Biomedical subjects

S Horie

Publications and source records attributed to S Horie.

At least 37 records · Page 2Linked to original sources

PubMed2001

Characterization of the antitumor activities of IFN-alpha8 on renal cell carcinoma cells in vitro.

Interferon-alpha (IFN-alpha) has a number of therapeutic applications in the treatment of various human cancers and diseases of viral origin. IFN-alpha includes several subtypes, and little has been reported on the biologic properties of the individual subtypes. Here, we report on the individual antitumor effects of five IFN-alpha subtypes, alpha1, alpha2, alpha5, alpha8, and alpha10, against six renal cell carcinoma (RCC) cell lines in vitro. Among the subtypes, IFN-alpha8 most potently inhibited cell proliferation and delayed the G(1)/S transition. Synergistic induction of apoptosis was shown in two of the RCC cell lines when treated with the combination of IFN-alpha and IFN-gamma rather than with either IFN-alpha or IFN-gamma alone. IFN-alpha8 was most effective in the induction of apoptosis when combined with IFN-gamma. In addition, IFN-alpha8 had the strongest ability to upregulate HLA class II antigen expression in the subtypes examined. These data indicate that subtypes of IFN-alpha have disparate antitumor effects in vitro, and in vitro distinctions among the IFN-alpha subtypes should be appreciated more in clinical application.

Antineoplastic Agents↗

PubMed2001

Contribution of CD54 to human eosinophil and neutrophil superoxide production.

We have reported that CD54 on eosinophils is involved in eosinophil degranulation. However, the role of CD54 in eosinophil and neutrophil superoxide production is still uncertain. We assessed the effect of CD54 on eosinophils and neutrophils in recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF)- or phorbol myristate acetate (PMA)-induced superoxide production through CD18. Anti-CD54 monoclonal antibody attenuated leukocyte aggregation and superoxide production of rGM-CSF- or PMA-stimulated neutrophils and PMA-stimulated eosinophils. Anti-CD18 monoclonal antibody or theophylline attenuated superoxide production of eosinophils and neutrophils stimulated by either stimuli. Flow cytometric analysis demonstrated CD54 expression on freshly isolated neutrophils but not on freshly isolated eosinophils. CD54 newly expressed on eosinophils reached its peak expression 30 min after PMA stimulation. The increase in CD18 and CD54 expression on neutrophils caused by rGM-CSF stimulation was partially inhibited by theophylline. These data demonstrated that CD54 and CD18 interaction of eosinophils or neutrophils is involved in superoxide production and that the inhibition of superoxide production by theophylline may be at least partly due to the inhibition of CD54 and CD18.

Analysis of Variance↗

PubMed2001

Theophylline inhibits TNF-alpha-induced CD4 expression on human eosinophils and CD4+ eosinophil migration.

BACKGROUND: Increasing evidence regarding asthma suggests that CD4+ cells are preferentially recruited to sites of bronchial inflammation. Interleukin (IL)-16 has been reported as playing an important role in the accumulation of CD4+ cells. We have shown that the CD4 molecule is expressed on normal human eosinophils by tumor necrosis factor (TNF)-alpha stimulation. METHODS: We evaluated the effects of theophylline, KF19514 [a selective phosphodiesterase (PDE) IV inhibitor] and dexamethasone on CD4 expression on eosinophils and eosinophil migration in response to IL-16, a natural soluble ligand of the CD4 molecule. RESULTS: The maximum eosinophil migration was observed when eosinophils were cultured with TNF-alpha at 10 ng/ml for 18 h and the concentration of IL-16 was 10 pg/ml. CD4+ eosinophil migration in response to IL-16 was mostly, if not fully, chemokinetic and this migration was significantly inhibited by Fab of anti-CD4 monoclonal antibody. Theophylline (10(-4)-10(-3) M), KF19514 (10(-7)-10(-6) M) and dexamethasone (10(-8)- 10(-6) M) significantly inhibited CD4 expression on eosinophils induced by TNF-alpha. Theophylline (10(-3) M) and KF19514 (10(-6) M) inhibited CD4+ eosinophil migratory responses induced by IL-16, but 10(-6) M dexamethasone did not. Theophylline and KF19514 augmented the intracellular adenosine-3',5'-cyclic monophosphate (cAMP) concentration in eosinophils, suggesting modulation by cAMP of CD4 expression and eosinophil migration. CONCLUSIONS: These data suggest that TNF-alpha-induced CD4+ eosinophils may contribute to eosinophil migratory responses induced by IL-16. Theophylline and selective PDE IV inhibitor may prevent airway inflammation by downregulating CD4 expression on eosinophils and inhibiting eosinophil migration through CD4 and IL-16 interaction.

