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Biomedical subjects

K Tsukamoto

Publications and source records attributed to K Tsukamoto.

At least 109 records · Page 6Linked to original sources
PubMed1999

Identification of SK-951, a novel benzofuran derivative, as an agonist to 5-HT4 receptors.

The pharmacological profile of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl) ethyl]-5-chloro-2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide hemifumarate) was identified in relation to serotonin 5-HT3 and 5-HT4 receptors by the receptor binding assay and functional studies. The receptor binding assay showed that SK-951 bound to the 5-HT3 receptor with a high affinity, to the 5-HT4 receptor with relatively higher affinity and to the muscarinic M2 receptor with a low affinity, but not to dopamine D1 and D2 and serotonin 5-HT1 and 5-HT2 and muscarinic M1 and M3 receptors. SK-951 caused relaxations of tunica muscularis mucosae preparations from rat esophagus which were precontracted with carbachol, and the effects were antagonized by GR113808, a selective 5-HT4 antagonist. In the longitudinal muscle with myenteric plexus (LMMP) preparations from guinea pig ileum, SK-951 enhanced the electrically-stimulated contraction of preparations in which the 5-HT1, 5-HT2 and 5-HT3 receptors were blocked, and it enhanced the electrically-stimulated release of [3H]acetylcholine (ACh). These effects of SK-951 were antagonized by GR113808. SK-951 inhibited the 5-HT3 receptor-mediated contractions. These results indicate that SK-951 possesses properties of an agonist for the 5-HT4 receptor and an antagonist for the 5-HT3 receptor. Thus, SK-951 is a new and potent 5-HT4-receptor agonist and causes contractions of guinea pig ileum mediated by enhancement of ACh release via the 5-HT4 receptor.

Acetylcholine↗
PubMed1999

Effects of SK-951, a benzofuran derivative, as a prokinetic agent in rats and dogs.

The gastrokinetic activity of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3-dihy dro-2-methylbenzo[b]furan-7-carboxamide hemifumarate), a benzofuran derivative with 5-hydroxytryptamine (5-HT)4-receptor agonist activity, was studied in rats and dogs. The effects of SK-951 were also investigated in a model of vagotomy-induced gastroparesis in comparison with cisapride. In rats, both SK-951 and cisapride enhanced gastric emptying of liquids (phenol red) at a dose of 1-100 mg/kg, p.o. Gastric emptying of liquid (acetaminophen) in fasted beagle dogs was enhanced significantly by SK-951 (1.0 mg/kg, i.v.), whereas the effect of cisapride (0.2-1.0 mg/kg, i.v.) was not statically significant. Similar results were found when radiopaque markers were given with standard meal to dogs with vagotomy-induced gastroparesis. The delayed gastric emptying of radiopaque markers by vagotomy was reversed by SK-951 (1.0 mg/kg, i.v.), whereas cisapride showed no effect at doses from 0.1 to 1.0 mg/kg, i.v. These results indicated that oral and intravenous administration of SK-951 accelerates gastric emptying of both liquids and solids in animal models. Thus, SK-951 may be a highly potent and useful prokinetic agent in comparison to cisapride.

Animals↗
PubMed1999

Biphasic change in correlation between ovarian lipid peroxides and progestational activity during pseudopregnancy induced in immature rats.

We measured ovarian lipid peroxide (LP) levels and plasma progestins, progesterone (P4) and 20alpha-dihydroprogesterone, throughout pseudopregnancy in gonadotropin-primed immature rats. Plasma P4 fluctuated, with two peaks on days 5 (PSP5) and 8 of pseudopregnancy, and then declined to the basal level by PSP12. Ovarian LP increased from PSP1 to PSP4, decreased temporarily until PSP8, and then rose gradually until PSP14. From PSP1 through PSP7, ovarian LP was positively correlated with total progestins according to the Spearman ranked correlation coefficient (r=+0.829, p<0.05). In contrast, a negative correlation between ovarian LP and plasma P4 was apparent (r=-0.816, p<0.05) from PSP8 to PSP14. These results show the biphasic correlation of LP with luteal progestational activity depending on the luteal stage.

