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Biomedical subjects

S Okabe

Publications and source records attributed to S Okabe.

At least 253 records · Page 14Linked to original sources
PubMed1994

Effect of anterior unilateral vagotomy on healing of kissing gastric ulcers induced in rats.

Unilateral vagotomy causes atrophy of the denervated fundic mucosa in rat stomachs. We examined whether or not unilateral vagotomy delays healing of gastric ulcers induced on the denervated mucosa. Kissing ulcers were induced in the fundus of rat stomachs by intraluminal application of an acetic acid solution. Anterior unilateral vagotomy was performed subdiaphragmatically at the time of ulceration. The healing of gastric ulcers induced on the denervated side was significantly enhanced, whereas that on the vagally intact side was not affected. In unilaterally denervated animals, the total gastric acid secretion (both basal and 2-deoxy-D-glucose stimulated) was inhibited, and the pH around the ulcers was increased only in the anterior side. Repeatedly administered histamine failed to affect the enhanced ulcer healing in unilaterally denervated animals. Gastric emptying and mucosal cell proliferation stimulated by food or pentagastrin were unaffected. Serum gastrin significantly increased 19 days after vagotomy. Gastric relaxation on refeeding was inhibited on the denervated side, but this inhibition of relaxation was reversed by hexamethonium treatment. A liquid diet significantly enhanced the healing of ulcers on both the denervated and vagally intact sides. The mechanism by which unilateral vagotomy accelerates the healing of ulcers on the denervated side appears to relate to the inhibition of both gastric acid secretion and gastric relaxation.

Animals↗
PubMed1994

Mechanisms underlying stimulation of gastroduodenal HCO3- secretion by NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, in rats.

We investigated the mechanism underlying stimulation of HCO3- secretion by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the gastroduodenal mucosa of anesthetized rats. A chambered stomach (in the presence of omeprazole) or a duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 by a pH-stat method. Intravenous administration of L-NAME increased gastroduodenal HCO3- secretion with a concomitant rise in arterial blood pressure and a decrease in heart rate, and the changes were all antagonized by simultaneous administration of L-arginine. Vagotomy had no effect on the increased blood pressure response, but significantly inhibited the decrease of heart rate and increase of HCO3- secretion caused by L-NAME. The HCO3- stimulatory action of L-NAME was also inhibited by prior administration of yohimbine or prazosin. These agents alone lowered blood pressure and reduced the magnitude of the blood pressure response caused by L-NAME, leading to inhibition of heart rate changes. When delta HCO3- output induced by L-NAME was plotted against delta blood pressure change (from basal values) under various conditions, a significant relationship was found between these two factors. These results suggest that L-NAME stimulates gastroduodenal HCO3- secretion in association with the inhibition of endogenous NO production, and this mechanism may be in part mediated by a neural reflex through the vagal efferent nerve, resulting from the pressor response to L-NAME.

Animals↗
PubMed1994

Acceleration of healing of gastric ulcers induced in rats by liquid diet: importance of tissue contraction.

We examined the effect of a liquid diet or a combined diet of liquid plus cellulose on the healing of gastric ulcers induced in rats in comparison with that of solid chow. Ulcers were induced in the fundus of the stomach by luminal application of an acetic acid solution. The healing of ulcers could be divided into two phases based on the healing rate: early phase (days 1 to 10) and late phase (days 10 to 20). The liquid diet, but not the combined one, administered for 10 days significantly accelerated ulcer healing in both the early and late phases. The length of the ruptured muscularis mucosa decreased only in the liquid diet group in both phases. Regeneration of the ulcerated mucosa in the chow diet group was observed only in the late phase, it being markedly inhibited in the liquid diet group. The serum gastrin level significantly decreased in the liquid and combined diet groups in contrast to that in the chow group. The liquid and combined diets significantly reduced gastric mucosal DNA synthesis. We conclude that 1) the healing in this gastric ulcer model comprises two phases, and 2) tissue contraction is a major factor for the healing of gastric ulcers in the early phase, while both tissue contraction and regeneration of the ulcerated mucosa are involved in the healing in the late phase.

Acetates↗
PubMed1994

Upper airway muscle activity during REM and non-REM sleep of patients with obstructive apnea.

