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S Okabe

Publications and source records attributed to S Okabe.

At least 145 records · Page 8Linked to original sources
PubMed1998

POU transcription factors control expression of CNS stem cell-specific genes.

Multipotential stem cells throughout the developing central nervous system have common properties. Among these is expression of the intermediate filament protein nestin and the brain fatty acid binding protein (B-FABP). To determine if common mechanisms control transcription in CNS stem cells, the regulatory elements of these two genes were mapped in transgenic mice. A 257 basepair enhancer of the rat nestin gene is sufficient for expression throughout the embryonic neuroepithelium. This enhancer contains two sites bound by the class III POU proteins Brn-1, Brn-2, Brn-4, and Tst-1. Only one of the two POU sites is required for CNS expression. An adjacent hormone response element is necessary for expression in the dorsal midbrain and forebrain. The regulatory sites of the B-FABP gene are strikingly similar to those of the nestin gene. A hybrid POU/Pbx binding site is recognized in vitro by Pbx-1, Brn-1 and Brn-2. This site is essential for expression in most of the CNS. In addition, a hormone response element is necessary for forebrain expression. Both the nestin and B-FABP genes therefore depend on POU binding sites for general CNS expression, with hormone response elements additionally required for activity in the anterior CNS. These data indicate that regulation by POU proteins and hormone receptors is a general mechanism for CNS stem cell-specific transcription.

Animals↗
PubMed1998

Twist form of teleocidin derivatives is active in in vivo tumor promotion by (-)-benzolactam-V8-310.

Teleocidin derivatives and the core structure, (-)-indolactam-V ((-)-IL-V), adopt two conformations in solution, the "twist" and the "sofa" forms. (-)-Benzolactam-V8-310 ((-)-BL-V8-310), which specifically adopts the twist form in solution, has been reported to have a significant effect on HL-60 cells and protein kinase C affinity. In this paper, we describe the biological activity with regard to tumor promotion on mouse skin and the wide variety of biological activity of (-)-BL-V8-310 and its derivatives. In both twist and sofa forms (-)-BL-V8-310 inhibited specific 3H-12-O-tetradecanoylphorbol-13-acetate (TPA) binding to a particulate fraction of mouse skin more strongly than (-)-IL-V. The doses for 50% inhibition (IC50) of (-)-IL-V, (-)-BL-V8-310, and teleocidin B-4 were 1000, 400 and 12 nM, respectively. As for the induction of tumor necrosis factor-alpha (TNF-alpha) release into the medium from HL-60 cells, the EC200 values, which are the concentrations of the compound required to achieve 200 pg/ml TNF-alpha in the medium, were 1700, 500 and 19 nM for (-)-IL-V, (-)-BL-V8-310 and teleocidin B-4, respectively. The same amounts (5.5 nmol per application) of (-)-BL-V8-310 and teleocidin B-4, induced tumors on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA) in 13.3% and 86.7% of tumor-bearing mice, respectively, in week 20. These results confirmed that the twist form of teleocidin derivatives is the active form as far as the induction of biological activity is concerned. Also (-)-BL-V8-310 is a new synthetic tumor promoter designed from data obtained using the receptor cavity model of TPA-type tumor promoters.

Animals↗
PubMed1998

[Rodent models of Helicobacter pylori infection and their utility].

Small animal models for Helicobacter pylori (H. pylori) infection have been widely examined and developed. Recently, the novel laboratory strain (the Sydney strain) of H. pylori, having a high ability to colonize the gastric mucosa of normal mice, was established. In the mice infected with the Sydney strain, chronic gastritis slowly develops, progressing to severe atrophy. The Sydney strain may become the standard one for experimental research. On the other hand, mice expressing Leb antigen were genetically produced. H. pylori well colonizes the gastric mucosa of the transgenic mice, but the gastric pathology remains unclear. However, formation of gastric ulcers has not been observed in mice. In contrast, H. pylori chronically infects Mongolian gerbils and causes severe gastritis and gastric ulcers. The H. pylori-induced gastric ulcers do not heal spontaneously, but are cured by drugs. To examine H. pylori colonization in the gastric mucosa and eradication of the bacteria, mouse models are satisfactory. However, in the case of studies on H. pylori-associated gastric pathology, the Mongolian gerbil model is better. Although these models have both merits and demerits, they are useful for elucidation of the pathogenesis of H. pylori-associated diseases and for development of drugs and therapies.

