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Biomedical subjects

S Okabe

Publications and source records attributed to S Okabe.

At least 199 records · Page 11Linked to original sources
PubMed1996

Effects of leminoprazole, omeprazole and sucralfate on indomethacin-induced delayed healing of kissing gastric ulcers in rats.

We have examined whether or not repeated treatment with indomethacin delays the healing of kissing gastric ulcers induced in rats. The effects of leminoprazole, omeprazole and sucralfate on any delay in ulcer healing caused by indomethacin were also determined in relation to myeloperoxidase activity. Kissing gastric ulcers were induced by luminal application of an acetic acid solution. Indomethacin significantly delayed ulcer healing in a dose-dependent manner. Leminoprazole and omeprazole decreased the size and depth of ulcers, the healing of which was delayed by indomethacin, while sucralfate only decreased the ulcer depth. Histological studies showed that indomethacin inhibited tissue contraction and regeneration of the ulcerated mucosa. Leminoprazole and omeprazole prevented the inhibition of these parameters. The myeloperoxidase (MPO) activity of the ulcer portion in animals treated with indomethacin was markedly higher than in the control group. Both leminoprazole and omeprazole, but not sucralfate, significantly reduced MPO activity in contrast to the control value (in the presence of indomethacin). There was a significant relationship between the ulcerated area and myeloperoxidase activity. These results suggested that: (i) leminoprazole and omeprazole prevent the indomethacin-induced delay in ulcer healing by promoting tissue contraction and regeneration of the ulcerated mucosa; (ii) sucralfate prevents the indomethacin-induced delay in ulcer healing via the promotion of the formation of granulation tissue; and (iii) MPO activity will be useful to biochemically ensure the healing state of ulcers.

Animals↗
PubMed1996

Microtubule-associated proteins regulate microtubule function as the track for intracellular membrane organelle transports.

Axonal microtubules have two essential roles: providing the track for organelle transport and forming the cytoskeletal framework to maintain axonal morphology. Microtubule-associated proteins (MAPs) are essential for the formation of cytoskeletal architecture. However, they may have additional roles on the regulation of organelle transport by their interaction with motor proteins on the microtubules. We first examined the effects of axonal MAPs on the organelle movement along microtubules in a heterologous system using COS fibroblasts, which express no axonal MAPs, such as tau or MAP2C. Transfection of tau or MAP2C gene suppressed organelle movement almost completely in this cell type, hence interaction of axonal MAPs with microtubules interferes with organelle transports. It is known that the phosphorylation of MAPs reduces their interaction with microtubules. In this sense, phosphorylation of MAPs can be a good candidate for the molecular switch to regulate the organelle transport. As a second set of experiments, we investigated the effects of modulating cAMP dependent protein kinase pathway on organelle transports in primary sensory neurons, where high-molecular-weight tau protein is the major MAP. We found that the application of dibutyryl cAMP enhanced transports of large organelles in the axon. Furthermore, this drug treatment phosphorylated endogenous tau protein and thus reduced the affinity of tau to microtubules. These results indicate that axonal MAPs can work as a phosphorylation-dependent regulator of organelle transport. Local activation of protein kinase pathways in the axon might play an important role on the segregation of microtubules serving for either organelle transport or cytoskeletal architecture.

Animals↗
PubMed1996

Synthesis and cytoprotective antiulcer activity of 2- or 4-(1H-pyrazol-1-yl)pyrimidine derivatives related to mepirizole and dulcerozine.

(1H-Pyrazol-1-yl)-, (1H-imidazol-1-yl)-, and (1H-1,2,4-triazol-1-yl)pyrimidines were prepared and evaluated for cytoprotective antiulcer activity. Among them, 4-methoxy-6-methyl-2-(1H-pyrazol-1-yl)pyrimidine (18) showed potent inhibition of the HCl-ethanol-induced and water-immersion stress-induced ulcers in rats, as well as low acute toxicity.

