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Biomedical subjects

K Kohno

Publications and source records attributed to K Kohno.

At least 397 records · Page 22Linked to original sources
PubMed1989

Analysis of structural features of dihydropyridine analogs needed to reverse multidrug resistance and to inhibit photoaffinity labeling of P-glycoprotein.

Synthetic dihydropyridine analogs were screened to determine whether they would reverse multidrug resistance of a multidrug-resistant human KB carcinoma cell line, KB-C1. Among twenty-four dihydropyridine analogs examined, thirteen almost completely overcame drug resistance (group A), nine partially overcame resistance (group B) and two did not reverse resistance (group C). The twenty-two compounds that reversed drug-resistance (groups A and B) were hydrophobic dihydropyridine derivatives. Three compounds that reversed resistance, NK-113, NK-138 and NK-194, increased the accumulation of [3H]vincristine in the resistant KB-C1 cells, but not in the parental KB cells, nor in a revertant cell line, KB-C1-R2. NK-101 (group C), which did not reverse resistance, had no effect on drug accumulation. Enhanced efflux of vincristine from the resistant cells was inhibited completely by NK-194, but NK-194 did not affect vincristine influx. Nine of the twenty-four compounds were screened to determine whether they inhibited photoaffinity labeling of the cell surface protein gp170 (P-glycoprotein) in KB-C1 cells by N-(p-azido-[3-125I]-salicyl)-N'-beta-aminoethylvindesine [( 125I]NASV). All five compounds of group A, NK-138, NK-194, NK-200, NK-203 and NK-220, inhibited the photoaffinity labeling of gp170 at less than 10-100 microM, whereas NK-113 and NK-196 of group B inhibited the labeling at 100-200 microM. By contrast, NK-101 and NK-102 of group C did not inhibit labeling even at 2000 microM. These studies confirm the relationship among reversal of multidrug resistance, decreased efflux of vincristine, and inhibition of [125I]NASV labeling of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Bioavailability and pharmacokinetics of an oral dopamine prodrug in dogs.

The bioavailability and pharmacokinetics of an oral dopamine prodrug, N-(N-acetyl-L-methionyl)O,O-bis(ethoxycarbonyl)dopamine (1), were examined in dogs, and the mechanism of its absorption and bioactivation was discussed. Compound 1 showed a plasma dopamine concentration that was several times higher than that of dopamine (DA) following oral administration to dogs, while the plasma concentrations of dopamine-30-sulfate (DA-SO4) and 3,4-dihydroxyphenylacetic acid (DOPAC) are lower in comparison with that of DA. The conversion of 1 to DA occurred in proportion to the dose administered. Compound 1 also showed a plasma DA concentration that was several times higher than that of other DA prodrugs reported hitherto. In dog plasma, in vitro, 1 was converted to its deethoxycarbonylated form, N-(N-acetyl-L-methionyl)dopamine (2), while other related compounds, N-(L-methionyl)dopamine (3), N-(L-methionyl)O,O-bis(ethoxycarbonyl)-dopamine (4), and O,O-bis(ethoxycarbonyl)dopamine (5), were rapidly converted to DA (however, 2 was stable in plasma). Bioavailability, based on the AUC of DA, 1, 2, and 5 following oral administration to dogs, increased in the following order: 1, 2, 5, and DA. Thus, it was shown that the two protective groups introduced in 1 served to reduce the first-pass metabolism of the DA moiety in the absorption process. It was also confirmed that 1 is converted to 2 or DA in blood, liver, and intestine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Direct projection from the dorsal hypothalamic area to the nucleus raphe pallidus: a study using anterograde transport with Phaseolus vulgaris leucoagglutinin in the rat.

A hypothalamic projection to the nucleus raphe pallidus of the medulla was examined using the anterograde tracing technique based on Phaseolus vulgaris leucoagglutinin (PHA-L) in the rat. After the iontophoretic application of PHA-L to the dorsal hypothalamic area, labeled fibers that finally ended in the nucleus raphe pallidus were observed descending through the most medial part of the ventral tegmental area and the nucleus reticularis tegmenti pointis to reach the medial aspect of the pyramid. Many varicose fibers forming a loose plexus were observed in the nucleus raphe pallidus, especially ventrally. The ventral surface of the pyramid and the most ventral region of the nucleus reticularis paragigantocellularis lateralis (PGCL) contained labeled varicose fibers. At the electron microscopic level, the labeled profiles in the nucleus raphe pallidus were small-sized unmyelinated axons and axon terminals. Labeled axon terminals containing spherical synaptic vesicles formed synapses on spine-like protrusions or small-sized dendritic shafts. These results strongly indicate that neurons in the dorsal hypothalamic area have a direct connection with neurons in the nucleus raphe pallidus and the ventral part of the PGCL. The possible involvement of this pathway in cardiovascular regulation was discussed.