20-alpha-Dihydroprogesterone↗
PubMed1999

Relationship between glycosylated hemoglobin and the prevalence of proteinuria in Japanese men.

A total of 5,174 Japanese men were included in a cross-sectional study to examine the relationship between the glycated hemoglobin (HbA1C) level and the prevalence of proteinuria as determined using a reagent strip. The prevalence of proteinuria rose significantly at HbA1C levels above 5.9%, whereas no relationship was observed at HbA1C levels below 5.9%. Multiple logistic regression analysis showed that blood pressure and a family history of diabetes were independent factors associated with proteinuria in subjects with a HbA1C below 5.9% who were not under medication for diabetes. In contrast, HbA1C, obesity and smoking were associated with proteinuria in subjects who were under medication for diabetes and/or have a HbA1C above 5.9%. These findings suggest that maintaining a HbA1C level below 5.9%, non-smoking and a standard body weight may reduce the prevalence of proteinuria in Japanese men. Healthy life-style and standard body weight are especially important for subjects with a family history of diabetes.

Adult↗
PubMed1999

[A case of pulmonary alveolar proteinosis presenting with peripheral infiltrates].

We report a case of pulmonary alveolar proteinosis (PAP). A 39-year-old asymptomatic woman was admitted to our hospital because of abnormal shadows on chest X-ray films. Chest X-ray films revealed peripheral infiltrates in both lungs. Computed tomographic examination showed patchy peripheral ground-glass attenuation, concentrated subpleurally. Bronchoalveolar lavage fluid was clear. Because transbronchial lung biopsy findings were inconclusive, a VATS-biopsy was performed. The specimens demonstrated accumulation of proteinaceous materials within alveolar spaces. The patient was given a diagnosis of PAP. Although the distribution of radiographic shadows varies in patients with PAP, perihilar or centralized shadows usually predominate. In our patient, subpleural areas of the lung were affected almost exclusively.

Adult↗
PubMed1999

[Recurrent pulmonary infarction associated with familial protein S deficiency type III].

A 38-year-old woman was admitted to our hospital because of recurrent chest pain and fever. Chest X-ray films and computed tomograms showed subpleural consolidation containing small cavity-like opacities. Open lung biopsy revealed non-infectious abscess and vessels with organizing thrombus. The patient was given a diagnosis of pulmonary infarction due to the existence of deep venous thrombosis. Coagulation studies demonstrated that she had decreased plasma protein S activity, whereas her free and total protein S antigen levels were normal. Because her mother and maternal uncle and aunt also demonstrated decreased protein S activity with normal plasma protein S antigen levels, the patient was considered to be affected by familial protein S deficiency type III.

Adult↗
PubMed1999

[Pyothorax associated lymphoma treated by chemotherapy after thoracostomy].

A 62-year-old man with a medical history that included artificial pneumothorax therapy at the age of 18 was admitted to our hospital because of persistent cough. Chest computed tomographic scans disclosed atelectasis in the right lung and pyothorax surrounded by calcifications. Radiographic examination failed to disclose any tumors. After admission, high grade fever developed due to aggravated pyothorax infection. Because antibiotic therapy and drainage failed, open window thoracostomy was performed. Tumors were found along the wall of the pyothorax cavity, and examination of resected specimens yielded a diagnosis of non-Hodgkin's lymphoma, diffuse large cell type (B-cell lineage). It was difficult to close the pyothorax cavity due to infection and lymphoma. Therefore, with the thoracic window open, the patient was given combination chemotherapy including CHOP (6 courses) and DeVIC (7 courses). He died of disseminated intravascular coagulation 17 months after thoracostomy. In patients with pyothorax associated lymphoma, chemotherapy is sometimes difficult to perform because of persistent pyothorax infection. Although edema and ascites due to protein loss from the tumor complicated the treatment of our patient, we concluded that open window thoracostomy is effective in managing pyothorax prior to and during chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Hepatic overexpression of microsomal triglyceride transfer protein (MTP) results in increased in vivo secretion of VLDL triglycerides and apolipoprotein B.