We measured electromyograms (EMGs) of genioglossus muscle (GG) and inspiratory intercostal muscle (IIM) in both rapid eye movement (REM) sleep and non-REM sleep of 12 patients with obstructive sleep apnea (OSA) to examine the influence of different sleep stages on upper airway muscle activity during sleep apnea. Quantifications of both muscle activities were assessed by their individual peak amplitude of integrated inspiratory EMG. Genioglossus and IIM activities showed a qualitatively similar cyclic change with an alteration of apneic and ventilatory phases during both non-REM and REM sleep. Both muscle activities increased gradually in the late apneic phase and reached each peak at the opening of the upper airway and, subsequently, decreased gradually. There were no significant differences in both muscles activities in either the ventilatory or early apneic phase between non-REM sleep and REM sleep. On the other hand, GG and IIM activities in the late apneic phase during REM sleep were significantly lower than those during non-REM sleep. The relative activity of GG to IIM in the late apneic phase was significantly lower during REM sleep than that during non-REM sleep. These results indicate that upper airway and intercostal muscle activation in the later apneic phase during REM sleep were inhibited compared with those during non-REM sleep and that this inhibition was observed predominantly in upper airway muscles.

Adult↗
PubMed1994

[Mass screening for prostate cancer at a local town--five-year results and screening system].

The results of a mass screening examination for prostate cancer conducted from 1989 to 1993 at a local town, Kawagoe-cho, in Mie Prefecture were evaluated. Among the 216 examinees, 4 were found to have prostate cancer. The most accurate examination was the prostate specific antigen (PSA), which was followed by digital examination and transrectal ultrasound. The applicants for the prostate cancer screening accounted for only 8% of the Kawagoe-cho male residents over 40 years old. An educational campaign of prostate disease in the area must be started to increase the number of applicants. We concluded that the most effective modality for the screening program was a combination of PSA and digital examination in the field study, and transrectal ultrasound accompanied by systemic biopsy results in the second tool for screening.

Adult↗
PubMed1994

DNA alterations in cells from hereditary non-polyposis colorectal cancer patients.

To determine if the MCC, DCC or p53 gene is associated with susceptibility to hereditary non-polyposis colorectal cancer (HNPCC), these genes in normal cells from 12 HNPCC patients were analysed by polymerase chain reaction-single strand conformation polymorphism analysis. No changes which may alter the amino acid sequences of these genes were detected, suggesting that these genes are not associated with the susceptibility to HNPCC. Only one of nine HNPCC cancers showed mutations in the MCC and p53 genes on the same analysis. Loss of heterozygosity in chromosomes 5q, 17p, 18q and 22 was detected in four of the nine cancers, all of them being positive as to metastasis to lymph nodes. Abnormalities of the (CA)n repeat were found in six cancers, including all four without metastasis. These data indicate that tumor suppressor genes in chromosomes 5q, 17p, 18q and 22 are associated with the late stage of colorectal tumorigenesis in HNPCC, whereas the (CA)n repeat abnormalities are an early event of tumorigenesis and more essential to HNPCC.

Adult↗
PubMed1994

A new tumor promotion pathway and its inhibitors.

Tumor promotion is a critical point in multistage carcinogenesis in humans. We have identified a common biochemical and molecular tumor promotion mechanism, the okadaic acid pathway, applicable in various organs. Tumor promotion by the okadaic acid class of compounds is mediated through inhibition of protein phosphatases 1 and 2A, resulting in an increase of protein phosphorylation and a subsequent expression of cell proliferation genes. Recently, we demonstrated that okadaic acid induced the release of mouse tumor necrosis factor-alpha (mTNF-alpha) from BALB/3T3 cells. The first part of this review discusses the link between the okadaic acid pathway and TNF-alpha as endogenous tumor promoters in vivo. Inhibitors of tumor promotion are varied. For the purpose of cancer chemoprevention in humans, the inhibitors sarcophytol A, canventol, and (-)-epigallocatechin gallate (EGCG) were studied and the results are presented. The inhibitory mechanisms also were varied: sarcophytol A inhibited H2O2 formation by TPA-activated human polymorphonuclear leukocytes; canventol inhibited protein isoprenylation in the cells; and EGCG, which is a main constituent of Japanese green tea, is an antioxidant. These inhibitors are promising cancer chemopreventive agents. Study of the essential tumor promotion mechanisms will facilitate the development of cancer chemopreventive agents.

