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Biomedical subjects

T Kodama

Publications and source records attributed to T Kodama.

At least 307 records · Page 17Linked to original sources
PubMed1998

Oxidation of histamine H1 antagonist mequitazine is catalyzed by cytochrome P450 2D6 in human liver microsomes.

Mequitazine [10-(3-quinuclidinylmethyl) phenothiazine] is a long-acting and selective histamine H1-receptor antagonist that is mainly biotransformed by human liver microsomes to yield hydroxylated and S-oxidized metabolites. Mequitazine hydroxylase was inhibited by propranolol and quinidine. Lineweaver-Burk plots for the hydroxylation and the S-oxidation indicated that the hydroxylation occurred with a low Km (0.72 +/- .26 microM) in human liver microsomes. Microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochrome P450 2D6 (CYP2D6) efficiently metabolized mequitazine to the hydroxylated and S-oxidized metabolites. The results indicate that CYP2D6 isozyme is a major form of CYP responsible for the metabolism of mequitazine in human liver microsomes. Inhibition of CYP3A-catalyzed midazolam 1'-hydroxylase by various histamine H1 antagonists, including mequitazine, suggested that mequitazine and some other histamine H1 antagonists could also be inhibitors of CYP3A in human liver microsomes.

1-Propanol↗
PubMed1998

[Intracranial mesenchymal chondrosarcoma arising from the cerebellar tentorium: case report].

A 22-year-old woman presented with a 3-year history of progressive frontal headache. Computerized tomography (CT) and magnetic resonance imaging (MRI) revealed a tumor in the left trigone of the lateral ventricle and which enhanced homogeneously. The tumor was attached to the cerebellar tentorium and was compressing the brain stem. On the angiography, no tumor staining was seen. On November 26, 1996, total removal of the tumor was performed using the left subtemporal approach. The tumor was attached to the cerebellar tentorium. The pathological diagnosis was mesenchymal chondrosarcoma. After surgery, gamma-knife radiosurgery was carried out on the tentorium at the place where the tumor had been attached. There has been no recurrence for 6 months. Mesenchymal chondrosarcoma in the brain is very rare and therapy for this tumor is difficult. We report this rare tumor and the therapy is discussed.

Adult↗
PubMed1998

[The mechanism of corneal epithelial disorder induced by prostaglandin F2 alpha isopropyl unoprostone].

Deleterious effects of isopropyl unoprostone (PG-F2 alpha) on the ocular surface were evaluated using the in vivo barrier function assay of corneal epithelial cells and the proliferation assay of human corneal epithelial cells in vitro. The barrier function of corneal epithelial cells in vivo was not impaired by treatment with PGF2 alpha, but it was significantly suppressed by timolol. The result of cell proliferation assay of human corneal cells showed that the 0.12% PGF2 alpha ophthalmic solution caused greater suppression of cell proliferation and acuter cell toxicity than 0.5% timolol ophthalmic solution. Further study showed that not the vehicle but the PGF2 alpha itself was responsible for these deleterious effects. We conclude that the 0.12% PGF2 alpha ophthalmic solution affects cell migration and proliferation but not the barrier effects of the ocular surface. These results suggest that the corneal epithelial defect of glaucoma patients may be caused by these two independent mechanisms, namely suppression of cell proliferation by PGF2 alpha and the destruction of the barrier function of the ocular surface by timolol.

Adrenergic beta-Antagonists↗
PubMed1998

Monoclonality of both pale cells and cuboidal cells of sclerosing hemangioma of the lung.

Sclerosing hemangioma of the lung remains poorly understood, and it is still unclear whether this lesion is neoplastic or not. It consists of two major cell types, pale cells and cuboidal cells. We analyzed the clonality of each cell types from six female cases of surgically resected sclerosing hemangioma. The pale cells and cuboidal cells were separated by microdissection from methanol-fixed sections, and DNA was extracted for clonal analysis based on an X-chromosome-linked polymorphic marker, the human androgen receptor (HUMARA) gene or the phosphoglycerate kinase (PGK) gene. The HUMARA and PGK genes were found to be amplified with or without digestion by the methylation-sensitive restrictive endonuclease HpaII. Five of six cases were informative. Pale cells and cuboidal cells showed the same monoclonality in all of the informative cases, whereas the control cells showed a polyclonal pattern. Our results demonstrated that sclerosing hemangioma is caused by monoclonal expansion of cells, confirming that it is a neoplasia. Moreover, the present data indicate that both pale cells and cuboidal cells are derived from the same cell.

Adolescent↗
PubMed1998

Isolation of macrophage-like cell mutants resistant to the cytotoxic effect of oxidized low density lipoprotein.