Animals↗
PubMed1989

Newly developed transarterial chemoembolization material: CDDP-lipiodol suspension.

Cis-Diamminedichloroplatinum (CDDP)-lipiodol suspension (CLS) was developed as a transarterial chemoembolization (TACE) material. The CLS was injected into the proper hepatic artery or distal branches of patients with hepatocellular carcinoma. Strong anticancer effects were observed. Plasma concentrations of total and filtrable CDDP following TACE were much lower than those following intravenous administration of CDDP solution. No major adverse complications were noted, presumably due to low CDDP concentrations in circulating plasma. The CLS appears to be an excellent TACE material.

Carcinoma, Hepatocellular↗
PubMed1989

Outcome in elderly patients with ruptured intracranial aneurysm.

Sixty-nine elderly patients over 65 years old with ruptured aneurysms had a significantly worse outcome than 192 younger patients with respect to overall management results and operative results (p less than 0.01). The results of an early operation were better in the elderly patients with grade I-III than in those receiving a delayed operation. Concomitant diseases significantly influenced the results in elderly patients (p less than 0.05). It is possible that an early operation results in the better outcome in elderly patients by decreasing the incidence of delayed ischemic complications and preventing rebleeding.

Adult↗
PubMed1989

Impairement of vascular reactivity and changes in intracellular calcium and calmodulin levels of smooth muscle cells in canine basilar arteries after subarachnoid hemorrhage.

We examined vascular reactivity to various vasoconstrictors and dilators, and the changes in calcium-calmodulin levels in canine basilar arteries after subarachnoid hemorrhage (SAH). Contractile responses to noradrenaline, serotonin, and potassium chloride were markedly attenuated at 48 hours (P less than 0.05), and further attenuated at 7 and 14 days after SAH (P less than 0.01). Dilation responses to calcium antagonist were maintained at 48 hours after SAH, but were markedly reduced at 7 and 14 days after SAH (P less than 0.05). Transmission electron micrographs of the basilar artery showed contraction of the media between 48 hours and 7 days and degeneration of smooth muscle cells over the 7 days after SAH. Electron microscopic cytochemical examination for calcium showed that intracellular deposits of calcium pyroantimonate increased in smooth muscle cells of basilar arteries at 1 hour after the first intracisternal injection of blood (early spasm), but decreased in smooth muscle cells at 48 hours after SAH (at the beginning of delayed vasospasm). They decreased further in the vessels 7 days after SAH. The calmodulin contents in the basilar arteries were decreased slightly at 6 hours, and significantly (P less than 0.05) at 48 hours after SAH, as determined by radioimmunoassay and phosphodiesterase assay. Therefore, it is considered that delayed vasospasm is not simply an active contraction of the vessels, but a functional or structural derangement of contractile elements of smooth muscle cells after 48 hours after SAH.

Animals↗
PubMed1989

Altered expression of epidermal growth factor receptor gene in a classical multidrug-resistant variant of a human cancer cell line, KB.

A variant clone resistant to high doses of colchicine (KB-C1) derived from human cancer KB cell line is resistant to various anticancer agents. The KB-C1 cells were much more resistant to epidermal growth factor and a chimeric toxin, EGF-Pseudomonas exotoxin (PE), than the parental KB cells. KB-C1 cells have decreased numbers of EGF-receptors, though the affinity of the receptors is similar to that in the parental KB cells. A drug-sensitive revertant (C1-R2) partially recovered its EGF-receptor activity. Northern blot analysis showed a decreased level of EGF-receptor mRNA in KB-C1 cells, while the multidrug-resistance gene, mdr-1, was expressed at very high levels in KB-C1 cells, but not in KB or C1-R2 cells. The drug-resistant cells were less tumorigenic than the parental cells when injected into nude mice. A decreased expression of EGF-receptor in these cells may be one of the pleiotropic properties of multidrug-resistant cells and may perhaps represent the basis for their reduced tumorigenicity.

Animals↗
PubMed1989

Potentiation of some anticancer agents by dipyridamole against drug-sensitive and drug-resistant cancer cell lines.

