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Biomedical subjects

K Kondo

Publications and source records attributed to K Kondo.

At least 271 records · Page 15Linked to original sources
PubMed1998

OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats.

The pharmacological profile and the acute and chronic aquaretic effects of OPC-41061, a novel nonpeptide human arginine vasopressin (AVP) V2-receptor antagonist, were respectively characterized in HeLa cells expressing cloned human AVP receptors and in conscious male rats. OPC-41061 antagonized [3H]-AVP binding to human V2-receptors (Ki = 0.43 +/- 0.06 nM) more potently than AVP (Ki = 0. 78 +/- 0.08 nM) or OPC-31260 (Ki = 9.42 +/- 0.90 nM). OPC-41061 also inhibited [3H]-AVP binding to human V1a-receptors (Ki = 12.3 +/- 0.8 nM) but not to human V1b-receptors, indicating that OPC-41061 was 29 times more selective for V2-receptors than for V1a-receptors. OPC-41061 inhibited cAMP production induced by AVP with no intrinsic agonist activity. In rats, OPC-41061 inhibited [3H]-AVP binding to V1a-receptors (Ki = 325 +/- 41 nM) and V2-receptors (Ki = 1.33 +/- 0. 30 nM), showing higher receptor selectivity (V1a/V2 = 244) than with human receptors. A single oral administration of OPC-41061 in rats clearly produced dose-dependent aquaresis. In treatment by multiple OPC-41061 dosing for 28 days at 1 and 10 mg/kg p.o. in rats, significant aquaretic effects were seen throughout the study period. As the result of aquaresis, hemoconcentration was seen at 4 hr postdosing although, no differences were seen in serum osmolality, sodium, creatinine and urea nitrogen concentrations at 24 hr postdosing. Furthermore, there was no difference in serum AVP concentration, pituitary AVP content or the number and affinity of AVP receptors in the kidney and liver at trough throughout the study period. These results demonstrate that OPC-41061 is a highly potent human AVP V2-receptor antagonist and produces clear aquaresis after single and multiple dosing, suggesting the usefulness in the treatment of various water retaining states.

Animals↗
PubMed1997

Variant exons v6 and v7 together expand the repertoire of glycosaminoglycans bound by CD44.

Isoforms of the glycoprotein CD44 are cell surface receptors for the glycosaminoglycan hyaluronate. They have been implicated in many biological processes, but their function in these is poorly understood and cannot be explained solely by hyaluronate binding. In the present work we examine the ligand binding properties of alternatively spliced CD44 variant isoforms which are functionally involved in the immune system, embryonic development, and tumor behavior. We show that these isoforms bind directly to the purified glycosaminoglycans chondroitin sulfate, heparin, and heparin sulfate, in addition to being able to bind to hyaluronate. Binding to this extended repertoire of glycosaminoglycans by CD44 depends on the inclusion of peptide sequences encoded by the alternatively spliced exons v6 and v7, and occurs both when the CD44 is solubilized from the plasma membrane and when it is expressed on intact cells. A single point mutation in the most N-terminal hyaluronate binding motif of CD44 ablates both hyaluronate and chondroitin sulfate binding, suggesting that glycosaminoglycans are bound through a common motif, and that only one of the hyaluronate binding motifs is responsible for the majority of glycosaminoglycan binding by CD44 on the cell surface. Taken together, these observations indicate that alternative splicing regulates the ligand binding specificity of CD44 and suggest that structural changes in the CD44 protein have a profound effect on the range of ligands to which this molecule can bind with potentially wide-ranging functional consequences.

Alternative Splicing↗
PubMed1997

GDNF-induced neurite formation was stimulated by protein kinase inhibitors and suppressed by Ras inhibitors.

The effects of various inhibitors on the glial cell line-derived neurotrophic factor (GDNF)-induced neurite formation in TGW human neuroblastoma cells were investigated. Treatment of cells with Ser/Thr protein kinase inhibitors such as staurosporine, H-7, H-8 and HA-1004, induced neurite formation without GDNF. On the other hand, tyrosine kinase inhibitors such as erbstatin, genistein and herbimycin A did not produce neurites per se, but effectively enhanced the GDNF-induced neurite formation. A phosphatase inhibitor, okadaic acid, and Ras inhibitors such as oxanosine, damnacanthal and conophylline strongly suppressed the effect of GDNF. These results suggest that a tyrosine protein kinase has a suppressive role in the neurite formation induced by GDNF and that Ras is necessary for the signaling initiated by GDNF.