CD4 Antigens↗

PubMed2001

Enhancement of phenylephrine-induced contraction in the isolated rat aorta with endothelium by H2O-extract from an Oriental medicinal plant Leonuri herba.

Leonuri herba (I-mu-ts'ao, the Chinese motherwort) is an ancient Chinese traditional herb. Although the pharmacological effects of extracts of Leonuri herba have been shown in platelets and uteri, the effect on the vascular system has not been determined. In the present study, we investigated the effects of extracts of Leonuri herba on the contraction of the isolated rat aorta. Although the H20-extract (0.3-3 mg/ml) by itself showed a limited effect, the extract enhanced phenylephrine-induced contraction of the aorta with endothelium, but not without endothelium. The H20-extract, like N(G)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), significantly inhibited the relaxation induced by acetylcholine in the aorta with endothelium. The inhibitory effect of H20-extract on the relaxation decreased by co-addition with 1 mM L-arginine. The vasoconstrictive effect of H20-extract was not due to leonurine, which is a constituent in Leonuri herba and shows uterotonic activity. Intravenous injection of the H20-extract (1.5 mg/kg) to rats caused an increase in blood pressure for 5 min, like L-NAME (1.35 mg/kg). These findings suggest that there is a component(s) in Leonuri herba, which shows a vasoconstrictive activity in rat aorta in vitro and in vivo and has similar pharmacological profile to that of L-NAME.

Animals↗

PubMed2001

Gastric acid secretion by central injection of dynorphin A-(1-17), an endogenous ligand of kappa-opioid receptor, in urethane-anesthetized rats.

Gastric acid secretion has been proposed to be regulated by opioid receptors in the central nervous system (CNS). Previously, we reported that central injection of synthetic agonists of kappa-opioid receptors stimulated gastric acid secretion in rats, and the secretion by the agonists was inhibited by norbinaltorphimine (an antagonist of kappa-opioid receptor). In the present study, we investigated the effect of dynorphin A-(1-17), an endogenous ligand of kappa-opioid receptor on the gastric acid secretion in the perfused stomach of urethane-anesthetized rats. Injection of dynorphin A-(1-17) (0.1-1 microg per rat) into the lateral cerebroventricle (LV) stimulated the secretion in a dose-dependent manner. The effect of dynorphin A-(1-17) was almost completely inhibited by the LV injection of norbinaltorphimine (10 microg) and in vagotomized rats. Although some studies of dynorphin A-(1-17) after central injection showed non-opioid effects such as the involvement of N-methyl-D-aspartate (NMDA) receptor, the effect of dynorphin A-(1-17) was not inhibited by a selective antagonist of the NMDA receptor ((+/-)-3-(2-carboxypiperazin-4-yl)-1-propylphosphonic acid, 10 microg). The LV injection of naloxone benzoylhydrazone (a kappa3-opioid receptor agonist, 100 microg) also stimulated the secretion in norbinaltorphimine-sensitive manner. These findings showed that both an endogenous ligand dynorphin A-(1-17) and a synthetic kappa3-opioid receptor agonist stimulated gastric acid secretion via kappa-opioid receptors in the CNS of rats in vivo.

Anesthesia↗

PubMed2001

Alterations in palatal ruga patterns in Jcl:ICR mouse fetuses from dams treated with all-trans-retinoic acid.