Administration, Oral↗
PubMed1996

Inhibition of collagen-induced platelet aggregation in Japanese black cattle with inherited platelet disorder, Chediak-Higashi syndrome.

Aggregation properties of platelets were examined in Japanese Black cattle with Chediak-Higashi syndrome (CHS) and normal control cattle. Platelet aggregation induced by collagen was decreased in platelets of the cattle with CHS, but not ADP (10-20 microM), thrombin (0.5-1.0 U/ml) and phorbol-12-myristate 13-acetate (PMA, 3.2 microM). The aggregation response induced by collagen in CHS platelets lacks the change in shape which usually occurs in normal platelets. Simultaneous stimulation by collagen (10 micrograms/ml) + ADP (10 microM) is effective in restoring collagen-induced aggregating response in CHS platelet, although pretreatment of ADP (10 microM) could not restore the collagen (10 micrograms/ml)-induced aggregating response, suggesting that there is a certain threshold of stimulation intensity above which collagen-induced aggregation of CHS platelet can begin. Control normal platelets, previously exposed to ADP (10 microM) and collagen (10 micrograms/ml), showed no further response to exposure to a third aggregating agent (arachidonic acid, 5 mM). On the other hand, the final agent was able to elicit aggregating responses in CHS platelets, suggesting that the arachidonate aggregating system may be suppressed in CHS cattle, but fully activated in control animals. Furthermore, normal platelets showed a significant decrease in aggregating response to collagen when pretreated with a cyclooxygenase inhibitor, indomethacin (10(-5) M), whereas CHS platelet was insensitive to indomethacin. This indomethacin-treated normal platelet mimicked the CHS collagen-induced aggregation pattern. These data suggest that a signal transduction process from receptor-operated events to arachidonate metabolism is suppressed in collagen-induced CHS platelet aggregation.

Adenosine Diphosphate↗
PubMed1996

Effects of the novel histamine H2-receptor antagonist (+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3-[2-[[[5- (methylamino)methyl-2-furyl]methyl]thio]ethyl]-2-(methylsulfonyl) guanidine on gastric secretion and gastroduodenal ulcers in rats.

The effects of (+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3-[2- [[[5-(methylamino)methyl-2-furyl] methyl]thio]ethyl]-2-(methylsulfonyl)guanidine (CAS 140695-21-2, T-593), a new histamine H2-receptor antagonist, on gastric secretion and experimental gastric and duodenal lesion/ulcer models in rats were examined. The drug administered orally or intraduodenally significantly and dose-dependently inhibited both basal and histamine-stimulated acid secretion. Pepsin output was also inhibited by the drug nearly dose-dependently. The acid-inhibitory effect of T-593 persisted for 12 h after a single oral administration. T-593 potently protected the gastric mucosa against water-immersion stress-, indometacin- and HCl.acetylsalicylic acid-induced lesions, but it had no effect on HCl.ethanol-induced lesions. T-593 significantly prevented the development of mepirizole-induced duodenal ulcers. Spontaneous healing of kissing gastric ulcers was significantly enhanced when T-593 was administered for 14 days. The antisecretory and antilesion/antiulcer effects of T-593 were similar to those of ranitidine and omeprazole. It is concluded that T-593 is a potent antisecretory and antiulcer drug.

Animals↗
PubMed1996

[Hepatic intra-arterial 5-fluorouracil and CDDP administration in patients with colorectal cancer metastasis to the liver].

Eleven patients with hepatic metastasis from colorectal cancer were treated by combined chemotherapy with 5-FU and CDDP. Metastatic tumor was not resected or incompletely removed in all cases. 5-FU (180 mg/m2/day) as a 7-day continuous hepatic arterial infusion (HAI) with CDDP (10 approximately 20 mg/2 weeks) or intermittent high dose 5-FU HAI (1,000 mg/m2/5 h) with CDDP (10 approximately 20 mg/2 weeks) was administered, followed by a one-week rest. The overall response rate was 63.8%. There was a significant prolongation in overall survival compared with controls. Drug-related toxicity was observed in 10 cases (91.0%), but nothing serious. Survival can be prolonged with almost normal quality of the life in patients with colorectal liver metastasis.