Enzyme Inhibitors↗
PubMed1997

Mutations of the p53 gene in human lung cancer from chromate-exposed workers.

We examined p53 mutations in 20 cancer samples from 19 chromate workers with lung cancer by Polymerase chain reaction-Single strand conformation polymorphism analysis and direct sequencing. Six missense mutations were identified in 4 (20%) of the 20 chromate lung cancer samples. Fewer mutations were found in the patients with lung cancers who had been exposed to chromate than in those who had not. However, the pattern of p53 mutations in lung cancer patients exposed to chromate differed from that of common lung cancers in 3 respects. There were no apparent G to T transversions, which are common base changes in lung cancers. Half of the mutational sites (3/ 6) had changes of AT base-pairs, and 2 of 4 mutational tumor samples had double missense mutations. Our results suggested that chromate exposure may induce point mutation of the p53 gene.

Adenocarcinoma↗
PubMed1997

Interaction of DA41, a DAN-binding protein, with the epidermal growth factor-like protein, S(1-5).

Recently, we have identified a new protein (DA41) which can associate with candidate tumor-suppressor DAN protein. In the present study, we have searched for DA41-interacting protein(s), using a yeast two-hybrid system. An adult rat lung cDNA library was screened by using a truncated form of DA41 (1-308) which lacks a DAN-binding region as bait. One of the positive clones, T16, contained a cDNA sequence of 1934 nucleotides with a single open reading frame of 493 amino acids. A data base search revealed that T16 exhibited a strong sequence similarity to the human epidermal growth factor (EGF)-like protein, S(1-5). The region encoding amino acids 155-232 of DA41 was identified for the interaction with T16. Since DAN and S(1-5) proteins are known to suppress and stimulate DNA synthesis, respectively, it is possible that functional interaction of DAN with S(1-5) through DA41 might play an important role(s) in the regulation of cell growth.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Cloning and characterization of HB2, a candidate high density lipoprotein receptor. Sequence homology with members of the immunoglobulin superfamily of membrane proteins.

The protection against coronary artery disease attributed to high density lipoprotein (HDL) may be associated with several functions, including its central role in reverse cholesterol transport, possible antioxidant and antithrombotic properties and others not yet identified which may depend on specific interactions between HDL and cell receptors. Several HDL-binding proteins have been identified including two candidate liver HDL receptors, HB1 and HB2 recently purified in this laboratory. We now report the cloning, sequencing, and some properties of HB2, the most abundant of the pair. It shows significant homology with the adhesion molecules ALCAM and BEN of the immunoglobulin superfamily and the cDNA, when transfected into HepG2 or COS cells, caused specific HDL3 binding to increase by 80-100%. Further, ligand blotting of glycoproteins isolated from phorbol 12-myristate 13-acetate-treated THP-1 cells or from transfected HepG2 and Chinese hamster ovary cells also provided evidence of increased binding of HDL3 to HB2. Differentiation of THP-1 cells into macrophages resulted in a striking increase in HB2 mRNA which was attenuated if cells were cholesterol-loaded by incubation with acetylated low density lipoprotein. If the interaction between HDL and HB2 reduces the adhesion-induced inflammatory cellular events that characterize arterial wall injury, thereby achieving the protection associated with higher plasma levels of HDL, these findings may provide a clue to one mitigating effect of HDL in heart disease.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1997

Relation of duration of ST reelevation at reperfusion and improvement of left ventricular function after successful primary angioplasty of the left anterior descending coronary artery in anterior wall acute myocardial infarction.

We conducted a prospective study to investigate the relation between ST reelevation during primary angioplasty and improvement in left ventricular function. The duration, not the occurrence, of ST reelevation at reperfusion was associated with improvement in left ventricular function in patients with anterior wall acute myocardial infarction successfully recanalized by primary angioplasty.

Aged↗
PubMed1997

Antithrombotic effects in a rat model of aspirin-insensitive arterial thrombosis of desethyl KBT-3022, the main active metabolite of a new antiplatelet agent, KBT-3022.

