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S Kishimoto

Publications and source records attributed to S Kishimoto.

At least 91 records · Page 5Linked to original sources
PubMed1998

[Pharmaceutical and pharmacological development of antitumor prostaglandins].

Antitumor Prostaglandins such as delta 12PGJ2 and delta 7PGA1 possess a cross-conjugated dienone unit and exhibit unique antitumor effect. Lipid microshere (w/o type emulsion) was selected as pharmaceutical formulation because of physicochemical properties of prostaglandin. 13,14-Dihydro-15-deoxy-delta 7-PGA1 methyl ester (TEI-9826) were selected as a candidate for clinical trial. In a rat and mouse serum in vitro, TEI-9826 rapidly metabolized to 13,14-dihydro-15-deoxy-delta 7-PGA1 (TOK-4528), but TOK-4528 is stable as well as delta 12PGJ2. Lipid microshere containing TEI-9826 at the content of 5 mg/ml exhibited administration route and schedule dependent antitumor effect in vivo using Colon 26 bearing mouse model, which suggested that duration of serum concentration was important for antitumor effect. One of the antitumor mechanism of antitumor PG might be an induction of the cyclin-dependent kinase inhibitor p21. PPAR gamma also might be important. New type homogenizer, high pressure jet flow type homogenizer was developed in the study of antitumor prostaglandin.

Animals↗
PubMed1997

Endogenous CCK inhibits colonic contractions in unrestrained conscious rats.

As cholecystokinin octapeptide (CCK-OP) and feeding have been reported to relax the circular muscle contractions of the proximal colon in unrestrained conscious rats under fasting conditions, the, action of cholecystokinin, released after duodenal infusion of a low residual diet of clinimeal, was studied on the motor activity of the proximal colon in unrestrained conscious rats. We used an implantable telemetry system with a miniature strain gauge force transducer introduced into the rat proximal colon. By using a specific radioimmunoassay system for CCK, plasma levels of CCK before and after duodenal infusion of clinimeal (0.5, 1.0, 2.0 ml) were determined at 0, 5, 10, 20, 30, 60 min in the portal blood. The clinimeal infusion caused a significant increase in CCK levels of the portal plasma during 5 and 30 min. This increase was in a dose-dependent manner. In accordance with this increase in plasma CCK, the motor activity of the proximal circular muscle was suppressed significantly. A bolus injection of the CCK A receptor antagonist, loxiglumide, CR 1505 (0.1, 0.5 and 1.0 mg/kg ip), prior to clinimeal blocked the inhibitory action of CCK on the motor activity in a concentration-dependent manner. These data suggest that endogenous CCK released by a residual diet is involved in the mechanism of inhibition of motor activity in the proximal colon.

Animal Feed↗
PubMed1997

Inhibition by 2-arachidonoylglycerol, a novel type of possible neuromodulator, of the depolarization-induced increase in intracellular free calcium in neuroblastoma x glioma hybrid NG108-15 cells.

2-Arachidonoylglycerol was found to inhibit the depolarization-induced increase in [Ca2+]i in NG108-15 cells differentiated with prostaglandin E1 and theophylline in a dose-dependent manner. Such an effect appears to be rather specific to polyunsaturated fatty acid-containing monoacylglycerols such as 2-arachidonoylglycerol. Neither 2-palmitoylglycerol nor free arachidonic acid exhibited appreciable inhibitory activity. These observations raise the possibility that 2-arachidonoylglycerol attenuates the increase in [Ca2+]i, thereby modulating several neural functions in this type of cell.

Arachidonic Acids↗
PubMed1997

Nitric oxide is involved in the inhibitory action of cholecystokinin octapeptide (CCK-OP) on proximal colonic motility.

To determine whether nitric oxide (NO) is a possible mediator in the inhibitory action of CCK-octapeptide (CCK-OP) on circular muscle contractions of the rat proximal colon, contractile activities of the circular muscle were recorded in the proximal colon of unrestrained conscious rats in the fasting state using a miniature strain gauge force transducer and an implantable telemetry system. Regular and rhythmic phasic contractions were observed during the fasted condition, similar to the myoelectric migrating complex seen in intestinal contractions of the fasting dog. These phasic contractions were almost completely inhibited after intraperitoneal (i.p.) administration of CCK-OP at a dose of 15 microg/kg body weight. N(omega)-nitro-arginine, methyl ester (L-NAME), at doses of 20 and 200 mg/kg i.p. administered prior to i.p. injection of CCK-OP, prevented the inhibitory action on the fasting phasic contractions. The degree of prevention was dose-dependent. 100 mg/kg body weight i.p. injection of L-arginine inhibited the circular muscle contractions. The same dose of D-arginine had no action on contractions of the circular muscle of the proximal colon in the fasted rat. From these data, we conclude that NO is one possible mediator in the inhibitory mechanism of CCK-OP on smooth muscle motor activity of the rat proximal colon in vivo.