Anticarcinogenic Agents↗
PubMed1993

Interaction of the tail domain of high molecular weight subunits of neurofilaments with the COOH-terminal region of tubulin and its regulation by tau protein kinase II.

We previously showed that neurofilaments interact with microtubules (MTs) via their high molecular weight subunits (NF-H) after alkaline phosphatase treatment. Here we studied the effects of phosphorylation of NF-H on this interaction. tau protein kinase II, Ser/Thr protein kinase, phosphorylated NF-H in the tail domain, decreased its electrophoretic mobility to a native level, and also restored its property to be less interactive with MTs. Phosphorylation by cAMP-dependent protein kinase caused no shift of electrophoretic mobility or dissociation from MTs. We conclude that the tail domain of NF-H directly interacts with the MT surface, and the interaction is regulated via phosphorylation of the tail domain of NF-H by Ser/Thr protein kinase like tau protein kinase II. To characterize the binding domain of NF-H on MTs, subtilisin digestion of MTs and competition analysis with the MT binding fragment of tau protein were performed. The dissociation constant of NF-H to subtilisin MTs was higher than that to intact MTs. The maximum binding of NF-H was reduced when tau fragments existed. These results revealed that the COOH-terminal region of tubulin is involved in the binding to NF-H, and the NF-H and microtubule-associated protein binding domains are closely apposed on the surface of MTs.

Animals↗
PubMed1993

Canventol inhibits tumor promotion in CD-1 mouse skin through inhibition of tumor necrosis factor alpha release and of protein isoprenylation.

A synthetic compound named canventol, 2-isopropyl-4-isopropylidencyclohex-2-ene-1-ol, inhibited tumor promotion of okadaic acid on mouse skin initiated with 7,12-dimethylbenz(a)anthracene in two-stage carcinogenesis experiments more strongly than sarcophytol A, isolated from a soft coral, although canventol has a simpler structure than sarcophytol A. Their mechanisms of action were studied based on our recent evidence that tumor necrosis factor alpha release induced by okadaic acid is an essential mechanism of tumor promotion. Canventol inhibited mouse tumor necrosis factor alpha release from BALB/3T3 cells less strongly than sarcophytol A, indicating that canventol has additional activity. Canventol inhibited isoprenylation of proteins with various molecular weights, such as M(r) 22,000, 17,000, and 13,000, whereas sarcophytol A did not show significant inhibition. Thus, a potent anticarcinogenic activity of canventol is mediated through the inhibitory bifunctions of tumor necrosis factor alpha release and of protein isoprenylation. Since canventol is less toxic to cells than sarcophytol A, these bifunctions are useful markers for screening for new cancer chemopreventive agents.

3T3 Cells↗
PubMed1993

Tumor necrosis factor acts as a tumor promoter in BALB/3T3 cell transformation.

Tumor necrosis factor (TNF), a cytokine, and okadaic acid, a tumor promoter, strongly phosphorylated the same proteins, vimentin and heat shock protein 27, although their time courses were different. Human TNF-alpha at a concentration of 0.6 nM markedly stimulated transformation of BALB/3T3 cells initiated with 3-methylcholanthrene. The human TNF-alpha was about 1000 times more effective than the chemical tumor promoters, okadaic acid and 12-O-tetradecanoylphorbol-13-acetate. TNF induced growth of v-Ha-ras transfected BALB/3T3 cells (Bhas 42 cells), whereas it did not induce growth of nontransfected BALB/3T3 cells. Okadiac acid induced mouse TNF-alpha from Bhas 42 and BALB/3T3 cells. The results suggest that a chemical tumor promoter induces the secretion of TNF-alpha from various cells. The TNF then acts as an endogenous tumor promoter in vivo.

3T3 Cells↗
PubMed1993

Absence of synergistic effects on tumor promotion in CD-1 mouse skin by simultaneous applications of two different types of tumor promoters, okadaic acid and teleocidin.