The antithrombotic effect of desethyl KBT-3022, which is the main active metabolite of the new antiplatelet agent, KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl] pyrrol-1-ylacetate; a cyclooxygenase inhibitor), was determined using a photochemically induced arterial thrombosis model in the rat femoral artery. Pretreatment with desethyl KBT-3022 (0.1, 0.3 and 1 mg/kg, i.v.) prolonged the time required to achieve thrombotic occlusion in the femoral artery and inhibited collagen-induced platelet aggregation in whole blood ex vivo, each in a dose-dependent manner. In all 6 rats used, particularly at the highest dose (1 mg/kg, i.v.) tested, cyclic variations in blood flow were hardly ever observed and complete cessation of blood flow did not occur during the 30-min observation time. BM-13505 (1, 3 and 10 mg/kg, i.v.), a thromboxane A2 receptor antagonist, also prolonged the time to occlusion, but cyclic variations in blood flow did occur. On the other hand, aspirin (10 and 30 mg/kg, i.v.) had little effect in terms of preventing thrombosis, although it inhibited collagen-induced platelet aggregation to the same extent as did desethyl KBT-3022. Desethyl KBT-3022 inhibited the thrombin-induced aggregation of washed platelets in a concentration-dependent manner (1-40 microM), whereas aspirin and BM-13505 did not. These findings suggest that the potent antithrombotic effect of desethyl KBT-3022 may be attributable in part to its additional ability to inhibit thrombin-induced platelet aggregation. Accordingly, thromboxane A2 and thrombin may be important thrombotic mediators in this rat model.

Animals↗
PubMed1997

Expression of an exogenous isopentenyl diphosphate isomerase gene enhances isoprenoid biosynthesis in Escherichia coli.

Escherichia coli expressing the Erwinia carotenoid biosynthesis genes, crtE, crtB, crtI and crtY, form yellow-coloured colonies due to the presence of beta-carotene. This host was used as a visible marker for evaluating regulatory systems operating in isoprenoid biosynthesis of E. coli. cDNAs enhancing carotenoid levels were isolated from the yeast Phaffia rhodozyma and the green alga Haematococcus pluvialis. Nucleotide sequence analysis indicated that they coded for proteins similar to isopentenyl diphosphate (IPP) isomerase of the yeast Saccharomyces cerevisiae. Determination of enzymic activity confirmed the identity of the gene products as IPP isomerases. The corresponding gene was isolated from the genomic library of S. cerevisiae based on its nucleotide sequence, and was confirmed to have the same effect as the above two IPP isomerase genes when introduced into the E. coli transformant accumulating beta-carotene. In the three E. coli strains carrying the individual exogenous IPP isomerase genes, the increases in carotenoid levels are comparable to the increases in IPP isomerase enzyme activity with reference to control strains possessing the endogenous gene alone. These results imply that IPP isomerase forms an influential step in isoprenoid biosynthesis of the prokaryote E. coli, with potential for the efficient production of industrially useful isoprenoids by metabolic engineering.

Amino Acid Sequence↗
PubMed1997

Lamprey fructose-1,6-bisphosphate aldolase: characterization of the muscle-type and non-muscle-type isozymes.

To study evolutionary aspects of fructose-1,6-bisphosphate (Fru-1,6-P2) aldolase during deuterostomian evolution, we have purified and characterized aldolases from the muscle and liver of lamprey (Entosphenus japonicus). Aldolase from the skeletal muscle and liver was identified to be the muscle-type isozyme and the non-muscle-type isozyme that was encoded by cDNAs M8 and L3, respectively, as described previously (Zhang, R., Yatsuki, H., Kusakabe, T., Iwabe, Miyata, T., Imai, T., Yoshida, M., and Hori, K., J. Biochem. 117, 545-553, 1995). The muscle-type isozyme has properties similar to vertebrate aldolase A, while the non-muscle-type isozyme shows a similarity to bacterial class I aldolase and vertebrate aldolase C but not to aldolase B, the liver-type aldolase, in terms of kinetic parameters: the Kcat values toward Fru-1,6-P2 and Fru-1-P, the Fru-1,6-P2/Fru-1-P activity ratio, and the Km values toward these substrates. The two enzymes have tetrameric forms with a molecular mass of approximately 160,000 and have similar pH optimum. The muscle-type and non-muscle-type isozymes from the tissues show different electrophoretic mobility; the muscle-type isozyme moves much faster than the non-muscle-type isozyme toward anodic side. The recombinant muscle-type and non-muscle-type aldolases gave similar characteristics as those from the tissues. The results presented in this paper, together with the data presented in the previous paper, strongly suggest that in lamprey it is possible to have two types of aldolase isozymes rather than one or three isozymes.

Amino Acid Sequence↗
PubMed1997

Somatic mutations of the von Hippel-Lindau tumor suppressor gene and loss of heterozygosity on chromosome 3p in human glial tumors.

