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Biomedical subjects

K Nishio

Publications and source records attributed to K Nishio.

At least 127 records · Page 7Linked to original sources
PubMed1997

Interferon-gamma-inducing factor gene transfection into Lewis lung carcinoma cells reduces tumorigenicity in vivo.

To investigate the immunoregulatory effect of murine interferon-gamma-inducing factor (mIGIF), we transfected Lewis lung carcinoma (LLC) cells with a mammalian expression vector containing the mIGIF complementary DNA. The culture medium of the transfectant cells stimulated interferon-gamma (IFN-gamma) production by spleen cells in vitro in the presence of anti-CD3 antibody and markedly potentiated the effect of interleukin-12 (IL-12) on IFN-gamma production by spleen cells. mIGIF transfectant cells showed reduction of tumorigenicity and induction of an in vivo immuno-protective effect against the parental LLC cells. To examine the combined effect of systemic administration of recombinant IL-12 (rIL-12) and local mIGIF on the tumorigenicity, mice were challenged with LLC or transfectant cells on day 0, and the tumor-bearing mice were injected with 50 ng of rIL-12 intraperitoneally from day 7 to 11. Systemic rIL-12 showed an anti-tumor effect. However, mIGIF gene expression did not potentiate this effect of systemic rIL-12 in vivo.

Animals↗
PubMed1997

Role of CD18-ICAM-1 in the entrapment of stimulated leukocytes in alveolar capillaries of perfused rat lungs.

This study aimed to examine the behavior of stimulated leukocytes in the pulmonary microcirculation. The leukocyte-endothelium interaction was visualized under physiological shear rates in perfused rat lungs using high-speed confocal laser video microscopy. Leukocytes labeled with carboxyfluorescein were stimulated with cytokine-induced neutrophil chemoattractant (CINC/gro), which caused L-selectin shedding and inverse upregulation of CD18. Neither unstimulated nor stimulated leukocytes exhibited rolling in either pulmonary arterioles or venules, whereas both were sequestered in capillaries. Approximately 50% of stimulated leukocytes showed a transient cessation of movement in pulmonary capillaries. The CINC/ gro stimulation, which inhibited leukocyte rolling and adhesion to mesenteric venules, reduced leukocyte velocity and increased leukocytes in pulmonary capillaries. Pretreatment with monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1) or CD18 attenuated these changes. Confocal microfluorography revealed constitutive expression of ICAM-1 not only in venules but also abundantly in capillary networks. These results suggest that selectin-independent, CD18-ICAM-1-dependent capillary sequestration is one of the major mechanisms by which activated leukocytes accumulate in the lungs.

Animals↗
PubMed1997

Effect of hyperoxia on adhesion molecule expression in human endothelial cells and neutrophils.

To investigate the pathogenesis of pulmonary oxygen toxicity, we examined the effect of hyperoxia on adhesion molecule expression in cultured human pulmonary artery endothelial cells (HPAEC) and human umbilical vein endothelial cells (HUVEC). Endothelial cell monolayers were exposed to either hyperoxic (90% O(2)-5% CO(2)) or normoxic (21% O(2)-5% CO(2)) conditions for various periods. The level of intercellular adhesion molecule (ICAM)-1 expression had increased in hyperoxia-exposed HPAEC and HUVEC at 48 h (194 +/- 38 and 233 +/- 56%, respectively; P < 0.001) and at 72 h (200 +/- 43 and 223 +/- 52%, respectively; P < 0.001) compared with normoxic conditions. These hyperoxia-induced ICAM-1 expressions were dose dependently attenuated by a protein kinase C inhibitor (H-7). In contrast, the levels of P-selectin and E-selectin expression in HPAEC and HUVEC were unchanged. The levels of ICAM-1 mRNA and the numbers of adherent neutrophils were increased in HPAEC and HUVEC at 48 and 72 h of hyperoxia. On the other hand, hyperoxia caused neutrophil H(2)O(2) production without affecting the level of CD11/CD18 expression. These results suggest that increased ICAM-1 expression in endothelial cells plays an important role in neutrophil accumulation during hyperoxia.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

Effects of active vasoconstriction and total flow on perfusion distribution in the rabbit lung.