Animals↗
PubMed1998

Effects of transforming growth factor alpha and hepatocyte growth factor on acid-induced damage in rat gastric epithelial cells.

We examined the effects of transforming growth factor alpha (TGF-alpha) and hepatocyte growth factor (HGF) on acid-induced damage in a rat gastric epithelial cell line. Pretreatment of cells for 30 min with TGF-alpha, but not HGF, significantly prevented the acid-induced cell damage in a concentration-dependent manner. Genistein significantly reduced the protective effect of TGF-alpha. DNA synthesis in RGM1 cells was increased when the cells were incubated with TGF-alpha and HGF for 24 hr. We conclude that the protective effect of TGF-alpha against acid-induced damage seems to be caused by the activation of Na+/H+ exchangers and not by enhanced DNA synthesis.

Animals↗
PubMed1998

Influence of sustained hypoxia on the sensation of dyspnea.

We assessed the effect of sustained isocapnic hypoxia (PCO2 = 40 Torr, SaO2 = 80%) on the sensation of dyspnea in 16 normal healthy males. Subjects rated the sensation of dyspnea (c) on 15 cm visual analog scales during 20 min of sustained hypoxia. Following this hypoxic period, 8 subjects undertook mild exercise (10-50 W on a bicycle ergometer for 3 min) under the continuation of hypoxia. During sustained hypoxia, psi increased initially with ventilation from 0.6 +/- 0.2 (n = 16, mean +/- SE) to 2.9 +/- 0.6 at peak ventilation, but it decreased with ventilatory depression to 1.6 +/- 0.4. Dyspnea intensity during hypoxic exercise was significantly smaller than that at peak ventilation in the resting hypoxic period (2.3 +/- 0.7 vs. 3.9 +/- 1.0), although the ventilation was greater during exercise (24.0 +/- 3.0 vs. 19.7 +/- 1.4 l/min). These results indicate that sustained hypoxia has a biphasic, i.e., initial stimulatory and delayed depressant, effect on dyspnea and on ventilation. It is suggested that the dyspnea sensing mechanism is suppressed during mild exercise under sustained hypoxia.

Adult↗
PubMed1998

The tetramerization domain-independent Ras activation by BCR-ABL oncoprotein in hematopoietic cells.

BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias. We have previously shown that BCR-ABL activates Ras signaling pathways required for transformation. To elucidate the mechanisms whereby BCR-ABL induced transformation in hematopoietic cells, we examined the biological effects of expression of a series of BCR-ABL mutants. We found that the Grb2 binding site-deleted BCR-ABL and the SH2 domain-deleted BCR-ABL, as well as the tetramerization domain-deleted BCR-ABL do not diminish the transforming properties of BCR-ABL in hematopoietic cells, although these mutations were previously shown to drastically reduce the transforming activity of BCR-ABL in fibroblasts. The tetramerization domain-deleted BCR-ABL did not induce tyrosine phosphorylation of CrkL, SHP-2, Vav and the interactions of BCR-ABL and Shc. However, Ras is activated, Shc is tyrosine phosphorylated and binds to Grb2 in the tetramerization domain-deleted BCR-ABL expressing hematopoietic cells. These results suggest that the tetramerization domain-independent Ras activation is mediated by Shc proteins and induces the transformation of hematopoietic cells.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Relationship between vascular endothelial growth factor and angiogenesis in spontaneous and indomethacin-delayed healing of acetic acid-induced gastric ulcers in rats.

Angiogenesis is an important event for gastric ulcer healing. Vascular endothelial growth factor (VEGF) is known to be a potent stimulator of angiogenesis. This study consequently examined VEGF production, VEGF mRNA expression and angiogenesis during the spontaneous and indomethacin-delayed healing of acetic acid-induced ulcers in rats. The production of VEGF, taking place in the normal mucosa, was significantly elevated by ulceration. The mRNA expression of three isoforms of VEGF (VEGF188, VEGF164 and VEGF120) was also detected. Following the increase in VEGF production, angiogenesis was significantly promoted in the ulcer base. VEGF-immunoreactivity was observed in granulocytes, fibroblasts and regenerated epithelial cells. Indomethacin markedly inhibited prostaglandin E2 synthesis in the ulcer base, resulting in the prevention of ulcer healing. Angiogenesis was also significantly inhibited by indomethacin, but neither VEGF production nor VEGF mRNA expression was reduced. Such results suggest that VEGF might play a role in angiogenesis in the spontaneous healing of gastric ulcers in rats. However, the inhibition of angiogenesis in indomethacin-delayed ulcer healing is not explainable on VEGF expression.