The microsomal triglyceride transfer protein (MTP) is essential for the hepatic secretion of apolipoprotein (apo) B-containing lipoproteins. Previous studies have indicated that inhibition of MTP results in decreased apoB plasma levels and decreased hepatic triglyceride secretion. However, the metabolic effects of overexpression of MTP have not been investigated. We constructed a recombinant adenovirus expressing MTP (AdhMTP) and used it to assess the effects of hepatic overexpression of MTP in mice. Injection of AdhMTP into C57BL/6 mice resulted in a 3-fold increase in hepatic microsomal triglyceride transfer activity compared to mice injected with Adnull. On day 4 after virus injection, AdhMTP-injected mice had significantly elevated plasma TG levels as compared to control virus (Adnull)-injected mice. Hepatic TG secretion rates were significantly greater in AdhMTP-injected mice (184 +/- 12 mg/kg/h) compared with Adnull-injected mice (65 +/- 9 mg/kg/h, P < 0.001). In addition, hepatic very low density lipoprotein (VLDL) apoB secretion in the AdhMTP-injected group was 74% higher than in the control virus group. Hepatic secretion of apoB-48 and apoB-100 contributed equally to this increase. These results provide the first data that hepatic overexpression of MTP results in increased secretion of VLDL-triglycerides as well as VLDL-apoB in vivo. These results suggest that MTP is rate-limiting for VLDL apoB secretion in wild-type mice under basal chow-fed conditions.

Animals↗
PubMed1999

Phase I study of irinotecan combined with carboplatin in previously untreated solid cancers.

Irinotecan (CPT-11) and carboplatin have broad anti-tumor activities. We conducted a Phase I study of CPT-11 combined with carboplatin in previously untreated solid cancers, especially advanced lung cancer. The aim of the study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this regimen. In addition, we prospectively evaluated the Chatelut formula for predicting carboplatin clearance. Patients with advanced cancer were treated with CPT-11 (days 1, 8, and 15) and carboplatin (day 1) of a fixed-target area under the concentration-time curve (AUC) of 5 mg x min/ml. Carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The CPT-11 dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2. A total of 27 patients, 26 lung cancer patients and 1 colon cancer patient, were enrolled in this study. Dose-limiting leukoneutropenia, thrombocytopenia, and diarrhea, including one treatment-related death, were observed at 60 mg/m2 CPT-11, indicating that this level was the MTD. In 11 patients, the actual AUCs of carboplatin almost achieved the target AUC of 5. Fifteen (60%) of 25 evaluable patients showed an objective response, with an 85% response rate [11 of 13 patients (complete response, 31%; partial response, 54%)] in small cell lung cancers and a 36% response rate (4 of 11 patients) in non-small cell lung cancers. Neutropenia, thrombocytopenia, and diarrhea were the dose-limiting toxicities in this regimen. CPT-11 (50 mg/m2) under the carboplatin target AUC of 5 using the Chatelut formula was the recommended dose for further Phase II study, and this regimen seems to be active for small cell lung cancer.

Adult↗
PubMed1998

Mg2+ binding and catalytic function of sphingomyelinase from Bacillus cereus.

The modes of Mg2+ binding to SMase from Bacillus cereus were studied on the basis of the changes in the tryptophyl fluorescence intensity. This enzyme was shown to possess at least two binding sites for Mg2+ with low and high affinities. The effects of Mg2+ binding on the enzymatic activity and structural stability of the enzyme molecule were also studied. The results indicated that the binding of Mg2+ to the low-affinity site was essential for the catalysis, but was independent of the substrate binding to the enzyme. It was also indicated that the alkaline denaturation of the enzyme was partly prevented by the Mg2+ binding, whereas no significant protective effect was observed against the denaturation by urea. The pH dependence of the kinetic parameters for the hydrolysis of micellar HNP and mixed micellar SM with Triton X-100 (1:10), catalyzed by SMase from B. cereus, was studied in the presence of a large amount of Mg2+ to saturate both the low- and high-affinity sites. The pH dependence curves of the logarithm of 1/Km for these two kinds of substrates were similar in shape to each other, and showed a single transition. On the other hand, the shapes of the pH dependence curves of the logarithm of kcat for these two kinds of substrates were different from each other. The pH dependence curve for micellar HNP showed three transitions and, counting from the acidic end of the pH region, the first and third transitions having tangent lines with slopes of +1 and -1, respectively. On the other hand, the curve for mixed micellar SM with Triton X-100 showed one large transition with a slope of +1 (the first transition) and a very small transition (the third transition). On the basis of the present results and the three-dimensional structure of bovine pancreatic DNase I, which has a primary structure similar to that of B. cereus SMase, we proposed a catalytic mechanism for B. cereus SMase based on general-base catalysis.