Okadaic acid, a specific inhibitor of protein phosphatases 1 and 2A, and teleocidin, an activator of protein kinase C, are both potent tumor promoters on mouse skin. The effects of simultaneous treatment of the two different types of tumor promoters on tumor promotion as well as on their biochemical activities were studied. Three independent experiments with different doses of tumor promoters revealed that simultaneous repeated applications of okadaic acid and teleocidin did not induce any synergistic or additive effects on tumor promotion in mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA). In Experiment 1, the group treated with a single application of DMBA, followed by repeated applications of 1.0 micrograms (1.2 nmol) okadaic acid and 2.5 micrograms (5.7 nmol) teleocidin, resulted in 64.3% tumor-bearing mice at week 20. But the groups treated with DMBA plus okadaic acid or DMBA plus teleocidin gave 73.3% and 71.4%, respectively. The biochemical activities were studied by means of induction of ornithine decarboxylase in mouse skin and protein phosphorylation in the cells. Simultaneous application of okadaic acid at three different doses with teleocidin did not induce ornithine decarboxylase activity synergistically or additively. Phosphorylation of proteins, cytokeratins, or heat shock protein 27 was not synergistically increased in human keratinocytes treated with okadaic acid and teleocidin, although the cotreatment in a cell-free system synergistically increased protein phosphorylation. Thus, the absence of synergistic effects on tumor promotion in mouse skin was also confirmed in two systems, induction of ornithine decarboxylase in mouse skin and protein phosphorylation in human keratinocytes. The effect of cotreatment of okadaic acid and teleocidin is discussed at the molecular level.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Effects of nitric oxide synthase inhibitors on duodenal alkaline secretion in anesthetized rats.

We examined the effects of NG-nitro-L-arginine methyl ester (L-NAME), the nitric oxide (NO) synthase inhibitor, on duodenal HCO3- secretion in anesthetized rats. L-NAME (1-5 mg/kg i.v.), given as a single injection, increased HCO3- secretion in a dose-dependent manner. This effect of L-NAME was mimicked by NG-monomethyl-L-arginine (50 mg/kg i.v.) and was significantly antagonized by the simultaneous administration of L-arginine (200 mg/kg i.v.) but not D-arginine. The increased HCO3- response to L-NAME was also significantly reduced in vagotomized animals. These findings suggest that the inhibition of NO biosynthesis leads to an increase of duodenal HCO3- secretion, partly mediated by the vagus nerves.

Amino Acid Oxidoreductases↗
PubMed1993

Mechanism by which histamine increases gastric mucosal blood flow in the rat. Role of luminal H+.

The mechanism by which histamine increases gastric mucosal blood flow (GMBF) was investigated in the anesthetized rat. The experiment was performed in the presence of tripelennamine, an H1 antagonist, to focus on the relationship between acid secretion (H2-receptor-mediated response) and GMBF. The stomach was mounted on a Lucite chamber, perfused with saline, and GMBF was measured by laser Doppler flowmetry simultaneously with acid secretion. Under these conditions, histamine at the submaximal dose significantly increased GMBF as well as acid secretion, and this increase of GMBF was completely blocked when acid secretion was inhibited by cimetidine or omeprazole. The elevation of GMBF caused by histamine was also significantly attenuated when luminal H+ was removed by intraluminal perfusion with NaHCO3 or glycine. Glycine by itself did not affect the increase of acid secretion induced by histamine and the increase of GMBF caused by isoproterenol, yet significantly inhibited the GMBF response induced by pentagastrin. Intraluminal perfusion with HCl also produced an increase of GMBF in a concentration-related manner, even in the presence of omeprazole during histamine infusion. Pretreatment of the animals with indomethacin significantly blocked the GMBF responses induced by either histamine or luminal HCl. These results suggest that the increase of GMBF during acid secretion induced by histamine may be caused by luminal H+ and involve endogenous prostaglandins in its mechanism.

Animals↗
PubMed1993

Reorganization of brain spectrin (fodrin) during differentiation of PC12 cells.

Fodrin has been shown to redistribute dynamically between cytoplasmic and plasma membrane-associated compartments upon the differentiation of T lymphocytes. We studied the changes of distribution of fodrin in PC12 cells upon neuronal differentiation induced by nerve growth factor. To visualize preferentially the elements that were tightly associated with cytoskeletal structures, we performed immunofluorescence and immunoelectron microscopy on saponin-extracted cells. In undifferentiated PC12 cells, fodrin was distributed mostly underneath the plasma membrane. However, after the administration of nerve growth factor, perinuclear spot-like aggregates of fodrin appeared. Double-labeling immunofluorescence revealed that the cytoplasmic fodrin spot was co-localized with the intermediate filament proteins, peripherin and neurofilament. Immunogold electron microscopy showed that fodrin and neurofilament were localized in close association in the perinuclear regions enriched with intermediate filaments. With prolonged exposure to nerve growth factor, fodrin and intermediate filaments spread to the cytoplasm and neurites. These results suggest that there is a dynamic reorganization of fodrin during differentiation of PC12 cells, and that fodrin is first recruited in the perinuclear region closely associated with intermediate filaments. This dynamic reorganization of fodrin may represent important, previously unrecognized aspects of the morphological differentiation of neurons.