In this study, we have used two different vincristine (VCR)-resistant variants, VJ-300 and HC-7-5/VCR. VJ-300 was isolated from a human cancer KB cell line and HC-7-5/VCR from a human cancer HC-7-5 cell line. VJ-300 and HC-7-5/VCR are both multidrug-resistant (MDR) variants, showing resistance to multiple anticancer drugs such as VCR, adriamycin, actinomycin D and daunomycin. Dipyridamole, a specific inhibitor of nucleoside transport, potentiated these anticancer drugs about 2- to 10-fold against KB and VJ-300. Dipyridamole almost completely reversed drug resistance to actinomycin D in VJ-300 cells with about a 70-fold higher resistance to actinomycin D. Dipyridamole inhibited the efflux of actinomycin D and VCR from VJ-300 cells. Dipyridamole enhanced the uptake of VCR but not that of actinomycin D in VJ-300 and KB. Dipyridamole at 10-100 microM inhibited photoaffinity labeling with [3H]azidopine of the cell-surface protein P-glycoprotein in VJ-300 cells. Dipyridamole potentiated 5-fluorouracil and hexylcarbamoyl-5-fluorouracil in cultured KB and VJ-300, but it annihilated the cytotoxic action of 5-fluorouridine. Potentiation of 5-fluorouracil by dipyridamole against HC-7-5 and HC-7-5/VCR was also observed, but appeared to be less than in VJ-300 and KB cells. Dipyridamole almost completely inhibited the cellular accumulation of 5-fluorouridine, but not that of 5-fluorouracil. Thus, dipyridamole appeared to potentiate anticancer agents through pleiotropic action sites, one of which is inhibition of enhanced efflux of MDR cell lines and the other of which is inhibition of nucleoside transport. Dipyridamole might be a useful and potent agent to potentiate anticancer agents and reverse drug-resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Two pathways for inducing interleukin 2 production in MOLT 16 cells, a human leukemic T-cell line: interleukin 1 pathway and interleukin 1-independent pathway.

Phytohemagglutinin (PHA)-stimulated MOLT 16 cells (a human leukemic T cell line, at a concentration of 2 x 10(6) cells/ml) secreted 6 U/ml of interleukin 2 (IL 2) into the culture supernatant during 24 h culture. When interleukin 1 (IL 1) (5 U/ml) or IL 1-producing cells such as human T cell leukemia virus-1 (HTLV-1)-transformed T cell line, C5/MJ, and myelomonocytic cell line, THP-1-O, were added to the MOLT 16 culture at a concentration of 4 x 10(5) cells/ml, far greater IL 2 production (greater than 65 U/ml) was observed. The activity of soluble IL 1 and membrane-associated IL 1 produced by these accessory (A) cells was completely neutralized by the treatment with anti-human IL 1 antibody. In sharp contrast, MOLT 16 cells co-cultured with BALL-1 cells (a human leukemic B cell line) resulted in comparable increases in IL 2 production (175 U/ml), although no IL 1 or IL 1-like activity was detected either in the supernatants or in the cell lysates of BALL-1 cells. An augmentation of IL 2 production was also induced with paraformaldehyde-fixed BALL-1 cells, and this augmentation could not be inhibited by anti-human IL 1 antibody. These data indicate that MOLT 16 provides a model for determining pathways for activating T cells leading to IL 2 production in response to mitogens. Two pathways have been described in the report: one involving secreted or membrane-associated IL 1, and a second independent pathway which involves contact of surface membranes in the presence of PHA.

Antigens, Surface↗
PubMed1989

Potentiation of vincristine and actinomycin D by a new synthetic imidazole anti-tumor agent YM534 active against human cancer cells and multidrug-resistant cells.