Animals↗
PubMed1998

A leukotriene receptor antagonist, ONO-1078, modulates drug sensitivity and leukotriene C4 efflux in lung cancer cells expressing multidrug resistance protein.

ONO-1078 is a new class of peptide leukotriene receptor antagonist, and multidrug resistance protein (MRP) is a membrane tranporter of multiple anticancer drugs and endogenous leukotriene C4 (LTC4). We investigated the effects of ONO-1078 on drug sensitivity and LTC4-efflux in MRP-expressing lung cancer cells. Drug sensitivity, intracellular vincristine accumulation, and intracellular and extracellular LTC4 concentrations were measured with or without ONO-1078. The effect of ONO-1078 on MRP-mediated calcein-efflux was determined by flow cytometry. ONO-1078 (1 to 10 microM) dose-dependently enhanced the sensitivity of NCI-H520 cells to vincristine with the reduced accumulation, and also enhanced the sensitivity to doxorubicin and etoposide. ONO-1078 inhibited both LTC4- and calcein-efflux from the cells with increased intracellular accumulations. Our findings indicate that ONO-1078 modulates multidrug resistance and inhibits LTC4-efflux in lung cancer cells, by inhibition of MRP function.

ATP-Binding Cassette Transporters↗
PubMed1998

Molecular cloning of a GPI-anchored aminopeptidase N from Bombyx mori midgut: a putative receptor for Bacillus thuringiensis CryIA toxin.

An aminopeptidase N (APN) with a molecular weight of 110kDa was released from the midgut membrane of Bombyx mori by phosphatidylinositol-specific phospholipase C (PI-PLC), and purified to a homogeneous state. This 110-kDa APN was different from the 100-kDa APN that we previously reported, in chromatographic behaviors, substrate specificity, and N-terminal and internal amino acid sequences. However, the N-terminal sequence of 110-kDa APN, DPAFRLPTTTRPRHYQVTLT, was highly homologous with those of Manduca sexta and Heliothis virescens APNs, which were identified as a receptor for an insecticidal toxin of Bacillus thuringiensis. From a B. mori midgut cDNA library, we cloned the 110-kDa APN cDNA that possessed a 2958-bp open reading frame encoding a 111573-Da polypeptide of 986 residues. The sequence of the eicosa-peptide Asp42Thr61 deduced from the cDNA was completely matched with the N-terminal sequence of the mature 110-kDa APN. One potential N-glycosylation site, HEXXHXW zinc-binding motif and characteristic proline-rich repeats were observed in the ORF. Moreover, the primary sequence contained two hydrophobic peptides on N- and C-termini. The N-terminal peptide sequence showed characteristics of leader peptide for secretion and the C-terminal peptide contained a possible glycosylphosphatidylinositol (GPI) anchoring site. Taken together, the deduced amino acid sequence suggests that the 110-kDa APN is a GPI-anchored protein and a specific receptor protein for B. thuringiensis CryIA delta-endotoxin.

Amino Acid Sequence↗
PubMed1998

Characterization of aminopeptidase N from the brush border membrane of the larvae midgut of silkworm, Bombyx mori as a zinc enzyme.

Three GPI-anchored proteins, aminopeptidase N, alkaline phosphatase and alkaline phosphodiesterase I were released from the midgut brush border membrane of Bombyx mori by phosphatidylinositol-specific phopholipase C and the aminopeptidase N was purified to a homogeneous state. N-terminus and 6 internal sequences, one of which possessed part of zinc-binding motif, showed homology with those from other species. The zinc content in purified aminopeptidase N was estimated as approximately 0.72 mol/mol of the protein and 1,10-phenanthroline completely inhibited the enzyme activity, suggesting zinc requirement for the activity. The aminopeptidase N activity was inhibited not only by probestin and actinonin, but also strongly depressed by amastatin, while leuhistin and bestatin were less inhibitory. These suggest that the active site of aminopeptidase N might be structurally different from those of mammals. Calcium and magnesium ions stimulated the aminopeptidase N activity, but copper ion was rather inhibitory. Zinc ion showed bi-modal effect on the activity, i.e., stimulatory at low concentration, but inhibitory at higher than 100 microM. This inhibition was completely restored by EDTA. These results suggest that the aminopeptidase N possesses two zinc ion-binding sites with high and low affinity as essential and inhibitory one, as well as some regulatory metal-binding sites.

