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T Horie

Publications and source records attributed to T Horie.

At least 55 records · Page 3Linked to original sources
PubMed2001

Alleviation by garlic of antitumor drug-induced damage to the intestine.

Antitumour drugs such as methotrexate (MTX) and 5-fluorouracil (5-FU) induce intestinal damage. This is a serious side effect of cancer chemotherapy. The present studies examined whether or not aged garlic extract (AGE) protects against damage from these antitumor drugs. Both drugs were administered orally for 4 or 5 d to rats fed a standard laboratory diet with and without 2% AGE. The small intestinal absorption of the poorly absorbable compound, fluorescein isothiocyanate--labeled dextran (FD-4; average molecular weight, 4400) was used to evaluate the damage to the intestine using the in vitro everted intestine technique and the in situ intestinal loop technique. FD-4 absorption increased in the antitumour drug-treated rats fed the diet without garlic. Interestingly, FD-4 absorption was depressed in rats fed the diet containing AGE. These results suggest that AGE may protect the small intestine of rats from antitumour drug-induced damage.

Administration, Oral↗
PubMed2001

Contribution of small GTPase Rho and its target protein rock in a murine model of lung fibrosis.

Excess fibroblasts and inflammatory cells may play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The small GTPase, Rho, and its target protein, Rho-associated coiled-coil-forming protein kinase (ROCK), have been recognized to be major regulators of cell locomotion mediated by reorganization of the actin cytoskelton. Activated ROCK inhibits myosin phosphatase, and this in turn induces phosphorylation of the myosin light chain (MLC). To determine the mechanisms underlying the deterioration process of IPF, we investigated the effect of Y-27632, a selective ROCK inhibitor, in a murine model of bleomycin (BLM)-induced lung fibrosis. The Aschcroft score and hydroxyproline content of the BLM-treated mouse lung decreased in response to Y-27632 treatment. The number of broncoalveolar cells was decreased by Y-27632, and migration of macrophages, neutrophils, and fibroblasts in vitro was inhibited by Y-27632 regardless of various stimuli. Although expression of ROCK-II mRNA in the lung homogenates of the BLM-treated mice was increased approximately 9-fold, expression of ROCK-II protein showed only a slight tendency to increase. BLM elevated MLC phosphorylation levels, and Y-27632 inhibited BLM response. These findings indicate that the Rho/ROCK-mediated pathway plays an important role in IPF, and that blocking of this pathway leads to inhibition of IPF development.

Animals↗
PubMed2001

Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway.

Myofibroblasts play an important role in the fibrogenic process of pulmonary fibrosis. Transforming growth factor (TGF)-beta is well known to induce the phenotypic modulation of fibroblasts to myofibroblasts; however, the intracellular signal regulating induction of the myofibroblastic phenotype of human lung fibroblasts (HLF) has not been determined. In the present study, we examined the role of the mitogen-activated protein kinase (MAPK) superfamily in inducing the phenotypic modulation of HLF to myofibroblasts characterized by alpha-smooth-muscle actin expression, in order to clarify this issue. The results showed that: (1) TGF-beta1 caused the phenotypic modulation of HLF to myofibroblasts in a dose- and a time-dependent manner; (2) TGF-beta1 induced increases in c-Jun-NH2- terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (Erk) phosphorylation and activity; (3) the inhibitors CEP-1347, SB 203580, and PD 98059 attenuated TGF-beta1-induced JNK, p38 MAPK, and Erk activity, respectively; and (4) CEP-1347, but not SB 203580 or PD 98059, attenuated the TGF-beta1-induced phenotypic modulation of HLF to myofibroblasts in a dose-dependent manner. These results indicate that TGF-beta1 is capable of inducing the myofibroblastic phenotype of HLF, and that JNK regulates the phenotypic modulation of TGF-beta1-stimulated HLF to myofibroblasts.

Carbazoles↗
PubMed2001

Inactivation of rat cytochrome P450 2D enzyme by a further metabolite of 4-hydroxypropranolol, the major and active metabolite of propranolol.