Animals↗
PubMed1997

Prostacyclin analog-suppressed ischemia-reperfusion injury of the rat liver: evaluation by calpain mu activation.

Prostaglandin I2 has a protective effect on hepatic ischemia-reperfusion injury. However, the exact intracellular mechanisms of this effect have not been elucidated. Calpain micro, a Ca2+-dependent protease, has been found to play a role in the ischemia-reperfusion injury of various organs. The hilar area of the left lateral and median lobes of rat livers was clamped for 60 min. A prostaglandin I2 analog (OP2507, C35H41NO4) was intravenously administered at 0.1, 0.32, or 1.0 microg/kg/min from 20 min before the ischemia. In addition to biochemical and microscopic analyses, the activation of calpain mu was investigated using specific antibodies against the intermediate (activated) and preactivated forms of calpain mu. The degradation of talin was also studied by Western blotting. When OP2507 was infused at 0.32 and 1.0 microg/kg/min, bile flow significantly increased after reperfusion compared with the control group, consistent with the decrease in serum transaminase levels. Membrane bleb formation and the appearance of the intermediate form of calpain mu were observed at 60 min of ischemia in the control and OP2507 (0.1 microg/kg/min) groups and remained present until 120 min after reperfusion. OP2507 (1.0 microg/kg/min) markedly suppressed not only membrane bleb formation but also calpain mu activation and the degradation of talin. In conclusion, OP2507 suppresses ischemia-reperfusion injury of the rat liver, and its cytoprotective effect is closely associated with the inhibition of calpain mu activation.

Alanine Transaminase↗
PubMed1997

Effect of enprostil on omeprazole-induced hypergastrinemia and inhibition of gastric acid secretion in peptic ulcer patients.

This study was performed to examine the effects of additional enprostil administration on hypergastrinemia and gastric acid suppression induced by omeprazole. Serum gastrin concentrations were measured in 10 peptic ulcer patients (six Helicobacter pylori-positive and four Helicobacter pylori-negative patients) before treatment, after two weeks of omeprazole (20 mg/day), and after two weeks of omeprazole and enprostil (50 micrograms/day). The additional acid inhibitory effect of enprostil was evaluated by 24-hr intragastric pH measurements in five healthy Helicobacter pylori-negative volunteers. After omeprazole treatment, the serum gastrin level of Helicobacter pylori-positive patients (3.5-fold of control) was markedly higher than that of Helicobacter pylori-negative patients (1.7-fold of control). Additional treatment with enprostil suppressed serum gastrin levels to 0.4-fold and 0.7-fold of omeprazole treatment levels in Helicobacter pylori-positive and Helicobacter pylori-negative patients, respectively. In healthy volunteers, median pH recorded during the nonmeal daytime interval increased significantly with additional enprostil. Thus, enprostil reduces undesirable omeprazole-induced hypergastrinemia, especially in Helicobacter pylori-positive patients, and effectively suppresses acid secretion.

Adult↗
PubMed1997

Calcium channel blockers suppress the contact hypersensitivity reaction (CHR) by inhibiting antigen transport and presentation by epidermal Langerhans cells in mice.

Since Langerhans cells (LC) are the principal antigen-presenting cells among epidermal cells, treatments suppressing LC function may inhibit CHR. Although calcium channel blockers (CCB) have been shown to suppress the functions of several immunologically active cells, little is known about their effect on LC. In this study we show that pretreatment with topical 1% nifedipine or verapamil HCl significantly suppressed both the sensitization and elicitation phases of a CHR in mice. We then investigated whether CCB affected LC. Flow cytometric analysis of regional lymph node cells obtained 24 h after applying FITC demonstrated that topical CCB treatment significantly reduced the percentage of FITC+ NLDC-145+ cells, suggesting that CCB had suppressed antigen transport by LC. In vitro treatment with nifedipine or verapamil significantly suppressed the antigen-presenting capacity of LC in a dose-dependent manner. In addition, in vitro CCB treatment reduced the percentage of class II MHC antigen-positive epidermal cells and significantly suppressed class II MHC and B7-1 levels in LC, as determined by flow cytometry and reverse transcriptase-polymerase chain reaction, whereas surface expression of B7-2 and mRNA was only weakly reduced. Neither expression of CD45 nor the percentage of CD45+ cells were affected, suggesting that the effects of CCB on LC were not due to cytotoxicity. Our results suggest that CCB inhibit CHR, at least in part, by suppressing the functions of LC.