A high concentration of oxidized low density lipoprotein (Ox-LDL) showed a cytotoxic effect on mouse macrophage-derived J774 cells. Mutant cells were selected from these cells that were resistant to the cytotoxic effect of Ox-LDL. One mutant form, named JO21b cells, was characterized in the present study. In spite of a marked resistance to the cytotoxic effect of Ox-LDL, JO21b cells were apparently as sensitive as the parent cells not only to toxic moieties of Ox-LDL, such as 7-ketocholesterol and lysophosphatidylcholine, but also to t-butyl hydroperoxide, an artificial lipid hydroperoxide analog. However, the cellular association of 125I-labeled Ox-LDL with, and subsequent endocytic degradation by JO21b cells was reduced by 70-80% compared with J774 cells. Similarly, accumulation of cholesteryl esters in JO21b cell by Ox-LDL was also reduced by 70%. Northern blot analyses of type I and type II macrophage scavenger receptors (type I and type II MSR) demonstrated that the mRNA levels of JO21b cells were lower than those of J774 cells. Moreover, peritoneal macrophages obtained from MSR-knockout mice showed a higher resistance to the cytotoxic effect of Ox-LDL than those from their wild-type littermates. Our results suggest, therefore, that macrophage scavenger receptor-mediated endocytic uptake of oxidized low density lipoproteins (Ox-LDL) may play an enhancing role in Ox-LDL cytotoxicity to macrophages or macrophage-derived cells.

Animals↗
PubMed1998

Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice.

To clarify the role of type I and type II macrophage scavenger receptors (MSR-A) in the progression of diet-induced atherosclerosis, we generated mice lacking both MSR-A and low-density lipoprotein receptor (LDLR). After 4 or 12 weeks of a high-fat diet, the sizes of atherosclerotic lesions in MSR-A/LDLR double knockout mice were significantly reduced (p < 0.05) compared with those in LDLR single knockout mice. However, atherosclerotic lesions mainly composed of foamy macrophages were still observed in double knockout mice. Formation of atherosclerotic lesions in double knockout mice was partially explained by the participation of scavenger receptors other than MSR-A such as MARCO, CD36, and macrosialin/CD68. These receptors were clearly demonstrated in the atherosclerotic lesions in double knockout mice as well as LDLR single knockout mice by immunohistochemistry or by reverse transcriptase-polymerase chain reaction. Because the very low density lipoprotein (VLDL) fraction was elevated in the double and single knockout mice, we further examined the possibility that VLDL may participate in foam cell formation in atherosclerotic lesions. When incubated with VLDL isolated from LDLR-deficient mice, cholesterol ester accumulation and foamy transformation occurred in MSR-A-deficient macrophages as well as in normal macrophages. These data indicate that MSR-A plays an essential role in the development of diet-induced atherosclerosis. It also appears that other scavenger receptors, such as MARCO, CD36, and macrosialin/CD68, as well as uptake of VLDL are involved in foam cell formation during atherogenesis in MSR-A/LDLR double knockout mice.

Animals↗
PubMed1998

[Evaluation of brain tumor by 99mTc-MIBI: comparison study with 201Tl and predictivity of therapeutic effect].

We compared the detectability of 99mTc-MIBI and 201Tl-chloride for brain tumor in relationship with histopathology. We also evaluated correlation between therapeutic effect using ACNU, Cisplatine and the degree of MIBI tumor uptake. The subjects were 31 brain tumor histologically confirmed by operation or biopsy. Dual-isotope SPECT technique was performed at both 20 min and 180 min after tracer injection. A tumor to normal lung ratio on both early (ER) and delayed image (DR) and retention index (RI) were calculated. The positive rates of 99mTc-MIBI (90.3% and 77.4%) were comparable to that of 201Tl (90.3% and 80.6%). In the relationship with histopathology, both MIBI and Tl accumulated in 100% of glioblastoma (GBM), metastasis (meta), anaplastic astrocytoma and 25% of low grade astrocytoma on both early and delayed images. On semiquantitative analysis, there were no statistical significance among GBM, meta and anaplastic astrocytoma of ER, DR, RI in the both radiopharmaceuticals. However, both ER and DR in GBM tended to be higher than those of anaplastic astrocytoma. In spite of intense MIBI uptake, GBM patients died within six months except one patient. We concluded that MIBI can be helpful in detecting brain tumor as Tl. MIBI also might be useful in estimating the degree of malignancy in glioma. However, intense MIBI uptake did not mean favorable therapeutic effect in patients with GBM treated with ACNU and Cisplatine.

Adult↗
PubMed1998

[Role of cytokines in the pathogenesis of gastrointestinal diseases associated with Helicobacter pylori infection].