Pregnant Jcl:ICR mice were orally given all-trans-retinoic acid (RA) at dose levels from 0.08 to 80 mg/kg once at days 10.5, 11.5, or 12.5 (vaginal plug = day 0) of gestation. The dams were sacrificed at day 18.5 of gestation, and the fetuses were dissected. After fixation in Bouin's solution, the fetal palates were observed under a dissecting microscope. Pattern alterations rare in the control fetuses were shortness, fusion, maldirection, trirugal malalignment, modified cross, and cross. These alterations were defined as abnormalities. Cleft palate was induced at dose levels of 20 mg/kg and above. At each treatment day, the total incidence of abnormal rugae increased from the dose of 0.3 or 0.6 mg/kg, dose-dependently. Although missing ruga-8 was a common pattern alteration in vehicle controls, its incidence increased dose-dependently. The incidence of supernumerary posterior to ruga 3 increased dose-dependently after treatment at day 11.5 or day 12.5 of gestation, however the increase was not observed after treatment at day 10.5 of gestation. These findings indicate that the abnormalities of ruga, missing ruga-8 and supernumerary posterior to ruga 3 are very sensitive indicators of teratogenicity of RA.

Animals↗

PubMed2000

Oxidized low-density lipoprotein impairs the anti-coagulant function of tissue-factor-pathway inhibitor through oxidative modification by its high association and accelerated degradation in cultured human endothelial cells.

We have examined whether oxidized low-density lipoprotein (ox-LDL) affects the function of tissue-factor-pathway inhibitor (TFPI), an anti-coagulant regulator in the extrinsic pathway of coagulation, in cultured human umbilical vein endothelial cells (HUVEC). Treatment of culture medium of HUVEC with ox-LDL, but not with native or acetylated LDLs, drastically decreased the reactivity of TFPI to its antibody specific for Kunitz domain 1 or one specific for the conformation between Kunitz 1 and 2 of TFPI, and caused a rapid, concentration-dependent decrease in the functional activity of TFPI to inhibit Factor X activation. When 5 ng of recombinant TFPI (rTFPI) was mixed with 10 microg of ox-LDL for 30 min, almost all of the rTFPI was detected in the ox-LDL fraction and no free rTFPI was observed on non-denaturing PAGE, in contrast with the virtual absence of rTFPI in the native LDL fraction. Ox-LDL decreased the antigen level of TFPI in the lysate of HUVEC in a time-dependent manner. It did not affect the mRNA level, but ox-LDL-dependent reduction of the TFPI antigen level in HUVEC was reversed by the simultaneous treatment of ox-LDL with bafilomycin A1, an inhibitor of the lysosomal proton pump. These results indicate that ox-LDL lessens the anti-coagulant function of TFPI through both oxidative modification and accelerated degradation of the molecule outside and inside HUVEC respectively.

Anticoagulants↗

PubMed2000

Acceleration of thrombomodulin gene transcription by retinoic acid: retinoic acid receptors and Sp1 regulate the promoter activity through interactions with two different sequences in the 5'-flanking region of human gene.

The interactions between retinoic acid- (RA)-dependent transcriptional regulatory sequences of the 5'-untranslated region of the thrombomodulin gene and nuclear RA-responsive proteins were studied using human pancreas BxPC-3 cells. Deletion mutants of pTM-CAT plasmid revealed the presence of distal and proximal RA-responsive regions containing direct repeat with 4 spaces (DR4) and three of four Sp1 sites, respectively. Cotransfection of a pTM-CAT plasmid with expression plasmids of RA receptors (RARalpha, RARbeta, and RARgamma) augmented the promoter activity under the condition of lower retinoid X receptor-alpha (RXRalpha) expression, whereas the activity was greatly diminished when RXRalpha was highly expressed. An electrophoretic mobility shift assay with cDNA containing the DR4 indicated that heterodimers of RAR and RXRalpha interacted with the DR4 site, although the interaction gradually disappeared with the increase in the ratio of RXRalpha/RAR. On the other hand, Sp1 protein interacted especially with the tandem Sp1 site corresponding to the first and second Sp1 sequences of the four Sp1 sites in the proximal RA-responsive region. The binding of Sp1 to Sp1 sites was independent of RAR-RXR heterodimer but increased with the increase in Sp1 concentration in the presence of unknown factor(s) of reticulocyte lysate. Upon treatment of the cells with RA, time-dependent increases in the ratio of RARbeta to RXRalpha and the phosphorylated form of Sp1 were observed. We concluded that two genomic DNA regions, the DR4 site (-1531 to -1516) and the first and second Sp1-binding sites (-145 to -121), were involved in the RA-dependent augmentation of thrombomodulin gene expression through increased interactions of the two regions with heterodimer of RAR-RXRalpha and nuclear Sp1, respectively.