Animals↗
PubMed1997

Merkel cell carcinoma with partial spontaneous regression: an immunohistochemical, ultrastructural, and TUNEL labeling study.

We report a case of Merkel cell carcinoma that partially regressed after biopsy. A 76-year-old woman presented with an 1 month history of a rapidly enlarging nodule on her left cheek. After biopsy, the nodule reduced to almost half the size and was excised 1 month later. The excised specimen showed a dense cluster of lymphocytes and fibrosis around the tumor nests. In addition, lymphocytes showed apposition with tumor cells. An immunohistologically dense, even infiltration of CD4+ and CD8+ cells was found around the tumor nests, and more CD8+ cells than CD4+ cells were seen in the tumor nests. By electron microscopy (EM), apoptosis of tumor cells and lymphocytes was observed. Many apoptotic cells were also detected by in situ nick end-labeling (TUNEL) of DNA-breaks, especially in the marginal area of tumor nests surrounded by dense lymphocytic infiltrates. It seems likely that T-cell immunity, which induces apoptosis of tumor cells, may have been involved in tumor regression.

Aged↗
PubMed1997

Protein expression of fibroblast growth factor receptor-1 in keratinocytes during wound healing in rat skin.

Fibroblast growth factors have been shown to play important roles in wound healing. To define their sites of action, we examined the expression of fibroblast growth factor receptor-1 (FGFR-1) during burn wound healing in rat skin by immunohistochemistry and western blot analysis. In cryostat sections of intact skin, little or no staining was observed. After a burn, however, staining for FGFR-1 was found in newly forming epidermis. The suprabasal layer of such epidermis, composed mostly of regenerating keratinocytes, was stained intensely, whereas keratinocytes in newly forming hair follicles were devoid of staining. Staining gradually decreased week by week after wound closure and was hardly visible 10 weeks after the burn, when the thickness of the epidermis had returned to the normal level. Staining was also found in small blood vessels and capillaries of granulation tissues of the dermis. Western blot analysis using the same antiserum was performed in the newly forming epidermis 10 d after the burn. A single band was detected with an apparent molecular weight of 120 kDa, corresponding to the short membrane-bound form of rat FGFR-1. Our study indicates that FGFR-1 is expressed during wound healing, mainly in regenerating epidermis and to some extent in blood vessels of the dermis. Fibroblast growth factors may affect the proliferation and differentiation of epidermal keratinocytes as well as angiogenesis in the dermis via the FGFR-1 expressed during wound healing.

Animals↗
PubMed1997

Comparison of platelet-activating factor receptor mRNA levels in peripheral blood eosinophils from normal subjects and atopic asthmatic patients.

Platelet-activating factor (PAF) modulates the functions of eosinophils, which play an important role in allergic inflammation, through a specific receptor(s) expressed on the cell surface. We compared expression levels of mRNA for the PAF receptor (PAF-R) in peripheral blood eosinophils from atopic asthmatic patients with those from normal healthy subjects using a relative quantification method based on the reverse transcription-polymerase chain reaction (RT-PCR). We found that the levels of PAF-R mRNA in eosinophils from the patients were significantly higher than those in normal subjects. These results suggest that the increased expression of PAF-R in eosinophils may be relevant to the pathogenesis of atopic asthma.

Adult↗
PubMed1997

Acute cutaneous barrier perturbation induces maturation of Langerhans' cells in hairless mice.

Perturbation of the cutaneous water permeability barrier has been shown to result in many physiological events in keratinocytes, including upregulation of proinflammatory cytokine production. However, little is known about the effect of barrier disruption on Langerhans' cells (LC). In the present study, we examined whether acute barrier perturbation by acetone treatment or tape stripping affects the phenotypes and functions of LC in male hairless mice. Both procedures resulted in a two- to five-fold increase in the expression of MHC class II antigens, B7-2 and intercellular adhesion molecule-1 on LC, whereas no significant changes were detected in levels of B7-1. Levels of intracellular interleukin-1 beta, as determined by flowcytometry, were also increased 1 h after acetone treatment or tape stripping. LC obtained from barrier-disrupted mice induced a significant increase in syngeneic and allogeneic T-cell proliferation, compared to those from saline-treated mice. These results indicate that LC play a crucial role in maintaining cutaneous homeostasis against increasing exposure to external substances resulting from barrier disruption.