Repetitive administration of propranolol (PL) in rats decreases the activities of cytochrome P450 (CYP) 2D enzyme(s) in hepatic microsomes. We examined the properties of 4-hydroxypropranolol (4-OH-PL) as an inactivator of rat liver microsomal CYP2D enzyme(s) using bunitrolol (BTL) 4-hydroxylation and PL 5- and 7-hydroxylations as indices of CYP2D enzyme activity. Rat microsomal BTL 4-hydroxylase activity was inhibited by the addition of 4-OH-PL to the incubation medium. The inhibition was greater after preincubation of microsomes with 4-OH-PL in the presence of NADPH than in its absence. The type of inhibition kinetics of BTL 4-hydroxylase by 4-OH-PL was changed from a competitive type to a noncompetitive type by the preincubation. The inhibition of rat liver microsomal PL 5- and 7-hydroxylases by 4-OH-PL was blocked efficiently by co-incubation with quinine, a typical inhibitor of rat CYP2D enzyme(s), or to a lesser extent by BTL. However, quinidine, a diastereomer of quinine, did not significantly protect against the enzyme inactivation. The protective capacities of the substrate and inhibitors reflected their affinities for rat CYP2D enzyme(s). BTL hydroxylase was not affected by either 1,4-naphthoquinone or 1,4-dihydroxynaphthalene which are possible metabolites of 4-OH-PL. These results provide further evidence to support the notion that PL is biotransformed by rat CYP2D enzyme(s) to 4-OH-PL, which is further oxidized to a chemically reactive metabolite in the active site. The inactivation of CYP is likely the result of covalent binding of the reactive species to an amino acid residue of the active site.

Adrenergic beta-Antagonists↗
PubMed2001

Intracellular glutathione regulates tumour necrosis factor-alpha-induced p38 MAP kinase activation and RANTES production by human bronchial epithelial cells.

BACKGROUND: RANTES plays an important role in the production of allergic inflammation of the airway through its chemotactic activity for eosinophils. The cellular reduction and oxidation (redox) changes are involved in the activation of p38 mitogen-activated protein (MAP) kinase and the induction of cytokine expression. It has previously been shown that tumour necrosis factor (TNF)-MA activates p38 mitogen-activated protein (MAP) kinase to produce cytokine, including RANTES, that N-acetylcysteine (NAC) attenuates cytokine production by human bronchial epithelial cells (BECs), and that sensitivity to TNFalpha is inversely correlated with cellular redox state. However, a role of cellular redox regulated by intracellular glutathione (GSH) in TNFalpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs has not been determined. OBJECTIVE: Human BECs were exposed to NAC or buthionine sulfoximine (BSO). TNFalpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs were then examined in order to clarify these issues. RESULTS: The results showed that: NAC attenuated TNFalpha-induced p38 MAP kinase activation and RANTES production; SB 203580 as the specific inhibitor of p38 MAP kinase activity attenuated TNF-alpha-induced RANTES production; BSO facilitated TNF-alpha-induced p38 MAP kinase activation and RANTES production; SB 203580 attenuated BSO-mediated facilitation of TNF-alpha-induced RANTES production; and the intracellular GSH increased in NAC-treated cells, whereas the intracellular GSH was reduced in BSO-treated cells. CONCLUSIONS: These results indicate that cellular redox regulated by GSH is critical for TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs.

Acetylcysteine↗
PubMed2001

Mechanism-based inactivation of CYP2C11 by diclofenac.