It is well known that Helicobacter pylori can cause gastritis, gastroduodenal ulcers and malignant diseases. The infiltration of polymorphonuclear leukocytes is recognized in the lesions of these diseases, and the infiltration disappears by antibiotic therapy. However, it is not yet clarified how Helicobacter pylori induces the formation of lesions including leukocyte infiltration. Recently, we have confirmed that several kinds of cytokines are expressed in the gastric biopsy specimens of gastroduodenal diseases. Especially, it is conjectured that chemokines such as interleukin-8 (IL-8) which are expressed in the specimens, induce leukocyte infiltration, gastric mucosal inflammation and gastroduodenal ulcers. It is possible that Helicobacter pylori CagA gene is closely related with IL-8 expression because this cytokine is more strongly expressed in the specimens from the patients infected with CagA-positive Helicobacter than those with CagA-negative one.

Anti-Bacterial Agents↗
PubMed1998

[Single dose intravenous toxicity studies of T-3762, a novel parenteral quinolone antimicrobial agent, in rats, dogs and monkeys].

Single dose intravenous toxicity studies of T-3762, a novel parenteral quinolone antimicrobial agent, were conducted in rats, dogs and monkeys. The following results were obtained. 1. In the rat study, all males and females given 260 mg/kg survived and all males and 3 of 5 females given 391 mg/kg died. Approximate lethal doses in male and female rats were between 260 and 391 mg/kg. In survived animals, decrease in locomotor activity and irregular respiration were observed. These clinical signs were recovered within 1 hour after dosing. In female rats given 260 mg/kg, no abnormalities were observed in general signs. In dead animals, decrease in locomotor activity, irregular respiration, staggering gait and tonic convulsion were observed and died within about 90 minutes after dosing. Macroscopic examinations in dead animals showed dark red discoloration in lung and had white foamy liquid in trachea. In histopathological examinations of dead animals, congestion, hemorrhage and edema were observed in lung. 2. In the dog study, 2 animals given 260 mg/kg survived and 2 animals given 521 mg/kg died. Approximate lethal dose in dogs was between 260 and 521 mg/kg. In the 260 and 521 mg/kg groups, decrease in locomotor activity, lateral position, vomiting, salivation and decrease in body temperature were observed. In the 521 mg/kg group, one animal died at 4 minutes and another 7 days after dosing. Histopathological examinations in 2 dead animals showed congestion or hemorrhage in heart, lung, liver, kidney, spleen and digestive tract. Erosion and necrosis at cartilage layer and cluster of chondrocyte were observed in scapular fossa and head of humerus in the 260 and 561 mg/kg groups. 3. In the monkey study, 2 animals given 260 mg/kg survived and 2 animals given 520 mg/kg died. Approximate lethal dose in monkeys was between 260 and 520 mg/kg. In the 260 mg/kg group, soft feces was observed. In the 520 mg/kg group, paleness mucosa of oral cavity, muscle weakness, mydriasis and dyspnea were observed and animals died within 4 minutes after dosing. Macroscopic and histopathological examinations in 2 dead animals showed congestion in lung, liver and kidney.

Alanine Transaminase↗
PubMed1998

[Three months intravenous repeated dose toxicity study of T-3762 in rats].

A three months intravenous repeated dose toxicity study of T-3762, a novel parenteral quinolone antibacterial agent, was carried out in rats at dose levels of 4, 13, 39, 130 mg/kg. Fifteen rats of each sex were used in each group. Out of these, 5 rats of each sex were used for the recovery study. The following results were obtained. 1. There were no death caused by T-3762 within the study period. In clinical signs, the squeaks during injection in 130 mg/kg group were observed, but they decreased day by day. In body weight changes, a tendency to very slight decrease of weight gain in male 130 mg/kg group were seen, but there was no significant difference from control group. In food and water consumption, there was no abnormality. 2. There were no abnormality caused by T-3762 in urinalysis, hematological examination and ophthalmological examination. 3. In blood chemistry examinations, increase of A/G ratio was seen in 13, 39 and 130 mg/kg groups, but it showed tendency of recovery after withdrawal period. 4. In macroscopic and histological findings, erosion and cavitation of the articular cartilage were seen in 3 of 20 rats in 130 mg/kg group and 1 of 20 rats in 39 mg/kg group. 5. Non-toxic dose levels is estimated to 13 mg/kg, that showed no abnormality in the articular cartilage in this study.

Alanine Transaminase↗
PubMed1997

The novel genes, cbbQ and cbbO, located downstream from the RubisCO genes of Pseudomonas hydrogenothermophila, affect the conformational states and activity of RubisCO.