Ethyl 6-p-5-(l-imidazolyl) pentyloxyphenoxy-2, 2-dimethylhexanoate hydrochloride (YM534) is a new synthetic anti-tumor compound. Combinations of YM534 with other anti-cancer agents were examined to ascertain whether YM534 potentiated other anti-cancer agents against the KB cell line and its multidrug-resistant counterpart, VJ-300. YM534 potentiated the cytotoxic action of vincristine and actinomycin D about 2-fold against KB cells, but not those of daunomycin and adriamycin. By contrast, YM534 only slightly reversed drug-resistance to adriamycin and daunomycin in VJ-300 while it reversed 5-fold vincristine resistance and 60-fold actinomycin D resistance in VJ-300. The reversal effect of YM534 on actinomycin D and vincristine-resistance in VJ-300 cells appeared to be due to enhanced accumulation of [3H] actinomycin D and [3H] vincristine in VJ-300 cells by YM534. YM534 inhibited efflux of actinomycin D and vincristine from VJ-300 cells, and it also enhanced cellular uptake of these anti-cancer agents. YM534 enhanced cellular accumulation of both actinomycin D and vincristine in the sensitive KB cells. YM534 is thus a unique anti-cancer agent since combinations of other anti-cancer agents with YM534 are expected to augment anti-tumor activity of them. By contrast, YM212, a carboxy analog of YM534, had much less activity to potentiate vincristine and actinomycin D). YM534 at 100-1000 microM almost completely inhibited the photoaffinity labeling of [3H] azidopine to the 170-kD P-glycoprotein of VJ-300 cell membranes, but YM212 showed much less inhibitory action on the photoaffinity labeling. YM534 could also inhibit the photoaffinity labeling of deglycosylated P-glycoprotein.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

[A cases of isoniazid-induced lupus].

A case of isoniazid (INH)-induced lupus occurring in a 62-year-old man is presented. He visited our hospital in May 1986 and a cavitary lesion was found in the right upper lobe on a chest roentgenogram. He had no previous history of treatment with antituberculotic agents. Though acid-fast bacilli were not found in his sputum, pulmonary tuberculosis was strongly suspected and INH, rifampicin and ethanbutol were administered. Four days after starting the treatment, minimal left pleural effusion was seen on chest X-ray film. Three months later he began to complain polyarthralgia in his digital joints. In a pleural effusion many lymphocytes were found; and the antinuclear antibody (ANA), the anti-extractable nuclear antigens (ENA) antibody, and the RNase resistant anti-ENA antibody were positive, and their titres were 20x, 1000x and 1000x, respectively, and the immune complex (IC) was 16.0 micrograms/ml (LT5). In blood serum, the ANA test the anti-ENA antibody and the RNase resistant anti-ENA antibody were positive with titres 40x, 640x and 640x respectively; and the IC was 14.0 micrograms/ml, and the RA test was positive. The improvement of clinical findings and disappearance of auto-antibodies seen after stopping INH confirmed the diagnosis as INH-induced lupus.

Antibodies, Antinuclear↗
PubMed1989

The causes and value of hyperphosphatemia in experimental strangulation obstruction.

In model experiments with mongrel dogs, intestinal strangulation obstruction was induced by occluding the superior mesenteric veins, and a rise in the inorganic phosphate value of the blood was observed. The high inorganic phosphate values of the fluid exuding from the strangulated bowel suggest that intestinal factors associated with the strangulated bowel may be partly responsible for this elevated phosphatemia. However, hyperphosphatemia was also found in a model experiment in which the route through which the fluid was absorbed into the blood from the peritoneal cavity was interrupted by keeping the strangulated bowel in an intestinal bag. After this, in the model experiments in which a systemic blood pressure depression curve with a percentage reduction similar to that of the decreasing arterial blood pressure resulting from strangulation was produced (by exsanguination, and even by exsanguination with adequate perfusion of the gut), plasma inorganic phosphate values also increased. Therefore it is undeniable that systemic factors other than the above-mentioned local factors are related to the rise in plasma inorganic phosphate values in experimental strangulation obstruction. Because it is not possible to assert that phosphatemia is specific to intestinal strangulation, the importance of a rise in inorganic phosphate values in the early diagnosis of intestinal strangulation cannot be considered very great.

Animals↗
PubMed1988

A new class mutation of low density lipoprotein receptor with altered carbohydrate chains.

In a monensin-resistant mutant (Monr-31) of Chinese hamster ovary cells, the O-linked sugar chains of the low density lipoprotein (LDL) receptor are altered, suggesting a mutation at a Golgi apparatus gene. In a compactin-resistant mutant (MF-2) of Chinese hamster V79 cells, the mature LDL receptor is apparently 5000 daltons smaller; the difference is due to altered glycosylation of O-linked sugar chains. Hybrids between MF-2 and Monr-31 still produced LDL receptor molecules with aberrant sugar chains; thus both mutants are in the same complementation group. Krieger and his colleagues (Krieger, M., Kingsley, D., Sege, R., Hobbie, L., and Kozarsky, K. (1985) Trends. Biochem. Sci. 10, 447-452) have classified Chinese hamster ovary cell mutants with altered LDL receptor structure into four groups: ldlA, ldlB, ldlC, and ldlD. Cell-cell hybrids between their ldl mutants and Monr-31 produced wild type mature LDL receptors with normal molecular sizes, suggesting that these compactin- and monensin-resistant mutants define a new class of LDL receptor mutant. Since both of our mutants are defective in internalization of LDL, we assign them as int mutants. This may imply a further etiology for hypercholesterolemia, and cases can now be examined for such a class.