It has been known that diclofenac is biotransformed into chemically reactive metabolites, which bind covalently to liver microsomal proteins, including cytochrome P450 enzyme(s). We have investigated the ability and selectivity of diclofenac to inactivate P450 enzymes. Preincubation of microsomes of untreated rats with diclofenac in the presence of NADPH resulted in time-dependent loss of testosterone 2alpha- and 16alpha-hydroxylation activities. No effect of the preincubation was observed on ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, or testosterone 6beta-hydroxylation activity. The time-dependent decreases in testosterone 2alpha- and 16alpha-hydroxylation activities followed the pseudo-first order kinetics and were saturable with increasing diclofenac concentrations. Reduced glutathione was not capable of protecting against the decrease in the enzyme activities. These data establish that a mechanism-based inactivation of CYP2C11 occurs during the oxidative metabolism of diclofenac. The diclofenac concentrations required to achieve the half-maximal rate of inactivation (K(I)) were 3 to 4 microM, which were close to K(m) for the low-K(m) components for diclofenac 4'- and 5-hydroxylation activities (7.29 and 4.43 microM, respectively). Anti-CYP2C11 IgG inhibited diclofenac 4'- and 5-hydroxylation activities, indicating that CYP2C11 is a major isozyme responsible for these aromatic oxidations. The preincubation of microsomes with 4'- or 5-hydroxydiclofenac did not cause a decrease in testosterone 2alpha- or 16alpha-hydroxylation activity, suggesting that neither of the primary metabolites is a precursor of the metabolite that inactivates CYP2C11. Therefore, a highly reactive intermediate(s) inactivating CYP2C11, probably arene-oxide, appears to be generated during the process of diclofenac 4'- and/or 5-hydroxylation. Diclofenac metabolism in human liver microsomes did not cause inactivation of CYP2C9, a major isozyme involved in diclofenac 4'-hydroxylation. Because the human microsomes have high diclofenac 4'-hydroxylation but not 5-hydroxylation activity, importance of the latter pathway in the inactivation is suggested.

Animals↗
PubMed2001

[Severe thrombocytopenia induced by radiographic non-ionic contrast medium].

A 70-year-old man was admitted to our hospital because of right hemiparesis. He had no allergies or previous exposure to radiographic contrast medium, and the platelet count on admission was within the normal range. On day 8 of hospitalization, he underwent computed tomography of the brain with 100 ml of iopamidol administered intravenously. Three hours later, his platelet count fell to 5,000/microliter, and he developed purpura. Because drug-induced thrombocytopenia was suspected, platelet transfusion was undertaken and corticosteroids were administered. The platelet count returned gradually to normal in 2 days. At the time, we were unable to ascertain the cause of the thrombocytopenia. To clarify whether the contrast medium had been responsible, iopamidol was added to the patient's heparinized whole blood. Subsequent platelet aggregation was observed microscopically and the platelet count decreased, suggesting that the thrombocytopenia had been due to contrast medium-induced platelet aggregation. Although thrombocytopenia after injection of contrast medium is extremely rare, such cases should be evaluated carefully because the condition can be life-threatening if severe.

Aged↗
PubMed2001

[Usefulness of combination post-stress dysfunction and perfusion imaging in technetium-99m-tetrofosmin myocardial scintigraphy].

OBJECTIVES: Myocardial perfusion imaging has lower sensitivity for the diagnosis of coronary artery disease in patients with three-vessel disease. The presence of post-stress dysfunction of the left ventricle, evaluated by electrocardiography(ECG) gated single photon emission computed tomography(SPECT) with a quantitative gated SPECT program, was investigated in patients with coronary artery disease, and also whether combining post-stress dysfunction and myocardial perfusion imaging improved the diagnosis of coronary artery disease. METHODS: ECG gated technetium-99m-tetrofosmin SPECT was performed using a one day, stress and rest, protocol in 139 patients. SPECT and coronary angiography were performed within 1 month. The coronary artery disease group consisted of 89 patients: 43 with one-vessel disease(1VD), 28 with two-vessel disease(2VD), and 18 with three-vessel disease(3VD). The group with zero-vessel disease(0VD) consisted of 50 patients. According to post-stress and rest ejection fraction(EF) and end-systolic volume (ESV), post-stress dysfunction is defined as follows: rest EF--post-stress EF > or = 5% and post-stress ESV--rest ESV > or = 5 ml. RESULTS: In the coronary artery disease group, post-stress ESV was larger than rest ESV(37.8 +/- 26.4, 34.0 +/- 24.2 ml, p < 0.001), and post-stress EF was lower than rest EF (61.5 +/- 11.1%, 64.2 +/- 10.8%, p < 0.001). In the 0VD group, ESV and EF were the same for post-stress and rest (25.7 +/- 20.8, 26.2 +/- 21.6 ml, NS; 70.4 +/- 9.5%, 70.0 +/- 9.6%, NS). Post-stress dysfunction was 6.0% in the 0VD group and 30.3% in the coronary artery disease group(p < 0.001). Furthermore, post-stress dysfunction in the 2VD (35.7%) and 3VD(38.9%) groups was higher than that in the 0VD group(p < 0.01, p < 0.01). Sensitivity of coronary artery disease diagnosis by myocardial perfusion imaging was 75%. The combination of post-stress dysfunction and myocardial perfusion imaging improved sensitivity from 75% to 82%(p < 0.05), but reduced the specificity from 92% to 86%(p = 0.08). CONCLUSIONS: Post-stress dysfunction is a useful parameter for clinical diagnosis of coronary artery disease.