We analyzed the effects of hypoxic vasoconstriction and total flow on the distribution of pulmonary perfusion in 38 isolated left rabbit lungs perfused under zone 3 conditions. Lungs were suspended in an upright position, oriented to the apicobasal line. Distributions of regional perfusion rates (RPR) along the vertical and horizontal axes were determined using nonradioactive microspheres labeled with heavy metal elements, which were detectable with X-ray fluorescence spectrometry. Changing the O2 concentration of a respirator and an extracorporeal membrane oxygenator independently, respective influences of active vasoconstriction induced by alveolar hypoxia and pulmonary artery hypoxia (PA hypoxia) on the RPR distribution were examined at a flow rate of 0.4 ml x min(-1) x g wet lung tissue(-1). To analyze the effects of changes in total flow, we investigated the RPR distribution at a perfusion rate of 1.2 ml x min(-1) x g wet lung tissue(-1). The RPR distribution in the absence of hypoxia was inhomogeneous and was augmented in the lower lung fields, whereas alveolar hypoxia shifted the RPR upward and significantly diminished the RPR in the lung base. RPR distributions along the horizontal axes under alveolar hypoxia conditions demonstrated that remarkable hypoxic pulmonary vasoconstriction (HPV) takes place in medial regions at the lung base. PA hypoxia altered the RPR distribution in qualitatively the same manner as alveolar hypoxia. Increased flow rate augmented the RPR in the lung, except in the dorsobasal region. These results suggest that the occurrence of HPV and the vascular conductance are not uniform throughout the lung.

Animals↗
PubMed1997

[Apoptosis and chemosensitivity].

Many antineoplastic drugs and cytotoxic irradiation induce apoptosis in cancer cells. ICE and ICE-like proteases play important roles in drug-induced apoptosis of cancer cells. We evaluated the cellular factors affecting susceptibility to apoptosis using gene-transfected cells. Introduction of bcl 2 gene into human small cell lung cancer cells conferred resistance to mitomycin C and irinotecan. DNA fragmentation was reduced in these cells. These results indicate apoptosis is one of the mechanisms of cell death caused by some antineoplastic drugs. Investigations are ongoing to elucidate the contribution of the Bcl 2 family proteins to antineoplastic drug induced apoptosis. Wild type p53-transfected cancer cells were sensitive to anticancer drugs. On the other hand, p53-depleted cells were reported to be more sensitive to taxanes than p53-proficient cells. Introduction of Rb gene and p16-gene enhanced cytotoxicity of taxanes and topoisomerase I inhibitors, respectively. In clinical studies, patients of non small cell lung cancer with high expression of Bcl-2 were reported to show longer survival than patients with lower expression. However, this result may be confusing because Bcl-2 reduced the efficacy of antineoplastic drugs. Further evaluation is required to determine the cellular proteins serving as markers for treatment efficacy or prognosis.

Antineoplastic Agents↗
PubMed1997

[gamma-Glutamylcysteine synthetase and chemosensitivity].

The gene transfectant with gamma-glutamylcysteine synthetase (gamma-GCS) gene, a rate limiting enzyme in GSH biosynthesis, exerted increased GSH content and ATP-dependent glutathione S-conjugate export pump (GS-X pump) decreased intracellular platinum and sensitivity against cisplatin. It is suggested that GS-X pump expression is related to cellular GSH metabolism and involved in cisplatin resistance. gamma-GCS transfectant also showed the resistance to MMC with the decreased DNA-MMC adduct. On the other hand, a MMC derivative, KW-2149, which is activated by thiol molecule, exhibited high cytotoxicity against the transfectant with an equal amount of DNA-MMC adduct compared with parental cells. It is suggested that KW-2149 could circumvent the GSH-mediated drug resistance.

3T3 Cells↗
PubMed1997

[Effects of hyperoxia on the behavior of leukocytes in rat pulmonary microcirculation assessed by confocal laser scanning microscopy].