Animals↗
PubMed1988

Differential innervation of specific motor neuron pools by serotoninergic fibers in the chick spinal cord.

A new technique in which cholera toxin subunit B conjugated to horseradish peroxidase is injected in chick muscles followed by perfusion with Zamboni's fixative for serotonin immunocytochemistry allows one to visualize immunoreactive fibers and retrogradely labelled motoneurons in alternate sections. Using these procedures, we have found that there is a differential innervation by serotoninergic fibers of motoneuron pools that project to specific muscles or muscle groups. Dense clusters of serotonin-positive fibers were located in the motoneuron pools of extensors of the hip joint consisting of the lateral iliotibialis, ischioflexorius, iliofibularis, accessorius and caudilioflexorius muscles.

Animals↗
PubMed1988

Participation of hup gene product in ori2-dependent replication of fertility plasmid F.

The fertility plasmid F'gal was not stably maintained in a hupA-hupB double mutant of Escherichia coli. Moreover, mini-F plasmids pFZY1, pFTC1 and pFTC2 were unable to transform the double mutant, though these plasmids efficiently transformed cells harboring a hupA or hupB single mutation. The composite plasmid pFHS1, which consists of the f5 DNA fragment of F plasmid and the whole DNA of a pSC101 derivative that carries a temperature-sensitive mutation for DNA replication, was not stably maintained in the hup double mutant at 42 degrees C. These findings strongly suggest that HU protein is required for ori2-dependent replication of the F plasmid.

Bacterial Proteins↗
PubMed1988

Ultrastructural features of functionally identified primary afferent neurons with C (unmyelinated) fibers of the guinea pig: classification of dorsal root ganglion cell type with reference to sensory modality.

Intracellular labeling of neurons permitted a direct correlation of neuronal profiles with sensory modality of cutaneous receptors. In the guinea pig, 47 neurons in the dorsal root ganglion (displaying C-fiber conduction velocities) were labeled with horseradish peroxidase (HRP) by iontophoresis after determining the sensory modality. Receptive field were explored with systematic "natural" stimuli. Cell areas of all C-fiber units were measured by tracing the cellular contour in light microscopy. The mean cellular diameter calculated from cell areas was 21.8 microns in the second cervical ganglion of the guinea pig. Mean cell diameter for high-threshold mechanoreceptors was 20.9 microns, 24.6 microns for polymodal nociceptors, and 25.7 microns for mechanical-cold nociceptors. Electron microscopic observations showed that all labeled neurons of C-fiber units had profiles of small, dark type-B neurons. Neurons representative of each sensory modality exhibited different cell features, each belonging to a distinct subtype of small B neurons. High-threshold mechanoreceptor and mechanical-cold nociceptor displayed a peripheral lamellar arrangement of cisternae of endoplasmic reticulum (ER), corresponding to the B1 subtype. Polymodal nociceptor units were characteristically of the B2 subtype, in which stacks of long and short cisternae of ER were distributed randomly throughout the cytoplasm, and the arrangement of Golgi bodies varied among these cells. Cooling receptors displayed poorly developed, flattened cisternae of ER and numerous vesicles, typical of the B3 subtype. These results imply that all C-fiber cells belong to the small B-type cell category and that the ultrastructural features of the neuron in the dorsal root ganglion may reflect the sensory modality of the receptive field.

Animals↗
PubMed1988

Novobiocin inhibits the SV40 enhancer activity.

Using a transient expression assay, we have analysed the effect of novobiocin, DNA topoisomerase II inhibitor, on simian virus 40(SV40) enhancer activities. We used the recombinant clones containing type I or II collagen promoters placed upstream of the bacterial chloramphenicol acetyltransferase (CAT) gene with or without SV40 enhancer. We observed the expected increase in CAT activities due to the presence of the SV40 enhancer. Interestingly, CAT gene expression of the enhancer-containing constructs were inhibited more sensitively by novobiocin than that of the enhancer-less construct. This findings lead us propose that DNA superhelicity mediated by topoisomeraseII is one of the important factor for the manifestation of SV40 enhancer activity.

Acetyltransferases↗