Acetic Acid↗
PubMed1998

Pontine injections of nitric oxide synthase inhibitor l-name consolidate episodes of rem sleep in the rat.

Dorsal mesopontine cholinergic neurons control rapid eye movement sleep (REMS) and wakefulness and contain nitric oxide (NO) synthase. To assess whether local inhibition of NO synthase has distinct effects on sleep, N-nitro-L-arginine methyl ester, an NO synthesis inhibitor (L-NAME, 80 mM), carbachol, a cholinergic agonist (2, 10 or 50 mM), or saline were microinjected (120-200 nl) into the dorsal mesopontine tegmentum in rats. Sleep-wake cycles were monitored during the subsequent 6 h periods. Compared to control injections, L-NAME changed the pattern of REMS by prolonging individual episodes with a small increase in the percentage time of REMS and no change in slow wave sleep (SWS). Carbachol, at 50 mM, enhanced wakefulness and suppressed both SWS and REMS, especially during the first 2 h post-injection. At the two lower concentrations, carbachol moderately enhanced REMS 2-6 h post-injection by increasing the frequency, rather than duration, of individual episodes. Thus, a reduced NO release in the dorsal pontine tegmentum has a powerful consolidating effect on REMS episodes, whereas the direction of the effect of carbachol on the amount of sleep, and REMS in particular, depends on the magnitude of cholinergic stimulation. The REMS-consolidating effects of NO synthase inhibition in the pons may result from modulatory effects of NO on the release of acetylcholine and other neurotransmitters within the dorsal mesopontine tegmentum.

Analysis of Variance↗
PubMed1998

Roles of extracellular Ca++ and calmodulin in roxatidine-stimulated secretion and synthesis of mucus by cultured rabbit gastric mucosal cells.

We found that roxatidine stimulates mucus secretion and synthesis by cultured rabbit gastric mucosal cells. In this study, we examined the roles of the extracellular Ca++ and calmodulin in these effects of roxatidine. Reduction of the extracellular Ca++ concentration decreased the roxatidine-induced increases in mucus secretion and synthesis by gastric mucosal cells. Roxatidine concentration-dependently promoted Ca++ influx and caused an increases in intracellular Ca++. After the addition of roxatidine, the increases in the secretion and synthesis reflected those in Ca++ influx and intracellular Ca++ concentration and then disappeared as Ca++ influx and intracellular Ca++ concentration returned to the control level. The roxatidine-stimulated Ca++ influx and intracellular Ca++ mobilization were abolished by reduction of the extracellular Ca++ concentration. Nifedipine and diltiazem inhibited both the effects of roxatidine, but even at 10 microM, the inhibition was partial. Furthermore, W-7 (a calmodulin antagonist) completely abolished the effects of roxatidine on mucus secretion and synthesis without causing a reduction of the stimulated Ca++ influx. Taken together, these results suggest that roxatidine promotes Ca++ influx through both voltage-sensitive Ca++ channels and other Ca++ entry gates and the subsequent intracellular Ca++ mobilization, leading to potentiation of mucus secretion and synthesis by rabbit gastric mucosal cells. In addition, Ca(++)-activated calmodulin may play a pivotal role in these stimulatory effects of roxatidine.

Animals↗
PubMed1998

Mechanism by which indomethacin delays the healing of acetic acid-induced ulcers in rats. Role of neutrophil antichemotactic and chemotactic activities.