Amino Acid Sequence↗
PubMed1998

Allelic loss on chromosome 1p is associated with progression and lymph node metastasis of primary breast carcinoma.

BACKGROUND: Frequent allelic losses on the short arm of chromosome 1 have been observed in a wide variety of human tumors. Cytogenetic and molecular genetic studies in breast carcinomas have shown frequent alterations on chromosome 1, involving loss of 1p or gain of 1q. METHODS: To define the locations of tumor suppressor genes, 143 primary breast carcinomas were examined for allelic loss using 15 highly polymorphic microsatellite markers on 1p. Correlations also were sought between allelic loss on 1p and several clinicopathologic parameters. RESULTS: Allelic loss was observed in 73 of the tumors (51%). Detailed deletion mapping identified target regions at 1p36, 1p34-p35, and 1p22-p31. Allelic losses at 1.36 or 1p34-p35 were observed more frequently in tumors of the solid tubular and scirrhous types than in less aggressive histologic types. Conversely, allelic loss at 1p22-p31 was correlated with lymph node metastasis and a tumor size > 2 cm. CONCLUSIONS: Inactivation of tumor suppressor genes that lie in either 1p36 or 1p34-p35 might affect carcinogenic mechanisms in a histologic type specific manner, especially the solid tubular and scirrhous types. Alterations of one or more tumor suppressor genes at 1p22-p31 may play a role at late stages of breast carcinogenesis, especially with regard to local progression and lymph node metastasis.

Adenocarcinoma↗
PubMed1998

Whole-body cortisol concentrations and ontogeny of aggressive behavior in yellowtail (Seriola quinqueradiata Temminck & Schlegel; Carangidae).

Ontogenetic changes in whole-body immunoreactive cortisol concentrations (IRC) and aggressive behavior were examined in yellowtail Seriola quinqueradiata (Temminck & Schlegel; Carangidae). Baseline IRC significantly increased during the transition from larval to juvenile stage and was correlated with the onset of aggressive behavior. Handled fish (13.1 +/- 2.6 ng/g tissue) showed an IRC level about three times higher than unhandled fish (4.7 +/- 1.4 ng/g tissue), indicating that whole-body immunoreactive cortisol level may be an indicator of stress in juvenile yellowtails. Behaviorally subordinate fish (8.6 +/- 1.6 ng/g tissue, n = 4) showed IRC levels significantly higher than dominant fish (0.6 +/- 0.3 ng/g tissue, n = 4). Whole-body immunoreactive cortisol levels may thus reflect stress and social status in juvenile yellowtails, and the inverse relationship between social rank and IRC may result from agonistic interactions.

Aggression↗
PubMed1998

Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human estrogen receptor beta locus.

A gene for a second type of human estrogen receptor, the estrogen receptor beta (ESR beta), was recently identified. We isolated a polymorphic dinucleotide CA repeat marker from a genomic clone containing the human estrogen receptor beta gene. High heterozygosity (0.93) makes this polymorphism a useful marker in the genetic study of disorders affecting female endocrine systems; calcium metabolism; and breast, uterine, and ovarian cancers.

Alleles↗
PubMed1998

Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human matrix Gla protein (MGP) locus.

Matrix Gla protein (MGP) is an 84-residue, vitamin K-dependent protein expressed by chondrocytes and vascular smooth muscle cells, and is a potent regulator of calcium deposition in cartilage and arterial wall. We isolated a polymorphic dinucleotide CA repeat marker from a genomic clone containing the human MGP gene. This polymorphism will be useful in genetic studies of arteriosclerosis and osteoporosis.

Alleles↗