To study the dynamic interaction between blood cells and endothelial cells in the pulmonary microcirculation, we developed a method for observing leukocytes and erythrocytes in the microcirculation of perfused rat lungs by confocal laser scanning microscopy. We examined the behavior of leukocytes in the microcirculation of rat lungs exposed to hyperoxia, because oxygen toxicity is known to be associated with leukocyte infiltration and endothelial cell damage. Rats were divided into two groups: control (21% O2) and hyperoxia (90% O2 for 48 hours). Lungs were perfused with Krebs-Henseleit solution equilibrated with 21% O2 and 5% CO2 through an artificial lung. Leukocytes stained with carboxyfluorescein diacetate succinimidyl ester and erythrocytes stained with fluorescein isothiocyanate were added to the perfusate, and images of the cells were observed and recorded with a confocal laser scanning microscope and a high-speed video camera. The mean velocities of erythrocytes (Vr) in arterioles, capillaries, and venules of the control group were 1.52, 0.50 and 1.61 mm/sec, respectively. Also in the control group, the velocities of the leukocytes were divided by the mean velocities of the erythrocytes in the same arterioles, capillaries and venules (Vw/Vr) and the results were 0.96, 0.97, and 0.98, respectively. The Vw/Vr values for arterioles in the hyperoxia group were not significantly different from those in the control group, but the Vw/Vr values for capillaries and venules were 27% and 37% lower than their respective control values. Leukocyte sequestration was seen mainly in capillaries in the hyperoxic group. These results suggest that an increase in adhesion in capillaries and venules, such as that caused by adhesion molecules, might play a key role in the behavior of leukocytes in the pulmonary microcirculation during hyperoxia.

Animals↗
PubMed1997

[A case report of spontaneous hemopneumothorax].

A 55-year-old man was admitted to the private hospital with chief complaints of left chest pain and increasing dyspnea. Chest X ray on admission revealed a collapsed lung and an air fluid line in the left hemothorax. A chest tube drainage was carried out, but hemorrhagic pleural fluid of 1,000 ml was drainaged. So was the patient transferred to our hospital for surgical treatment. Following blood transfusion because of hemorrhagic pleural fluid of 1,500 ml, urgent surgery was carried out. At the operation under thoracoscope, the bleeding from the apex of the thoracic cavity was noted. The bleeding was controlled with endoscopic surgical clip. As it was, however, very difficult to remove massive blood clots under endoscopic surgery, a small thoracotomy was carried out in addition to the thoracoscopic surgery, then the bulla in the apex of left lung was resected and also removed a large amount of blood clots.

Hemopneumothorax↗
PubMed1997

Leukocyte kinetics in the pulmonary microcirculation: observations using real-time confocal luminescence microscopy coupled with high-speed video analysis.

To quantitatively assess blood cell kinetics in the intact pulmonary microcirculation, in which arterioles, venules, and capillaries are exceedingly intricate and densely convoluted, we recently developed a real-time confocal laser luminescence microscope with a high-speed analysis component. The system has the capacity to yield confocal images of rapidly moving cells at a rate of 1000 frames/second and at sufficiently high degrees of magnification. Applying this novel method to isolated perfused rat lungs, we estimated the endothelial distributions of constitutively expressed intercellular adhesion molecule-1 (ICAM-1) and P-selectin and also studied leukocyte hemodynamic behavior in the pulmonary microvasculature under conditions in which ICAM-1, P-selectin, and L-selectin were inhibited, respectively, by 1A29 (monoclonal antibody to rat ICAM-1), ARP2-4 (monoclonal antibody to rat P-selectin), and fucoidin (competitive inhibitor of both P- and L-selectin). The results were compared with those obtained with a nonconfocal microscope using conventional epiluminescence. Intertwined microvessel networks in the lung were clearly distinguishable in confocal images but not in conventional nonconfocal views. ICAM-1 was perceptibly expressed along venular and capillary but not arteriolar endothelium, whereas P-selectin was undetectable in all microvessels examined. Leukocytes were not firmly adhered to venular or arteriolar endothelial cells. Leukocyte rolling was recognized more frequently along arteriolar walls than along venular walls and was suppressed in arterioles by L-selectin inhibition but not by either ICAM-1 or P-selectin inhibition. In capillaries, transient and sustained arrest of leukocytes occurred at physiologic shear rates. Inhibition of ICAM-1 or P-selectin had no remarkable effect upon either transient or sustained entrapment of leukocytes in capillaries. In conclusion, physiologic and biologic characteristics of pulmonary microvessels appear to be quite different from those of the systemic microcirculation.

Animals↗
PubMed1997

[Cerebral infarction due to bacterial emboli associated with methamphetamine abuse].