Acetone↗
PubMed1997

Angiosarcoma of the scalp associated with renal transplantation.

A case of cutaneous angiosarcoma occurring in a 51-year-old male renal transplant patient is reported. Multiple violaceous nodules surrounded by poorly demarcated red to purple discoloration were found on his scalp. Immunosuppressants consisting of azathioprine and prednisolone had been administered during the 12-year period since the renal transplantation. We diagnosed the lesion clinically as a cutaneous angiosarcoma and performed a wide surgical excision. The histopathological findings confirmed the diagnosis and showed tumour cells in the peripheral margin. Postoperatively, the patient started immunotherapy with systemic administration of recombinant interleukin-2 (rIL-2), but he refused to continue it because of the acute rejection of the transplanted kidney induced by the rIL-2. Instead he received radiation therapy (total 7000 rad) of the scalp. Although no recurrence was noticed for 15 months after the completion of radiation, he died due to lung metastasis from angiosarcoma. We review the seven cases, including ours, of angiosarcoma after renal transplantation that are reported in detail in the literature.

Fatal Outcome↗
PubMed1997

Verruciform xanthoma in association with a vulval fibroepithelial polyp.

We report the clinical, light microscopic, immunohistochemical and ultrastructural features of a verruciform xanthoma that developed in association with a vulval fibroepithelial polyp. To our knowledge, this is the first time that this association has been reported. Immunohistochemical findings confirmed that the xanthoma cells were of a monocyte/macrophage lineage. In addition to typical histological characteristics, prominent vascular ectasias were detected in the deep dermis at the periphery of this lesion. The ectasias may play a part in pathogenesis.

Female↗
PubMed1997

Expression of fas (CD95/APO-1) antigen induced by radiation therapy for diffuse B-cell lymphoma: immunohistochemical study.

Most malignant lymphomas show relatively high degrees of radiosensitivity, in which apoptosis has been shown to play an important role. Recently, the Fas (CD95/APO-1)/Fas ligand system has been identified as a key regulator of apoptosis in some types of lymphoma cell lines. In this study, we aimed to determine whether Fas antigen expression is induced by radiotherapy for malignant lymphoma and to clarify its possible correlation with the therapeutic effect of radiation therapy. Fifty-six patients with tumors of the tongue, oropharynx, and maxillary sinus were examined; four were confirmed as malignant lymphoma, and the rest were identified as squamous cell carcinoma. After obtaining the patients' informed consent, biopsies were performed before treatment and at doses of 4, 10, and 20 Gy of radiotherapy, and specimens were preserved in liquid nitrogen until further examination. Serial sectioning of 6 micrometer was performed using a cryostat, and samples were immunohistochemically stained using the streptoavidin-biotin peroxidase method and a monoclonal antibody against Fas. Two of the four patients with malignant lymphoma showed Fas antigen expression on their tumor tissue at 4 and 10 Gy of radiotherapy. These tumors showed high radiosensitivity and disappeared at a dose of 20 Gy of radiotherapy. In samples from these two patients, DNA ladder formation was identified at 10 Gy. In 52 squamous cell carcinomas, staining for the Fas antigen showed negative or only slightly positive results. However, in one of the cases of squamous cell carcinoma, lymphocytes infiltrating into cancer tissue showed Fas antigen expression at 4 Gy of irradiation, and these lymphocytes disappeared on the tumor tissue at 10 Gy. Therefore, the high radiosensitivity of malignant lymphoma among our samples could be explained by the overexpression of Fas antigen induced by small doses of radiation therapy, and Fas ligand could be produced by infiltrating lymphocytes or may be expressed simultaneously on the lymphoma cells.

Aged↗
PubMed1997

Immunohistochemical study of c-fos-positive lymphocytes infiltrated into human squamous cell carcinomas of the head and neck during radiation therapy and its clinical significance.