Aged↗
PubMed2001

[Three-dimensional computed tomography angiography of coronary artery bypass graft with electron beam tomography].

OBJECTIVES: Assessment of coronary artery bypass graft patency by three-dimensional reconstructed computed tomography angiography (3D-CTA) derived from electrocardiography-gated contrast-enhanced electron beam tomography (EBT) was evaluated. METHODS: Thirty-nine patients with 99 grafts (45 arterial grafts and 54 venous grafts) underwent 3D-CTA and selective coronary angiography within a 3-week interval. 3D-CTA images of the coronary bypass grafts were compared with the coronary angiography images used as the control. RESULTS: 3D-CTA defined 42 of 44 arterial grafts as patent (sensitivity: 95%), all 47 venous grafts as patent (sensitivity: 100%) and all 7 venous grafts as occlusive (specificity: 100%). The overall sensitivity and specificity were 98% and 88%, respectively. CONCLUSIONS: 3D-CTA is an useful noninvasive technique with adequate sensitivity and specificity to assess coronary artery bypass graft patency.

Aged↗
PubMed2001

Recurrent giant longitudinal duodenal ulcer with massive hemorrhage in a Helicobacter pylori-negative patient.

A 67-year-old man, in whom a linear ulcer running from the duodenal bulb to the descending part had been noted 3 years previously, was admitted to our hospital because of abdominal pain and melena. Duodenoscopy revealed a bleeding giant longitudinal ulcer, which was more extensive than before. Tests for Helicobacter pylori (Hp) were negative. The ulcer was cured by endoscopic hemostasis and repeated blood transfusions. Attention must be paid to Hp-negative post-bulbar duodenal ulcers because of the frequent complications including hemorrhage.

Aged↗
PubMed2001

[A case of intrathoracic extension of retroperitoneal fibrosis].

A 70-year-old man was diagnosed as having retroperitoneal fibrosis 12 years ago. The patient was admitted to our hospital with complaints of fever and left chest pain. On admission, chest radiography revealed left pleural effusion and left pleural thickening. Percutaneous pleural biopsy was performed, and the pleural tissue gave a chronic inflammatory reaction characterized by proliferation of collagen fibers and chronic inflammatory cellular infiltration. Since the retroperitoneal fibrosis had been diagnosed in similar tissue, it was considered that this condition had extended to the pleura. On administration of prednisolone, the intrathoracic lesions and clinical symptoms were improved, but the patient later died of pneumonia. Autopsy showed fibrous pleuritis and chronic fibrosing lung disease. This was an extremely rare case. Prednisolone appears to be useful in the treatment of intrathoracic extension of retroperitoneal fibrosis.

Aged↗
PubMed2001

Retinol binding protein in plasma to evaluate the hepatotoxicity of rats treated with CCl4.

Retinol binding protein (RBP) in plasma of rats treated with carbon tetrachloride (CCl4) was monitored to clarify if RBP is available for the evaluation of the drug-induced hepatotoxicity. Blood was withdrawn by heart puncture at 0 hr and 12 hr after i.p. administration of CCl4 (0.2 ml/kg) to rats. Lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) in plasma significantly increased at 12 hr after CCl4 administration, compared with the control, while RBP in plasma significantly decreased. On the other hand, albumin in plasma was unaffected at 12 hr after CCl4 administration. Thus RBP seems to monitor the different aspects in the drug-induced hepatotoxicity from LDH and ALT, and from the viewpoint of protein synthesis in the liver, to be more sensitively affected by the drug-induced hepatotoxicity than albumin.