We have recently discovered a neutrophil antichemotactic factor in the normal gastric mucosa of rats. In this study, we examined whether this antichemotactic factor as well as chemotactic factors are involved in the indomethacin-induced delayed healing of experimental gastric ulcers. Ulcers were induced in male rats by a submucosal injection of 20% acetic acid into the gastric wall. Experimental rats received a subcutaneous injection of indomethacin at 2 mg/kg once daily for 28 days, starting at day 0 of ulceration (defined as 5 days after acetic acid injection). In the control group (without indomethacin) antichemotactic activity was not detected in the ulcerated tissues on day 0, but gradually increased for up to 28 days. This activity did not recover in the indomethacin-treated group by day 28. However, a high level of neutrophil chemotactic activity was observed in the extract of the ulcerated area in day 0. This activity gradually declined as the ulcers healed. In the control group, chemotactic activity was negligible after dialysis of the extract. In the indomethacin-treated group, however, chemotactic activity was maintained from the 10th day after treatment, even after the extract was dialyzed. Similar to chemotactic activity, myeloperoxidase activity was also augmented significantly in the indomethacin-treated group throughout the experiment. We conclude that the mechanism by which indomethacin delays ulcer healing is associated with reduced antichemotactic activity and increased chemotactic activity in the ulcerated tissues, resulting in the persistence of neutrophil infiltration.

Acetic Acid↗
PubMed1998

Effects of acid-degraded products of leminoprazole on acid secretion, mucus secretion and synthesis, and indomethacin-induced damage in cell culture.

We examined the effects of four acid-degraded products of leminoprazole on [1] acid secretion by parietal cells, [2] mucus secretion and synthesis by epithelial cells and [3] indomethacin-induced damage to epithelial cells. These gastric cells were prepared from rabbit stomachs. Upon stimulation with 10 microM histamine, acid secretion by parietal cells was inhibited by leminoprazole, sulfide and 2-(isobutylmethylamino)benzylalcohol. Sulfide also inhibited dibutyryl cyclicAMP (100 microM)-stimulated secretion. However, the inhibitory effects of such compounds were observed only at high concentrations, in comparison with the antisecretory concentrations of leminoprazole. On the other hand, among acid-degraded products, only sulfide enhanced mucus secretion and synthesis by epithelial cells. The stimulatory effects of sulfide were the same as those of leminoprazole. Furthermore, the effects of sulfide as well as leminoprazole were suppressed by NG-nitro-L-arginine methyl ester (L-NAME), and L-arginine, not D-arginine, prevented the inhibition by L-NAME. In contrast, all degraded products failed to protect epithelial cells against indomethacin-induced damage. Overall, these results suggest that only the mucus-elevating effect of administered leminoprazole may be partly due to the stimulatory effects of sulfide derived from leminoprazole on mucus secretion and synthesis by epithelial cells.

Acids↗
PubMed1998

[A surgical case of cervical canal stenosis caused by atlas hypoplasia in an elderly patient].

We report an 81-year-old man with hypoplastic atlas resulting in a severe stiff feeling in the bilateral shoulders, spastic tetraparesis, and hypesthesia below the C2 segment level of the spinal cord. These symptoms are compatible with compression of the high cervical cord. Neuroimaging studies revealed a narrowing of the spinal cord by compression of the hypoplastic atlas. Laminoplasty of the atlas was performed under general anesthesia, and the patient's symptoms were resolved. Operated cases of older patient's with atlas hypoplasia have been rarely reported. Laminoplasty of the atlas is a safe and useful procedure for high cervical compression due to hypoplastic atlas.

Aged↗
PubMed1998

[p53 expression and response to hepatic intraarterial infusion chemotherapy in patients with colorectal cancer metastasis to liver].

We have reported that hepatic artery infusion (HAI) chemotherapy with 5-fluorouracil for unresectable colorectal liver metastasis may lead to improved overall survival for some patients compared with controls. The aim of this work is to determine whether p53 nuclear protein expression examined by immunohistochemical technique could predict the outcome of patients treated with HAI chemotherapy. No significant difference was found in the response rate (p > .99, Fisher's exact method.) and median survival time (12 months in patients with p53-positive tumors and 11 months with negative tumors). Our results indicate that HAI chemotherapy is an effective treatment for liver metastasis regardless of p53 nuclear protein expression.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Role of cyclooxygenase-2 in the healing of gastric ulcers in rats.