The cbbQ and cbbO genes are located downstream from the RubisCO genes (cbbLS) in the thermophilic hydrogen-oxidizing bacterium, Pseudomonas hydrogenothermophila. Recombinant RubisCO enzymes were purified from E. coli cells which were transformed with plasmids expressing cbbLS, cbbLSQ, cbbLSO, or cbbLSQO. Co-expression of cbbQ and/or cbbO with cbbLS made the maximal rates of carboxylation (Vmax) of the recombinant RubisCOs about two-fold higher than that of the enzyme derived from only cbbLS. The RubisCOs with high Vmax also had a high stability when undergoing ultrasonic treatment. The results of the circular dichroism spectra and the 8-anilino-1-naphthalenesulfonate binding assay indicated that these recombinant RubisCOs were conformationally different to each other.

Bacterial Proteins↗
PubMed1997

The conformation of the alpha-helical coiled coil domain of macrophage scavenger receptor is pH dependent.

Macrophage scavenger receptor is a trimerized membrane protein that binds ligands and undergoes internalization by endocytosis. The receptor releases the ligands in the endosome, and then is recycled. The mechanisms of the ligand release and the recycling of the receptor have not been clearly determined. We analyzed the structure of the alpha-helical coiled coil domain considered to be responsible for acid-mediated ligand dissociation, by chemical cross-linking, sedimentation equilibrium, Western blot, and circular dichroism analyses. This domain has 22 heptad repeats, which are characteristic of the sequence of an alpha-helical coiled coil structure, with a discontinuity in the middle. We prepared three peptides, corresponding to the entire alpha-helical coiled coil domain (alpha), its N-terminal half (alpha-N), and its C-terminal half (alpha-C), by expression of each gene in Escherichia coli. The alpha and alpha-N peptides show triple-stranded alpha-helical coiled coil structures, but in contrast, the alpha-C peptide shows a random structure. When connected to the N-terminus by a chemical ligation method, the alpha-C peptide also shows an alpha-helical coiled coil structure, but only at an acidic pH. These results suggest that the N-terminus of the alpha-helical coiled coil domain is responsible for the formation of a stable trimer and the C-terminus exhibits the pH-dependent conformational change that might be involved in the ligand release by the macrophage scavenger receptor.

Amino Acid Sequence↗
PubMed1997

The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock.

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mphi) to release inflammatory mediators such as tumor necrosis factor (TNF)-alpha, which can cause hypotension, organ failure, and often death. Several different receptors on Mphi have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mphi express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mphi to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-alpha and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-alpha activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mphi, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mphi of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

Animals↗
PubMed1997

Inhibition of oxidation of low-density lipoprotein by a novel antioxidant, BO-653, prepared by theoretical design.

2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran (BO-653) is a novel antioxidant synthesized by theoretical designing based on the previous experimental findings and consideration. The antioxidant activities of BO-653 against the oxidative modification of low-density lipoprotein (LDL) induced by free radicals were studied. BO-653 was consumed faster than endogenous alpha-tocopherol and inhibited the formation of lipid hydroperoxides, which was observed during the consumption of alpha-tocopherol. Doxyl stearic acids incorporated into LDL as spin probes competed with the antioxidants in scavenging radicals. It was found that the efficacy of radical scavenging by alpha-tocopherol became smaller as the radical went deeper into the interior of LDL particle, whereas that by BO-653 did not change. Ascorbic acid in the aqueous phase spared alpha-tocopherol efficiently during oxidation. On the other hand, the sparing effect of ascorbic acid for BO-653 was not remarkable, unlike that for alpha-tocopherol, which implied different locations of radicals derived from BO-653 and alpha-tocopherol within the LDL particle. It was concluded that BO-653 protected LDL from oxidative modification efficiently by scavenging peroxyl radicals and by reducing alpha-tocopheroxyl radicals and that this novel antioxidant might act as a potent inhibitor of development of atherosclerosis.

Amidines↗
PubMed1997

The lysine cluster in the collagen-like domain of the scavenger receptor provides for its ligand binding and ligand specificity.

Scavenger receptors bind modified low-density lipoproteins (LDL) on a collagen-like domain which possesses a lysine cluster at the carboxy end. We previously constructed a receptor model peptide containing the lysine cluster. In the present study, we evaluated the ligand specificity of the receptor model peptide. It selectively bound modified-LDLs, and not LDL. The binding of acetylated-LDL (Ac-LDL) was inhibited by dextran sulfate, fucoidan, and sulfatides in a manner similar to that of the natural receptor. Both polyguanylic and polyinosinic acids inhibit the Ac-LDL binding whereas polycytidylic acid did not. These results indicate that the lysine cluster in the collagen-like domain has important roles in both ligand binding and ligand specificity.

Amino Acid Sequence↗