Adult↗
PubMed1996

Effects of heat shock and teprenone on ethanol-induced damage to cultured rabbit gastric mucosal cells.

We examined whether or not heat shock and teprenone (a gastric mucosal protective drug), through the induction of heat shock proteins (HSPs), protect cultured rabbit gastric mucosal cells from ethanol-induced damage. Cell viability was assessed by mitochondrial function and membrane permeability assays. Exposure of mucosal cells to 5% ethanol for 1h caused an about 50% reduction in viability. When the cells had been heated at 43 degrees C for 1 h, the cell damage caused by ethanol was significantly prevented. However, pretreatment with teprenone at 1-100 microM failed to prevent the ethanol-induced damage. Western blot analysis with an anti-HSP-72 antibody showed that HSP-72 was apparently induced by heat treatment, but not by teprenone. Both the cytoprotection and induction of HSP-72 on heat treatment were potently inhibited by cycloheximide and actinomycin D. These results demonstrate that, in rabbit gastric mucosal cells, the induction of HSPs is strongly associated with cytoprotection against ethanol-induced damage, but that teprenone has no effect on the cytoprotection or HSP induction.

Animals↗
PubMed1996

The cytoprotective effect of leminoprazole on indomethacin-induced damage to rabbit gastric mucosal cells.

Leminoprazole (an acid pump inhibitor) has a mucosal protective effect against various experimental gastric lesions, but the underlying mechanism remains unknown. We examined whether leminoprazole prevents indomethacin-induced damage to cultured gastric mucosal cells. The viability of rabbit gastric mucosal cells was assessed by the 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide and dye exclusion methods. [35S]Methionine-labeled proteins were detected by autoradiography after sodium dodecylsulfate-polyacrylamide gel electrophoresis. Western blot analysis was carried out using anti-heat shock protein (HSP)-70 and anti-HSP-72 antibodies. Exposure of gastric mucosal cells to indomethacin for 4 hr apparently reduced their viability in a dose-related manner. Pretreatment with leminoprazole for 4 hr significantly prevented the reduction in cell viability caused by 50 microM indomethacin, although omeprazole was not effective. However, such pretreatment did not prevent the severe damage induced by 500 microM indomethacin. 16,16-Dimethyl prostaglandin E2 significantly prevented the cell damage induced by indomethacin at both 50 and 500 microM. Leminoprazole alone did not affect cell viability. The cytoprotection by leminoprazole was expressed after a 2-hr lag period. Leminoprazole did not promote prostaglandin E2 synthesis by cells, but it apparently induced the synthesis of 83-kDa, 72-kDa, 52-kDa and 35-kDa proteins. Both the cytoprotection and the induction of such protein synthesis were abolished by cycloheximide and actinomycin D. The leminoprazole-induced 72-kDa protein did not react with the antibodies against HSP-70 and HSP-72. These results indicate that leminoprazole directly protects gastric mucosal cells against mild damage caused by indomethacin and that its cytoprotective effect might be mediated through de novo synthesized proteins. In addition, it is suggested that the leminoprazole-induced proteins might be unknown proteins related to cytoprotection, although the exact characters of the proteins are unclear.

16,16-Dimethylprostaglandin E2↗
PubMed1996

[Intracranial fungal granuloma with CSF space dissemination: a case report].