Molecular genetic analysis of von Hippel-Lindau tumor suppressor gene (VHL gene) was performed on 38 tissues of human glial tumors (ependymoma, 1; astrocytoma, 6; oligodendroglioma, 1; oligoastrocytoma, 2; anaplastic oligoastrocytoma, 3; anaplastic astrocytoma, 14; glioblastoma multiforme, 11). Somatic DNAs extracted from frozen tumor specimens were examined by single-strand conformational polymorphism analysis and direct sequencing. In addition, loss of heterozygosity (LOH) on chromosome 3p in 15 glial tumor cases, lymphocyte DNAs of which were available, was examined by use of 10 microsatellite probes and two polymorphism markers for the VHL gene. Two cases of low-grade gliomas showed somatic sense mutations in exon 3 of the VHL gene, and 6 of 15 cases (40.0%) showed LOH of chromosome 3p. The VHL gene-mutated cases also showed LOH. The retention of heterozygosity and high pathological grade of glial tumors were correlated significantly. In addition, Kaplan-Meier survival analysis for patients with glial tumors showed that patients with LOH had a significantly longer survival time than those without LOH. These results suggest that somatic mutations on 3p, including the VHL gene, may be involved in tumorigenesis of some low-grade glial tumors.

Adult↗
PubMed1997

Adhesion molecules and TGF-beta1 are involved in the peritoneal dissemination of NUGC-4 human gastric cancer cells.

Peritoneal dissemination frequently occurs after surgery in patients with gastric cancer. The presence of peritoneal metastasis after surgery affects prognosis. Very little is known about the biochemical processes involved in the initial attachment of gastric cancer cells to peritoneal mesothelial cells. We conducted in vitro and in vivo studies to assess the role of adhesion molecules and TGF-beta1 in this process, using 4 cell lines derived from human gastric cancers. NUGC-4 cells, which disseminate early after inoculation into the abdominal cavity of nude mice, predominantly express CD44H and beta1 integrin. We found that NUGC-4 cells adhered to monolayers of mesothelial cells more firmly than to other cell lines. Adhesion of NUGC-4 cells to mesothelial cells was partially inhibited by antibodies against CD44H or the beta1 subunit of integrin and was completely blocked by a combination of these 2 antibodies. Treatment with ligands for CD44H and beta1 integrin also inhibited adhesion. In the NUGC-4 cell culture medium, larger amounts of TGF-beta1 were detected in relation to the increase in cancer cells than in the other cell lines. TGF-beta1 increased the expression of CD44H in NUGC-4 cells and in mesothelial cells and augmented adhesion and implantation of NUGC-4 cells to mesothelial cells accompanied by accumulation of extracellular matrix (ECM) components. Treatment with antibodies against both CD44H and beta1 integrin inhibited the dissemination of NUGC-4 cells in the peritoneal cavity of nude mice and prolonged their survival time. Our findings suggest that CD44H and integrins mediate the initial attachment of gastric cancer cells to mesothelial cells and that TGF-beta1 participates in the promotion of the disease. Increased expression of CD44H and of the amount of ligands for CD44H and integrins induced by TGF-beta1 promotes early development of peritoneal dissemination.

Animals↗
PubMed1997

Inhibition of peroxisomal degradation by 3-methyladenine (3MA) in primary cultures of rat hepatocytes.

BACKGROUND: A significant reduction in peroxisomes has been demonstrated in primary cultures of rat hepatocytes. This report demonstrates that 3-methyladenine (3MA), a potent inhibitor of autophagy, inhibits this effect. METHODS: Hepatocytes from male Wistar rats were isolated by a two-step in situ perfusion technique using collagenase and were cultured in Williams E medium. After a 2-hr attachment period (day 0 of culture), the cells were treated with 200 microM bezafibrate (BF), a peroxisome proliferator, and 5 mM 3MA for 3 days. The cells in the culture dish were fixed in situ, stained for catalase, and embedded in Poly/Bed 812. The number and size of peroxisomes in electron micrographs were analyzed morphometrically. RESULTS: After 3 days of culture, the number of peroxisomes had decreased to 30% of the day 0 level. However, the day 0 level was maintained by treatment with 3MA. In BF-treated cells, many autophagosomes were observed, and peroxisomes had proliferated significantly, although they did not exceed the day 0 level. In cells treated with a combination of 3MA and BF, the number and size of peroxisomes had increased remarkably. CONCLUSIONS: These results suggest that 3MA is effective in maintaining both the number and size of peroxisomes in the course of primary cultures of rat hepatocytes. Suppression of peroxisome proliferation by treatment with BF may be regulated by autophagic/lysosomal degradation.