The number of stimulant-drug addicts has recently been on the rise again, and they are being increasingly encountered in the emergency room. There are also frequent reports of cerebrovascular disorders complicating drug toxicity. These cerebrovascular disorders have included subarachnoid hemorrhage, intracranial hematoma, and a few cases of cerebral infarction. Here, we report the case of a 37-year-old male with drug toxicity, consciousness disorder, and hyperthermia. He was in a coma with a temperature of 43.1 degrees C and blood pressure of 58/35 mmHg when brought to our hospital. His condition worse rapidly deteriorated, and he died the same day. Cerebral infarction caused by gram-positive bacillus embolism, not necrotizing angiitis, was found at autopsy. Because drug addicts, especially stimulant-drug addicts, tend to inject themselves drug under unsanitary conditions, the possibility of this type of complication is always present. This is the first such case ever reported, and is therefore regarded as a rare complication of stimulant-drug intoxication.

Adult↗
PubMed1997

[Tubulin and its related signal].

Antimitotic agents are expected to exert the high antitumor potency on various solid tumors. One of the determining factors for the sensitivity/resistance to these antimitotic agents is the status of the tubulin to which these drugs bind. Quantitative and qualitative changes such as gene mutations of the beta-tubulin were suspected to be major determining factors. Microtubule-associated proteins and the related signaling by the mitogen-activated protein kinase cascade are also considered to be factors influencing the sensitivity/resistance of the tumor cells to the antimitotic agents. These are promising targets for development of new antimitotic agents.

Animals↗
PubMed1996

Role and initiation mechanism of the interaction of glycoprotein Ib with surface-immobilized von Willebrand factor in a solid-phase platelet cohesion process.

To know the role and initiation mechanism of the interaction of glycoprotein (GP) Ib with surface-immobilized von Willebrand factor (vWF), we examined the effect of shear stress levels on platelet binding to vWF-coated plates using a cone-and-plate type viscometer capable of loading various levels of shear stress. The extent of platelet binding to immobilized vWF reached a plateau at the shortest period tested (20 seconds) under high shear stress (90 dyne/cm2), whereas 9 to 12 minutes was necessary for saturable platelet binding under static conditions. This shear effect, which was found to be dependent on the vWF-GP Ib interaction, was observed even under the lowest shear stress (1.5 dyne/cm2) examined. In contrast with the high shear effect previously reported to initiate the interaction of GP Ib with soluble vWF, these results indicate that relatively low levels of shear stress can promote the interaction of GP Ib with surface-immobilized vWF. This effect of shear stress was observed regardless of the manner in which vWF was immobilized, suggesting that immobilization itself and not, as previously hypothesized, a conformational change in vWF induced by direct adsorption to the surface is responsible for the enhanced GPIb binding. Thus, the present findings suggest that the vWF-GP Ib interaction contributes optimally to rapid platelet cohesion on a thrombogenic surface when vWF is in a static state and when platelets are moved by an appropriate rheological force such as low shear stress.

Humans↗
PubMed1996

Reversal of adriamycin resistance with chimeric anti-ganglioside GM2 antibody.

Ganglioside GM2 is one of the major cell-surface gangliosides expressed in human tumors. We earlier established a mouse/human IgG1 chimeric anti-GM2 antibody, KM966, which displayed anti-tumor activity in human tumor cells both in vitro and in vivo. In this study, we have screened for changes in ganglioside expressions in several drug-resistant human cancer cell lines to examine the modulation of drug resistance by immunotherapy with anti-ganglioside antibodies. Increased GM2 expression, detected by flow cytometry and thin-layer chromatography, was observed in the SBC-3/ADM and AdrR MCF7 adriamycin-resistant cell lines, in contrast with their parental lines. In other related gangliosides, ganglioside GD2 levels in AdrR MCF7 were higher than those in MCF7 cells. We confirmed increased N-acetylgalactosaminyltransferase mRNA in adriamycin-resistant cell lines, as compared with the parental cells, by Northern-blot analysis. Moreover, to investigate the possibility of exploiting the anti-tumor activity of KM966 in order to overcome resistance to adriamycin, we investigated the antibody-dependent cell-mediated cytotoxity of human peripheral mononuclear blood cells and the complement-dependent cytotoxity of human serum with KM966 against SBC-3, SBC-3/ADM, MCF7 and AdrR MCF7. Significantly higher killing via KM966 was observed in SBC-3/ADM and AdrR MCF7 cells as compared with the parental cells. This suggests that passive immunotherapy using KM966 against human adriamycin-resistant cancer may be useful for overcoming resistance to adriamycin.

Antibiotics, Antineoplastic↗
PubMed1996

Hypersensitivity of NIH3T3 cells transformed by H-ras gene to DNA-topoisomerase-I inhibitors.