Binding Sites↗

PubMed2000

Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer.

Mechanisms for multifocal bladder carcinogenesis remain unclear. To see whether normal mucosa had already acquired genetic or epigenetic changes, we examined loss of heterozygosity (LOH) at 10 microsatellite loci and methylation of the p16(INK4) CpG island in multiple tumors and pathologically normal mucosa in six patients with bladder cancer. Either LOH or methylation was detected in 77% of samples of normal epithelium, and LOH detected in samples of normal epithelium was also observed in most tumor samples. This result indicated that a population of cells in morphologically normal epithelium possessed genetic or epigenetic aberrations in common with bladder cancer, which might provide a ground for multiple tumorigenesis.

Aged↗

PubMed2000

Basal layer reactivity in hyperplastic and metaplastic lesions of the bronchi as studied by lectin histochemistry.

The relationship between squamous metaplasia and squamous cell carcinoma of the bronchi has been the subject of controversy. We investigated basal cell hyperplasia, stratification, squamous metaplasia, and squamous cell carcinoma by means of lectin histochemistry with peanut agglutinin (PNA), Ulex europeus agglutinin-I, soybean agglutinin, and Dolichos biflorus agglutinin for all normal basal cells that are reactive. A basal layer stained with PNA was observed in basal cell hyperplasia, stratification, and squamous metaplasia, but this layer was not exhibited by squamous cell carcinoma. In hyperplasia and metaplasia, PNA staining was biased toward the lowest (basal) layer, whereas staining for the other lectins was more uniformly distributed across the layers. A PNA-positive basal layer may be important for the morphologic reversibility of the bronchial mucosa in hyperplastic and metaplastic lesions, and destruction of this layer may be associated with a progression from metaplasia to squamous cell carcinoma.

Adenocarcinoma↗

PubMed2000

Overexpression of MDM2 protein in intrahepatic cholangiocarcinoma: relationship with p53 overexpression, Ki-67 labeling, and clinicopathological features.

Aberration of the p53 gene is thought to be the most frequent genetic alteration in human cancers. Tp53 protein may be inactivated by the binding of the MDM2 protein. MDM2, the product of the mdm2 gene, is an oncoprotein that binds to Tp53 and inhibits the p53-mediated transactivation. MDM2 overexpression has been reported in several human cancers, but not in intrahepatic cholangiocarcinoma (ICC). Therefore, we have evaluated the immunohistochemical overexpression of MDM2 and the relationship between its expression and histological grade, clinicopathological features, Tp53 overexpression, and Ki-67 labeling index in 47 cases of ICC. MDM2 and Tp53 were found to be overexpressed in 38% and 57% of the tumor, respectively. MDM2 and Tp53 were not expressed in non-tumorous liver tissue. There was no significant difference between the MDM2 overexpression and ICC tumor grade. However, MDM2 overexpression correlated with the presence of metastases (P<0.01) and advanced tumor stage (P<0.05). MDM2 overexpression also correlated with Tp53 overexpression (P<0.03) and Ki-67 labeling index (P<0.03). Our findings suggest that MDM2 overexpression may play a role in the late stage of human ICC.

Bile Duct Neoplasms↗

PubMed2000

Spontaneous B-cell IgE production in a patient with remarkable eosinophilia and hyper IgE.