A 28-year-old male presented with a low grade fever, decreased activity, left hemiparesis and signs of intracranial hypertension. CT showed a moderate hydrocephalus and a large irregular mass in the right temporoparietal region with garland-like enhancement after injection of the contract medium. These findings suggested a malignant brain tumor. MR images demonstrated a mass with low-iso signal intensity on T1 weighted image and low-iso-high mixed intensity on T2, which is like a mosaic pattern. Multiple cerebrospinal fluid space seedings including the wall of the lateral ventricle, the surface of the cerebellum and pons, and the cervical spinal cord were clearly delineated on MR images after Gd-DTPA injection. The large mass was totally removed by craniotomy after ventricle drainage for hydrocephalus. Microscopic examinations showed dense fibrous connective tissue with infiltration of Langhans' giant cells, lymphocytes and fibroblasts around the necrotic centers. These hard components may have been responsible for the low signal intensity on T2-MR images. Many Candida elements were clearly shown with the periodic acid Schiff stain. The diagnosis was that the lesion was an intraparenchymal granuloma due to Candida infection. The patient died on the 8th postoperative day because of brain stem malfunction. Intracranial fungal infection rarely produces a granuloma in the central nervous system. Though it is difficult to diagnose a large irregular mass in the brain, MR images, especially T2 weighted images are useful for the diagnosis of fungal granuloma.

Adult↗
PubMed1996

Effects of sucralfate and its components on indomethacin-induced damage to cultured rabbit gastric mucosal cells.

We examined the effects of sucralfate and its components on indomethacin-induced damage to cultured rabbit gastric mucosal cells. Cell viability was assessed by colorimetric and dye exclusion methods. Exposure of mucosal cells to indomethacin at 50 and 500 microM for 4 hr significantly reduced their viability, the viability loss being bout 40% and about 90% respectively. Pretreatment of the cells with sucralfate for 30 min prevented the reduction in viability caused by 50 microM indomethacin in a dose-related manner. Furthermore, sucralfate also significantly protected mucosal cells against severe damage caused by 500 microM indomethacin. However, neither sucrose octasulfate nor Al(OH)3. (the components of sucralfate) significantly prevented the reduction in viability caused by 50 and 500 microM indomethacin, although these components tended to inhibit the viability loss. When mucosal cells were incubated with sucralfate or its components for 4 hr, the drugs did not affect the cell viability. These results indicate that sucralfate directly protects gastric mucosal cells against cell damage caused by indomethacin, and that the protective effect of sucralfate might be expressed as a synergistic action of its components.

Aluminum Hydroxide↗
PubMed1996

[Relief of dyspnea after lung volume reduction in patients with pulmonary emphysema].

We studied dyspnea and pulmonary function during treadmill exercise in 10 patients with pulmonary emphysema before and at least 3 months after thoracoscopic volume reduction. Dyspnea was significantly less after surgery. Ventilatory function, gas exchange, respiratory muscle function, and exercise performance also improved significantly. The degree of volume reduction, estimated by the decrease in FRC as measured by body plethysmography correlated with the degree to which dyspnea was relieved. Volume reduction may be appropriate as a treatment for dyspnea in patients with pulmonary emphysema.

Dyspnea↗
PubMed1995

Tautomycin: an inhibitor of protein phosphatases 1 and 2A but not a tumor promoter on mouse skin and in rat glandular stomach.

Tautomycin isolated from Streptomyces spiroverticillatus is an inhibitor of protein phosphatases 1 and 2A. Tautomycin induced hyperphosphorylation of cytokeratin peptides in human keratinocytes (PHK 16-I cells) 30 times less strongly than did okadaic acid. Repeated applications of tautomycin (30 micrograms, 40 nmol/application) did not induce tumor promotion in a two-stage carcinogenesis experiment on mouse skin initiated with 7,12-dimethylbenz[a]anthracene, whereas okadaic acid (1 microgram, 1.2 nmol/application) as a control induced tumor promotion strongly. As for mucosa of rat glandular stomach, tautomycin induced ornithine decarboxylase 4 h after intubation into the stomach. The tumor-promoting activity of tautomycin was next studied in the glandular stomach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Administration of tautomycin in the diet (1 mg rat-1 day-1), from week 9 to week 52 of the experiment, inhibited rather than enhanced tumor development in the glandular stomach initiated with MNNG. The percentages of tumor-bearing rats of the groups treated with MNNG plus tautomycin, MNNG alone, and tautomycin alone were 20.0%, 40.6%, and 0% respectively in week 52. The reason for the absence of tumor-promoting activity of tautomycin was studied in relation to tumor necrosis factor alpha (TNF alpha), an endogenous tumor promoter. We found that tautomycin neither enhanced TNF alpha mRNA expression in mouse skin nor induced TNF alpha release in a human stomach cancer cell line (KATO III cells), whereas okadaic acid did both. These results indicate that not all inhibitors of protein phosphatases are tumor promoters, and suggest that tumor promotion of the okadaic acid class of compounds is mediated by TNF alpha.