C-fos has been reported to be one of the immediate early genes in signal transduction systems after many kinds of stresses, including ionizing radiation. Changes in c-fos expression induced by radiation therapy in tumor tissues have not yet been reported. In this study, we have attempted to determine whether c-fos expression is induced by radiotherapy in human squamous cell carcinomas of the head and neck and to establish a possible correlation between c-fos expression and the therapeutic effects of radiation therapy. Twenty-seven patients with tumors of the oral cavity, oropharynx, and maxillary sinus were examined, all of which were confirmed as squamous cell carcinomas. After obtaining the patients' informed consent, biopsies were performed before treatment and at doses of 4, 10, and 20 Gy of radiotherapy, and the specimens were preserved in liquid nitrogen for further examination. Serial sectioning of 6 micrometer was performed using a cryostat, and samples were immunohistochemically stained using the streptoavidin-biotin peroxidase method and a monoclonal antibody against c-fos. Three of the 27 patients with squamous cell carcinoma showed slight expression of c-fos in their tumor cells before and/or at 4 or 10 Gy of radiotherapy. The tumors showed high radiosensitivity. Concerning tumor-infiltrating lymphocytes, the rate of moderate or remarkable grades of c-fos-positive lymphocytes before radiotherapy and at radiation doses of 4, 10, and 20 Gy was 8.0, 29.2, 4.8, and 0%, respectively. The relationship between the immunohistochemical findings and the antitumor effect at a radiation dose of 20 Gy was examined on the corresponding H&E-stained sections. In patients whose infiltration of c-fos-positive lymphocytes into tumor tissues were moderate or remarkable at 4 Gy of radiotherapy, the tumors responded significantly well to radiation therapy (P < 0.025, chi2 test), and the patients took a significantly favorable clinical course (P < 0.05, chi2 test). In a sample from one of the patients, c-fos-positive lymphocytes were identified as CD4 positive and CD8 negative. Therefore, the high radiosensitivity of squamous cell carcinomas in our samples could be explained by an overexpression of c-fos in the tumor-infiltrating lymphocytes induced by small doses of radiation therapy, and these activated lymphocytes exerted a cytotoxic effect against the cancer cells.

Adult↗
PubMed1996

2-Arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma x glioma hybrid NG108-15 cells.

Low concentrations of 2-arachidonoylglycerol were found to induce rapid, transient elevation of intracellular free Ca2+ in NG108-15 cells (EC50 was 150 nM). Free arachidonic acid, 2-palmitoylglycerol, 2-oleoylglycerol, 2-linoleoylglycerol and 2-docosahexaenoylglycerol were inactive. Anandamide acted as a partial agonist. Importantly, desensitization was observed upon sequential challenge with 2-arachidonoylglycerol. Furthermore, cross-desensitization was observed between 2-arachidonoylglycerol and WIN 55212-2, a cannabinoid receptor agonist. Pretreatment of the cells with SR141716A, a cannabinoid receptor antagonist, abolished the activities of both 2-arachidonoylglycerol and WIN 55212-2. These results strongly suggest that 2-arachidonoylglycerol and WIN 55212-2 bind to a common cannabinoid receptor to elicit cellular responses and that 2-arachidonoylglycerol has some physiological role in nervous tissues.

Arachidonic Acids↗
PubMed1996

Regulation by IL-5 of expression of functional platelet-activating factor receptors on human eosinophils.

Platelet-activating factor (PAF) and IL-5 are both important mediators of various allergic reactions, although the relationship between these mediators in allergic responses has not yet been fully elucidated. In this study, we investigated the effects of human rIL-5 on the expression of the PAF receptor (PAF-R) on eosinophils from healthy human volunteers. The specific binding of [3H]WEB 2086, a specific ligand for PAF-R, to eosinophils treated with 5 ng/ml of IL-5 for 12 h was significantly higher than that to untreated cells. The Bmax value for IL-5-treated eosinophils was 1.8-fold higher than that for untreated cells, while the Kd values remained unchanged. This clearly indicates that surface expression of PAF-R on eosinophils is enhanced by IL-5. The enhancement was first observed at 6 h and reached a plateau at 12 to 18 h. The effect of IL-5 was abolished in the presence of cycloheximide or actinomycin D. When the relative amount of PAF-R mRNA was determined by reverse transcription PCR, the message was found to be increased through activation of transcription of transcript 1 on exposure to IL-5. Furthermore, we found that the PAF-induced increase in intracellular calcium ion concentration in eosinophils was markedly augmented by exposure to IL-5 for 12 h. Several lines of data suggest that the enhanced expression of PAF-R on eosinophils due to IL-5 is the cause of the augmented response to PAF. These findings will be of value for understanding the mechanisms of selective infiltration and activation of eosinophils in allergic diseases in which PAF and IL-5 are crucially involved.

Azepines↗