BACKGROUND: The pathophysiology of eosinophilia and hyper-IgE is not fully elucidated yet. OBJECTIVE: To clarify the pathophysiology of a patient with remarkable eosinophilia and hyper IgE, we examined cytokine levels in serum, surface antigens of peripheral blood eosinophils and IgE production in vitro. RESULTS: Concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), and granulocyte/macrophage-colony stimulating factor (GM-CSF) in the serum were 21 pg/mL, <15 pg/mL, <15 pg/mL, 8 pg/mL, and <5 pg/mL pg/mL, respectively. Newly expressed surface antigens CD4, CD25, CD69, and HLA-DR, but not CD54, were observed on peripheral blood eosinophils. Extremely high levels of IgE secretion was found in the patient's mononuclear cells without stimuli; this was not enhanced by IL-4 or IL-4 plus anti-CD40 monoclonal antibody stimulation. Furthermore, highly purified B cells spontaneously produced large amounts of IgE and the production was not enhanced in addition of his T cells. CONCLUSION: The eosinophils were activated, and the B cells spontaneously produced IgE independently of T cells or cytokines, suggesting that intrinsic abnormality of B cells leading to dysregulated production of IgE in this disease.

Aged↗

PubMed2000

Inhibitory effects of antisense oligonucleotides on the expression of procollagen type III gene in mouse hepatic stellate cells transformed by simian virus 40.

The effects of phosphorothioate antisense oligonucleotides (ASO), complementary to the AUG start region, the junctional region of the intron and exon, and to exon of the procollagen type III gene, were investigated in a mouse hepatic stellate cell (HSC) line transformed by the simian virus 40 gene, SV68c-IS cells. ASO were transfected by lipofection. Immunohistochemistry, western and northern blotting showed inhibitory effects on procollagen type III gene expression by ASO that were complementary to the AUG start region and the junctional region of the intron and exon 2. However, ASO complementary to the exon 2 and 3, junctional region of the intron and exon 3, and sense oligonucleotides complementary to each ASO did not show any inhibitory effects. The effects of ASO complementary to the AUG start region were greater than those of ASO complementary to the junctional region. The effects of ASO were transient and a large amount of ASO was required to induce inhibitory effects without lipofection. ASO were effective in inhibiting the expression of the procollagen type III gene in the HSC which is well known to play a critical role in liver fibrosis.

Actins↗

PubMed2000

Epithelioid leiomyosarcoma with osteoclast-like giant cells in the rectum.

We report a rare case of rectal epithelioid leiomyosarcoma with osteoclast-like giant cells. A 71-year-old Japanese man was admitted to a hospital with melena. Results of a colonoscopy test revealed a polypoid tumor in the rectum, and a biopsy specimen from the lesion showed a sarcoma; the patient underwent rectosigmoidectomy. At gross inspection, the tumor measured 8 x 7 x 4 cm and was polypoid with ulcerations. Necrotic and hemorrhagic foci were scattered. Microscopically, the tumor consisted of 2 cell types: malignant tumor cells with epithelioid features and benign-appearing osteoclast-like giant cells. The tumor cells were polygonal and epithelioid in shape and had eosinophilic or clear cytoplasms, with scattered giant tumor cells. Immunohistochemical examination revealed that the tumor cells were positive for vimentin, muscle actin, alpha-smooth muscle actin, and desmin, whereas the osteoclast-like giant cells were positive for CD68, leukocyte common antigen, and lysozymes. We diagnosed this case as epithelioid leiomyosarcoma with osteoclast-like giant cells. To the best of our knowledge, this is the first case of rectal epithelioid leiomyosarcoma with osteoclast-like giant cells.

Aged↗

PubMed2000

Large macrophage colony-forming cells identical to high proliferative potential colony-forming cells in peripheral blood of patients with collagen vascular diseases: high occurrence among patients with systemic sclerosis and dermatomyositis.