Animals↗
PubMed1993

Dynamics of microtubules bundled by microtubule associated protein 2C (MAP2C).

MAP2C is a microtubule-associated protein abundant in immature nerve cells. We isolated a cDNA clone encoding whole mouse MAP2C of 467 amino acid residues. In fibroblasts transiently transfected with cDNA of MAP2C, interphase microtubule networks were reorganized into microtubule bundles. To reveal the dynamic properties of microtubule bundles, we analyzed the incorporation sites of exogenously introduced tubulin by microinjection of biotin-labeled tubulin and the turnover rate of microtubule bundles by photoactivation of caged fluorescein-labeled tubulin. The injected biotin-labeled tubulin was rapidly incorporated into distal ends of preexisting microtubule bundles, suggesting a concentration of the available ends of microtubules at this region. Although homogenous staining of microtubule bundles with antibiotin antibody was observed 2 h after injection, the photoactivation study indicated that turnover of microtubule bundles was extremely suppressed and < 10% of tubulin molecules would be exchanged within 1 h. Multiple photoactivation experiments provided evidence that neither catastrophic disassembly at the distal ends of bundles nor concerted disassembly due to treadmilling at the proximal ends could explain the observed rapid incorporation of exogenously introduced tubulin molecules. We conclude that microtubules bundled by MAP2C molecules are very stable while the abrupt increase of free tubulin molecules by microinjection results in rapid assembly from the distal ends within the bundles as well as free nucleation of small microtubules which are progressively associated laterally with preexisting microtubule bundles. This is the first detailed study of the function of MAPs on the dynamics of microtubules in vivo.

Animals↗
PubMed1993

Do photobleached fluorescent microtubules move?: re-evaluation of fluorescence laser photobleaching both in vitro and in growing Xenopus axon.

We previously documented differences in the behavior of microtubules in growing axons of two types of neurons, adult mouse sensory neurons and Xenopus embryonal spinal cord neurons. Namely, the bulk of microtubules was stationary in mouse sensory neurons both by the method of photoactivation of caged-fluorescein-labeled tubulin and photobleaching of fluorescein-labeled tubulin, but the bulk of microtubules did translocate anterogradely by the method of photoactivation. Although these results indicated that the stationary nature of photobleached microtubules in mouse neurons is not an artifact derived from the high levels of energy required for the procedure, it has not yet been settled whether the photobleaching method can detect the movement of microtubules properly. Here we report photobleaching experiments on growing axons of Xenopus embryonal neurons. Anterograde movement of photobleached microtubules was observed at a frequency and translocation rate similar to the values determined by the method of photoactivation. Our results suggest that, under appropriate conditions, the photobleaching method is able to reveal the behavior of microtubules as accurately as the photoactivation method.

Animals↗
PubMed1993

Dynamics of the neuronal intermediate filaments.

We have analyzed the dynamics of neuronal intermediate filaments in living neurons by using the method of photobleaching of fluorescently-labeled neurofilament L protein and immunoelectron microscopy of incorporation sites of biotinylated neurofilament L protein. Low-light-level imaging and photobleaching of growing axons of mouse sensory neurons did not affect the rate of either axonal growth or the addition of intermediate filament structures at the axon terminal, suggesting that any perturbations caused by these optical methods would be minimal. After laser photobleaching, recovery of fluorescence did occur slowly with a recovery half-time of 40 min. Furthermore, we observed a more rapid fluorescence recovery in growing axons than in quiescent ones, indicating a growth-dependent regulation of the turnover rate. Incorporation sites of biotin-labeled neurofilament L protein were localized as numerous discrete sites along the axon, and they slowly elongated to become continuous arrays 24 h after injection. Collectively, these results indicate that neuronal intermediate filaments in growing axons turn over within the small area of the axoplasm possibly by the mechanism of lateral and segmental incorporation of new subunits.

Animals↗