earlier suspension or a single anticancer agent.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Effects of thyroxine and its related compounds on cerebral GABA receptors: inhibitory action on benzodiazepine recognition site in GABAA receptor complex.

The effects of thyroxine and its related derivatives on gamma-aminobutyric acid (GABA) receptors in the rat brain were examined. D-Thyroxine strongly inhibited [3H]flunitrazepam binding to benzodiazepine receptor in crude synaptic membrane from the rat brain. The Scatchard analysis of the [3H]flunitrazepam binding in the presence of D-thyroxine indicated the decreases in the affinity and maximum number of binding site. Furthermore, D-thyroxine inhibited the enhancing effect of flunitrazepam on GABA-stimulated 36Cl- influx into membrane vesicles, although GABA-stimulated 36Cl- influx alone was not affected by D-thyroxine. On the other hand, the effects of thyroxine and its related derivatives on cerebral GABAB receptor binding were not noted. These results suggest that D-thyroxine may be a drug which is able to modulate the function of GABAA receptor complex via the inhibitory action on benzodiazepine recognition site.

Animals↗
PubMed1994

Alteration in cerebral GABAB receptor functions during formation of alcohol dependence.

Alterations in the function of cerebral GABAB receptor systems were studied in alcohol dependent animals and reconstituted GABAB receptor systems in vitro. The GABAB receptor binding at both high and low affinity sites showed a significant increase during the formation of alcohol dependence and alcohol withdrawal, although ethanol at a low concentration did not affect the GABAB receptor binding in vitro. On the other hand, a low concentration (100 mM) of ethanol, which had no significant effect on GABAB receptor binding, inhibited cAMP accumulation in vitro. The cAMP formation in brain did not show significant changes during the formation of alcohol dependence in spite of the increase in GABAB receptor binding. These results indicate that alcohol dependence induces an increase of GABAB receptor binding in the brain. This increase in GABAB receptor binding, however, may not be associated with the changes in the GABAB receptor mediated suppression of cAMP formation, possibly due to the deterioration of the coupling between the GABAB receptor and the Gi/Go type of GTP binding protein/adenylyl cyclase. Furthermore, the present results suggest that in vitro addition of ethanol may have differential effects on cerebral GABAB receptor systems as compared with those found in the brain of alcohol dependent subjects.

Administration, Inhalation↗
PubMed1993

Protein phosphatase inhibitor calyculin A induces hyperphosphorylation of cytokeratins and inhibits amylase exocytosis in the rat parotid acini.

Calyculin A, a protein phosphatase inhibitor with a chemical structure completely different from that of okadaic acid, reproduced the inhibitory effect of okadaic acid on cyclic AMP-mediated amylase release from rat parotid acinar cells. Calyculin A markedly enhanced phosphorylation of cytokeratins in the cytoskeletal fraction of the cells, whereas cAMP had apparently no effect on the phosphorylation. Microscopic observations showed that parotid acini incubated with 100 nM calyculin A for 15 min had large vacuoles in the cytoplasm and conspicuous blebs on the basal plasma membrane. K252a, a nonselective protein kinase inhibitor, clearly reduced calyclin A-induced phosphorylation of cytokeratins, and it markedly blocked the inhibition of amylase release and morphological changes evoked by calyculin A. These results suggest that hyperphosphorylation of cytokeratins profoundly affects the morphology and secretory activity of parotid acinar cells.

Amylases↗
PubMed1993

Cerebral GABAB receptor: proposed mechanisms of action and purification procedures.

The GABAB receptor in brain is one of the GABA receptor subtypes, and has been found to be negatively coupled to adenylate cyclase and phosphatidylinositide turnover. This receptor easily solubilizes from cerebral synaptic membrane preparations by 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS) in the presence of asolectin. GABAB receptor solubilized from bovine cerebral cortex was purified using baclofen-coupled affinity beads (baclofen-coupled Toyopearl beads). Using these procedures, almost pure GABAB receptor (80 KDa protein) was obtained in the affinity eluate. A monoclonal antibody has been also raised against the purified GABAB receptor. The antibody recognized a protein of about 80 KDa in bovine brain synaptic membrane. Immunoabsorbent agarose beads conjugated with the antibody were able to remove more than 90% of the baclofen suppressive GABA binding activity in the solubilized synaptic membrane, and this system was found to be useful for the immunoaffinity column chromatographic separation of GABAB receptor. Preliminary studies of immunohistochemical visualization of GABAB receptor in the rat cerebellum suggested that this receptor may be exclusively localized at the presynaptic site of GABAergic neurons.

Adenylyl Cyclases↗
PubMed1993

Effects of valinomycin on osmotic lysis of zymogen granules and amylase exocytosis from parotid acini.

The role of osmotic swelling of the secretory granules in adenosine 3',5'-cyclic monophosphate (cAMP)-mediated amylase exocytosis was evaluated by use of isolated zymogen granules and saponin-permeabilized acini of the rat parotid gland. The osmotic lysis of the isolated granules was markedly enhanced by the addition of valinomycin (> 10(-9) M) in the presence of isosmotic KSCN or KI medium. However, valinomycin (up to 10(-5) M) did not increase the granule lysis in KCl medium, although the granules were slightly less stable in KCl medium than in K2SO4 or potassium gluconate medium. Guanosine 5'-O-(3-thiotriphosphate) did not affect the granule lysis. Valinomycin alone had no effect on amylase release from saponin-permeabilized parotid acini incubated in KCl medium, but completely abolished cAMP-mediated amylase release in all K+ media used. The inhibition was clearly detected at 0.1 microM valinomycin in KCl medium, not blocked by the addition of 1 mM MgATP to the medium, and was greatly reduced in NaCl medium. cAMP-evoked amylase release was completely inhibited by SCN- and I- (permeant anions), the mean inhibitory dosages of which were approximately 25 and 50 mM, respectively. These results suggest that 1) the membrane of parotid zymogen granules has no detectable Cl- channels responsible for osmotic swelling of the granules, and 2) increase in K+ or anion conductance of the granule does not enhance but inhibits cAMP-mediated amylase exocytosis from parotid acini.

Amylases↗
PubMed1992

Treatment of hepatocellular carcinoma with a CDDP-epirubicin-lipiodol suspension: a pilot clinico-pharmacological study.

Lipiodol injection is a useful method for detecting liver tumors, especially hepatocellular carcinoma (HCC). We therefore prepared and tested a new emulsion of lipiodol containing epirubicin and cis-diammine-dichloroplatinum (CDDP), drugs that are very effective against HCC. This CDDP-epirubicin-lipiodol suspension (CELS) was injected into 18 HCC patients via a celiac angiographic catheter. In 11 of these patients, CELS was followed by transcatheter arterial embolization (TAE) therapy. Clinical and pharmacological investigations were performed in all 18 patients, and the following results were obtained. CELS is pharmacologically and chemically stable, and both the results of the dissolution test and the serum levels of these two drugs indicate that slow release can be obtained. After the injection of CELS, serum levels of AFP and PIVKA-II decreased immediately, and no fatal clinical side effects were encountered. Although no statistically significant difference was observed, the survival (Kaplan-Meier method) of patients injected with CELS in the presence or absence of TAE therapy can be estimated to be much longer than that of patients receiving CDDP-lipiodol suspension injection in the presence (16 patients) or absence (6 patients) of TAE therapy. A combination of CELS injection and TAE therapy might be effective and useful for the treatment of HCC.

Aged↗