We examined the effects of the introduction of H-ras oncogene into murine cell line NIH3T3 on growth inhibition by topoisomerase-I (topo-I) inhibitors. The H-ras-transformed cells (pT22-3) showed approximately 12-fold increased sensitivity to a novel topo-I inhibitor, NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo(2,3-a)pyrrolo(3,4-c) carbazole-5,7(6H)-dione], compared with the parental NIH3T3 cells. pT22-3 also showed increased sensitivity to other topo-I inhibitors such as camptothecin (approx. 3.0-fold) and CPT-11 (irinotecan, approx. 3.0-fold). Transformation of NIH3T3 by another oncogene (erbB2) did not affect their sensitivity to these topo-I inhibitors. pT22-3 had approximately 32-fold higher topo-I activity than NIH3T3, but the same topo-I content. In a cell-free system, topo-I activity was increased 2-fold by addition of the H-ras protein precipitated from pT22-3 cells. Topo I in the nuclear extract of pT22-3 was eluted easily by low concentrations of NaCl compared with that of NIH3T3, suggesting a qualitative change in pT22-3 topo 1. Increased phosphorylation of topo I was observed in pT22-3. Furthermore, NB-506 decreased the amount of the GTP-bound form of the H-ras product in pT22-3 cells. These results suggest that the high growth-inhibitory effect of a topo-I inhibitor, NB-506, on H-ras-transformed NIH3T3 cells is due to the H-ras-mediated signal-transduction pathway.

3T3 Cells↗
PubMed1996

Synergism between cisplatin and topoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancer cells.

Topoisomerase I-targeting anticancer agents such as 7-ethyl-10-[4-(1-piperidyl)-1-piperidyl]carbonyloxy-camptothecin (CPT-11) and 6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D- glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-di one (NB-506) have been developed and show strong antitumor activity against various cancers. We examined the interaction of these drugs and cisplatin (CDDP), and biochemical mechanisms of synergism between them. Interaction of drugs in human small cell lung cancer cells, SBC-3, was analyzed using the isobologram method. Combinations of CDDP with NB-506, CPT-11, and an active metabolite of CPT-11, 7-ethyl-10-hydroxy-CPT (SN-38), showed synergistic effects. Formation of DNA interstrand cross-links (ICLs) on the cells was analyzed using an alkaline elution assay and increased ICLs were observed by simultaneous exposure to CDDP (1.5 microM) and NB-506 (10 nM) compared with that in response to CDDP alone. DNA repair after ICL formation induced by 3-h exposure to CDDP (1.5 microM) was reduced by NB-506 (10 nM) exposure. On the other hand, a higher concentration of CDDP (150 microM) enhanced the topoisomerase I inhibitory activity of NB-506 and SN-38 determined by relaxation of supercoiled Escherichia coli DNA. These biological interactions might result in synergistic interactions between CDDP and NB-506 or SN-38. Topoisomerase I inhibitors and CDDP may be a key regimen for cancer chemotherapy and merit further examination.

Antineoplastic Agents↗
PubMed1996

Effects of beta- and gamma-carboline derivatives of DNA topoisomerase activities.

beta-Carbolines, harman (1-methyl-9H-pyrido[3,4-b]indole) and norharman (9H-pyrido[3,4-b]indole) and gamma-carbolines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-4-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), are present in cooked foods and cigarette smoke. We studied the effects of these heterocyclic amines on the activity of DNA topoisomerases. Trp-P-1 and Trp-P-2 inhibited topoisomerase I (topo I) activity with ED50 values of 1.48 and 1.55 micrograms/ml, respectively, in a relaxation assay. Harman and norharman inhibited topo I activity but with much higher ED50 values, 23.8 and 34.4 micrograms/ml, respectively. Trp-P-1 and Trp-P-2 also inhibited topoisomerase II (topo II) activity at about 50 micrograms/ml, in a decatenation assay. Harman and norharman showed a much lower inhibitory effect on topo II activity. None of these compounds stabilized the cleavable complex mediated by topo II. Trp-P-1 and Trp-P-2 intercalated into DNA at concentrations inhibitory to topoisomerases. We considered that the intercalation with DNA and the inhibition of DNA topoisomerases by heterocyclic amines might be partly related to their inhibition of DNA excision repair and their enhancing effect on UV- or chemically induced mutagenic activity.

Breast Neoplasms↗