To elucidate the role of cyclooxygenase (COX)-2 in ulcer healing, we compared the effects of NS-398 (COX-2-selective inhibitor) and indomethacin (nonselective COX inhibitor) on the healing of acetic acid-induced gastric ulcers in rats. Prostaglandin E2 (PGE2) production was elevated in ulcerated tissue, but remained unaffected in intact tissue. COX-2 mRNA was only detected in the ulcerated tissue, in which the COX-2 protein was found in fibroblasts, macrophages/monocytes and granulocytes. In contrast, COX-1 mRNA expression was not affected by ulceration. In an in vitro study, the increased PGE2 production was inhibited by NS-398; this had no effect on PGE2 production in the intact tissue. When NS-398 and indomethacin were administered to rats, 3 and 6 mg/kg NS-398 only reduced PGE2 production in the ulcerated tissue, but 10 mg/kg NS-398 and 0.5 to 2 mg/kg indomethacin inhibited the production in both the ulcerated and intact tissues. The healing of gastric ulcers was significantly impaired by 3 to 10 mg/kg NS-398 and 1 and 2 mg/kg indomethacin. The delay in ulcer healing was associated with the inhibition of PGE2 production in the ulcerated tissue. As observed upon histological analysis, regeneration of the mucosa, maturation of the ulcer base and angiogenesis in the base were significantly prevented by 6 mg/kg NS-398 and 2 mg/kg indomethacin, although the inhibitory effect of NS-398 was weaker than that of indomethacin. These results clearly indicate that COX-2 plays an important role in the healing of gastric ulcers in rats.

Animals↗
PubMed1997

In vitro-generated neural precursors participate in mammalian brain development.

During embryogenesis, pluripotent stem cells segregate into daughter lineages of progressively restricted developmental potential. In vitro, this process has been mimicked by the controlled differentiation of embryonic stem cells into neural precursors. To explore the developmental potential of these cell-culture-derived precursors in vivo, we have implanted them into the ventricles of embryonic rats. The transplanted cells formed intraventricular neuroepithelial structures and migrated in large numbers into the brain tissue. Embryonic-stem-cell-derived neurons, astrocytes, and oligodendrocytes incorporated into telencephalic, diencephalic, and mesencephalic regions and assumed phenotypes indistinguishable from neighboring host cells. These observations indicate that entirely in vitro-generated neural precursors are able to respond to environmental signals guiding cell migration and differentiation and have the potential to reconstitute neuronal and glial lineages in the central nervous system.

Animals↗
PubMed1997

Disruption of the Bcl6 gene results in an impaired germinal center formation.

The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells. To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6(-/-)RM). Lymphogenesis in primary lymphoid tissues of Bcl6(-/-)RM is normal, and Bcl6(-/-)RM produced control levels of primary IgG1 antibodies specific to T cell-dependent antigens. However, GCs were not found in these mice. This defect was mainly due to the abnormalities of B cells. Therefore, Bcl6 is essential for the differentiation of GC B cells.

Animals↗
PubMed1997

Expression of the tumor necrosis factor alpha gene and early response genes by nodularin, a liver tumor promoter, in primary cultured rat hepatocytes.

Nodularin is a new liver carcinogen possessing a potent tumor-promoting activity in rat liver, mediated through inhibition of protein phosphatases 1 and 2A, and a weak initiating activity. Since we previously reported evidence that nodularin up-regulated expression of the tumor necrosis factor alpha gene (TNF alpha) and early-response genes in rat liver after its i.p. administration, and since TNF alpha had tumor-promoting activity in vitro, it is possible that TNF alpha itself is involved in liver tumor promotion. We investigated whether hepatocytes themselves induce expression of the TNF alpha gene and early-response genes in primary cultured rat hepatocytes treated with nodularin. Like nodularin, microcystin-LR, which is another liver tumor promoter belonging to the okadaic acid class, strongly induced TNF alpha gene expression in rat hepatocytes, as well as TNF alpha release from those cells into the medium. On the other hand, 12-O-tetradecanoylphorbol-13-acetate, which has been reported to induce no tumor promotion in rat liver, induced no apparent expression of the TNF alpha gene in primary cultured rat hepatocytes. As for the expression of early-response genes, 1 microM nodularin or microcystin-LR induced expression of the c-jun, jun B, jun D, c-fos, fos B and fra-1 genes in the hepatocytes, and the expression of these genes was prolonged up to 24 h, suggesting mRNA stabilization induced by inhibition of protein phosphatases 1 and 2A. This paper presents new evidence that the TNF alpha gene and early-response genes were expressed in hepatocytes treated with a liver tumor promoter.

Animals↗