Animals↗
PubMed2000

Vasodilator effect of urotensin II, one of the most potent vasoconstricting factors, on rat coronary arteries.

The effects of human urotensin II on coronary flow were studied in the perfused rat heart. Urotensin II transiently decreased coronary flow, then induced sustained vasodilatation. In the presence of a cyclooxygenase inhibitor, diclofenac, coronary vasodilatation was significantly inhibited. A nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NNA), attenuated the urotensin-induced vasodilatation. These data suggest that urotensin II modulates coronary flow through factors such as cyclooxygenase products and nitric oxide to elicit coronary vasodilatation.

Animals↗
PubMed2000

Active remodeling of the coronary arterial lesions in the late phase of Kawasaki disease: immunohistochemical study.

BACKGROUND: Remodeling of the coronary artery lesions in Kawasaki disease has been observed in longitudinal angiographic studies. However, mechanisms of such remodeling have not yet been elucidated. METHODS AND RESULTS: We examined formalin-fixed specimens of the coronary arteries immunohistochemically by using antibodies against vascular growth factors (GFs) and their receptors in 7 children with Kawasaki disease, 9 children with no coronary disease, and 3 adults with atherosclerosis. In the thickened intima at stenotic sites and at recanalized vessels with Kawasaki disease, extensive expression of vascular GFs, such as transforming GF-beta(1), platelet-derived GF-A, and basic fibroblast GF, was observed both within and surrounding smooth muscle cells. Vascular endothelial GF was observed within smooth muscle cells. Furthermore, all of these GFs were strongly expressed in the newly formed microvessels within the intima. In the thinned media, these GFs were focally and weakly expressed. In contrast, these GFs were expressed only in the media in the control children. In cases of adult atherosclerosis, GFs were expressed diffusely in the media but focally and weakly if at all in the intima. CONCLUSIONS: Active remodeling of the coronary artery lesions in Kawasaki disease continues in the form of luxuriant intimal proliferation and neoangiogenesis for several years after the onset of the disease. This process is distinct from adult-onset atherosclerosis.

Adolescent↗
PubMed2000

Species difference in enantioselectivity for the oxidation of propranolol by cytochrome P450 2D enzymes.

We examined and compared enantioselectivity in the oxidation of propranolol (PL) by liver microsomes from humans and Japanese monkeys (Macaca fuscata). PL was oxidized at the naphthalene ring to 4-hydroxypropranolol, 5-hydroxypropranolol and side chain N-desisopropylpropranolol by human liver microsomes with enantioselectivity of [R(+)>S(-)] in PL oxidation rates at substrate concentrations of 10 microM and 1 mM. In contrast, reversed enantioselectivity [R(+)<S(-)] in PL 5-hydroxylation and N-desalkylation rates at the same substrate concentrations was observed in monkey liver microsomes, although the selectivity was the same for PL 4-hydroxylation between the two species. All oxidation reactions of the PL enantiomers in human liver microsomes showed biphasic kinetics, i.e. the reactions could be expressed as the summation of a low-K(m) phase and a high-K(m) phase. Inhibition studies using antibodies and characterization of CYP2D6 enzymes expressed in insect cells or human lymphoblastoid cells indicated that the enantioselectivity of PL oxidation, especially the ring 4- and 5-hydroxylations reflected the properties of CYP2D6 in human liver microsomes. In monkey liver microsomes, all of the oxidation reactions of S(-)-PL showed biphasic kinetics, whereas ring 4- and 5-hydroxylations were monophasic and side chain N-desisopropylation was biphasic for R(+)-PL. Similarly, from the results of inhibition studies using antibodies and inhibitors of cytochrome P450 (P450), it appears that the reversed selectivity [R(+)<S(-)] of PL oxidation rates is catalyzed by CYP2D enzyme(s) in monkey liver at low substrate concentrations. These results indicate that different properties of P450s belonging to the 2D subfamily cause the reversed enantioselectivity between human and monkey liver microsomes.

Animals↗