Adenine↗
PubMed1997

Pharmacokinetics and safety of the novel amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist YM90K in healthy men.

YM90K is a novel, selective and competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist with neuroprotective properties, and it is currently under development for the intravenous treatment of stroke and other conditions of acute neuronal degeneration. The safety and pharmacokinetics of YM90K in healthy men was investigated after single doses up to 36 mg and repeated doses of 24 mg given by intravenous infusion over 3 hours. YM90K was well tolerated in healthy men and induced only mild changes in kidney function markers. Unchanged plasma drug concentration reached a near steady state during 3-hour infusion and rapidly decreased in a biphasic manner after the completion of infusion. YM90K showed linear pharmacokinetics. In the repeated-dose study, no significant differences were observed in pharmacokinetics of YM90K between the first and fifth dose. Unchanged urinary drug excretion was as high as 63.2% to 78.3% of the dose, most of which was excreted within 1 hour after the completion of infusion. YM90K is thought to be excreted mainly by renal tubular secretion. YM90K showed neither significant adverse reactions nor severe abnormalities in physical and laboratory examinations of the study participants and demonstrated safety and pharmacokinetic profiles compatible with clinical use.

Adult↗
PubMed1997

Indications and problems of coronary artery bypass grafting without cardiopulmonary bypass.

As an alternative method of myocardial protection and to obviate the inherent risks of cardiopulmonary bypass (CPB), we have been performing coronary artery bypass grafting (CABG) without CPB in carefully selected patients. Since the first such operation was successfully performed in January 1995 on a patient with angina pectoris and lung cancer, four other patients have subsequently undergone this technique. This series of 5 patients, being 1 man and 4 women ranging in age from 68 to 80 years, is presented in this report. The reasons for the selection of this procedure were concomitant diseases including lung cancer, a calcified aorta, and myocardial infarction. The mean time of ischemia for each anastomosis was 15.3 +/- 5.3 min, and the maximum cardiac muscle creatine phosphokinase (CPK-MB) was less than 14 unit/l postoperatively. None of the patients required ventilatory support for longer than 24 h postoperatively, and oral intake was started within 24 h after extubation in all patients. Postoperative angiography confirmed graft patency and none of the patients developed any ischemic symptoms. All the patients were discharged between 1 and 2 months postoperatively. Thus, the off-pump technique is useful when concomitant diseases are present and will become an alternative method of treatment for coronary artery disease in selected patients.

Aged↗
PubMed1997

Invasive thymoma with endobronchial polypoid growth.

A rare case of invasive thymoma with endobronchial polypoid growth is presented. A 68-year-old woman presented with coughing and sputum. The chest X-ray and computed tomography (CT) findings demonstrated a large mass with a calcified lesion in the left hilar region. A bronchoscopic examination showed a polypoid tumor in the left B3b bronchus. The tumor was surgically resected and revealed a unique polypoid endobronchial extension. This tumor was pathologically diagnosed to be invasive thymoma.

Aged↗
PubMed1997

Angiotensinogen gene polymorphism in Japanese patients with hypertrophic cardiomyopathy.

To examine the contribution of the renin-angiotensin system to hypertrophic cardiomyopathy (HCM), we studied 96 patients with HCM (mean age 50 years, 55% male), 105 of their unaffected siblings and offspring, and 160 healthy subjects without known hypertension and left ventricular hypertrophy (LVH) who were frequency matched to cases by age and sex. Patients were divided into familial or sporadic HCM (FHCM or SHCM) groups with or without affected members of their family. The region of interest in the angiotensinogen (AGT) gene, the missense mutation with methione-to-threonine amino acid substitution at codon 235 in angiotensinogen (M235T), was amplified by polymerase chain reaction with the use of allele-specific oligonucleotide primers flanking the polymorphic region of the AGT gene to amplify template deoxyribonucleic acid prepared from peripheral leukocytes. The T allele frequency was higher in the SHCM group than in unaffected siblings and offspring (88% vs 78%, X2 = 4.6, p < 0.05). The M allele frequency was higher in unaffected siblings and offspring than in patients with SHCM (23% vs 12%, X2 = 4.6, p < 0.05). The T allele frequency among unaffected siblings and offspring was similar to that observed in healthy subjects (78% vs 78%). We conclude that HCM, especially in sporadic cases, is partially determined by genetic disposition. The molecular variant of angiotensinogen T235 seems to be a predisposing factor for cardiac hypertrophy in HCM and carries an approximately twofold increased risk.

Adult↗