OBJECTIVE: To examine peripheral blood (PB) of patients with various collagen vascular diseases (CVD) for the presence of colony-forming cells (CFC) that form large macrophage colonies (> 2.5 mm in diameter, > 10,000 cells). METHODS: Peripheral blood mononuclear cells were obtained from 92 patients with various active CVD and 20 healthy controls, and assayed for in vitro colony formation. There were 14 patients with systemic lupus erythematosus (SLE), 30 with rheumatoid arthritis (RA), 17 with systemic sclerosis (SSc), 20 with polymyositis (PM)/dermatomyositis (DM) (11 PM, 9 DM) and 11 with systemic vasculitis. RESULTS: Large macrophage CFC were detected in PB of 7% of patients with SLE (1/14), 17% with RA (5/30), 47% with SSc (8/17), 30% with PM/DM (6/20) [9% PM (1/11) and 56% DM (5/9)], 0% of those with systemic vasculitis (0/11) and 0% of the healthy subjects (0/20). There was a significant difference between the occurrence of CFC in patients with PM versus patients with DM (p < 0.05). The occurrence of CFC in patients with SSc or DM was significantly higher than that in patients with other CVD including SLE, RA, PM, and systemic vasculitis (p < 0.05). CONCLUSION: Based on the size of the colonies they formed, the CFC corresponded to high proliferative potential colony-forming cells, a subset of primitive hematopoietic cells. Our findings among patients with CVD indicate that these primitive hematopoietic progenitor cells, which are believed to constitute a noncirculating population in healthy individuals, are found most frequently in PB of patients with SSc and DM. It is likely that primitive hematopoietic cells are frequently mobilized into the peripheral circulation during the pathogenesis of SSc and DM.

Arthritis, Rheumatoid↗

PubMed2000

[A case of intrathoracic schwannoma derived from the left vagus nerve].

We report a case of schwannoma asymptomatic for 9 years, derived from the left vagus nerve in the middle mediastinum. This spindle-shaped tumor caused paralysis of the left recurrent nerve as an initial clinical manifestation with cough. T2-weighted magnetic resonance imaging (MRI) showed a neurogenic tumor with a characteristic target appearance and with constituents of different intensities: mucinous material in the peripheral zone and solitary tissue in the central zone. But, this different intensity is not directly reflected by the histopathologic features of Antoni types A and B. These findings suggest that MRI is useful for determining the parent nerve of a neurogenic tumor and is helpful for the diagnosis.

Adult↗

PubMed1999

The effect of leptin on feeding-regulating neurons in the rat hypothalamus.

Intense immunoreactivity for the leptin receptor was detected in the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMH), and lateral hypothalamus (LH) by immunohistochemistry. Cytosolic Ca2+ concentration ([Ca2+]i) in single neurons isolated from the ARC, VMH and LH was measured with dual wavelength fura-2 fluorescence imaging. A reduction of the superfusate glucose concentration from 10 to 1 mM increased [Ca2+]i in 21% of ARC neurons and 22% of LH neurons. Leptin at 0.1 nM inhibited the [Ca2+]i increase in 66 and 64% of these glucose-sensitive ARC and LH neurons, respectively. Inversely, 10 mM glucose increased [Ca2+]i in 49% of the VMH neurons, and 0.1 nM leptin at 1 mM glucose also increased [Ca2+]i in 84% of these glucose-responsive neurons. These results reveal that leptin inhibits the ARC and LH neurons and stimulates the VMH neurons via the leptin receptor expressed in these cells.

Animals↗

PubMed1999

Mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome: an autopsy case with a 24-year survival period.

We report an autopsy case of mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome. A 38-year-old Japanese male was found to have Zollinger-Ellison syndrome and pancreatic gastrinoma, and gastrectomy and resection of the pancreatic tumor were performed. However, hypergastrinemia persisted, and the patient died of disseminated carcinomatosis at 62 years of age, 24 years after the onset of Zollinger-Ellison syndrome. At autopsy, the main tumor was present in the residual pancreas, and metastases were noted in many organs. In the pancreas and other organs, ductal and endocrine carcinoma areas were mixed and there was a gradual transition between the two. No acinar differentiation was noted. The ductal elements were positive for mucins and carcinoembryonic antigen but negative for neuroendocrine markers, while endocrine elements were positive for chromogranin A and synaptophysin and to a lesser extent for gastrin, but negative for mucins and carcinoembryonic antigen. The ductal elements comprised about 30% of the tumor cells, and endocrine elements 70%. According to the revised World Health Organization classification, our case was diagnosed as mixed ductal-endocrine carcinoma. Our case is rare because the tumor manifested as gastrinoma with Zollinger-Ellison syndrome and the patient survived for 24 years. To the best of our knowledge, no such case has been reported. Our case suggests that pancreatic endocrine tumors may evolve into mixed ductal-endocrine carcinomas.

Adult↗