Animals↗
PubMed1995

Effects of nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on duodenal alkaline secretory and ulcerogenic responses induced by mepirizole in rats.

The inhibition of nitric oxide (NO) production by NO synthase inhibitors stimulates HCO3- secretion in the rat duodenal mucosa. Therefore, we examined the effects of NG-nitro-L-arginine methyl ester (L-NAME, the NO synthase inhibitor) and nitroprusside (the exogenous NO donor) on the duodenal HCO3- and ulcerogenic responses in anesthetized rats. Animals were administered mepirizole (200 mg/kg, subcutaneously) for induction of duodenal ulcers, and gastric acid and duodenal HCO3- secretions were measured with or without pretreatment with L-NAME (5 mg/kg, intravenously) or nitroprusside (4 mg/kg, intravenously). Mepirizole increased acid secretion, decreased the acid-induced duodenal HCO3- secretion, and induced hemorrhagic lesions in the proximal duodenum. The inhibition of NO production by L-NAME potentiated the acid secretory response, increased the duodenal HCO3- secretion, and prevented the duodenal lesions, and these changes were all antagonized by simultaneous administration of L-arginine (200 mg/kg, intravenously) but not D-arginine. On the other hand, nitroprusside slightly reduced the acid response but further decreased the HCO3- output, resulting in aggravation of duodenal lesions induced by mepirizole. These data suggest that the inhibition of endogenous NO production by the NO synthase inhibitor L-NAME increases duodenal HCO3- secretion and protects the duodenal mucosa against acid injury.

Animals↗
PubMed1995

Mechanism of gastric alkaline response in the stomach after damage. Roles of nitric oxide and prostaglandins.

The gastric mucosa responds to hypertonic NaCl by significantly decreasing acid secretion. We examined the role of nitric oxide (NO) in this phenomenon in comparison with endogenous prostaglandins (PGs). A rat stomach was mounted in an ex vivo chamber, perfused with saline, and the potential difference (PD), pH, and acid/alkaline responses were measured before and after the application of hypertonic NaCl (1 mol/liter) with or without pretreatment with NG-nitro-L-arginine methyl ester (L-NAME; an inhibitor of NO biosynthesis) or indomethacin (a cyclooxygenase inhibitor). NaCl at 1 M caused a PD reduction, a decrease in acid secretion, and an increase in luminal HCO3-. Prior administration of L-NAME (5 mg/kg, intravenously) as well as indomethacin (5 mg/kg, subcutaneously) did not affect PD and HCO3- responses, but significantly attenuated the inhibitory effect of 1 M NaCl on acid secretion, although the effect of L-NAME was more potent when compared to indomethacin. This effect of L-NAME was antagonized by the simultaneous administration of L-arginine but not by D-arginine (200 mg/kg, intravenously), whereas the effect of indomethacin was completely reversed by PGE2 (100 micrograms/kg, intravenously). The histamine-stimulated acid secretion in the normal stomach was significantly decreased by nitroprusside (the exogenous NO donor; 4 mg/kg, intravenously) and PGE2, but not by either L-NAME or indomethacin. These results suggest that in addition to PGs, NO is involved in the mechanism of the gastric alkaline response after damage with 1 M NaCl. Irritation of the gastric mucosa by hypertonic NaCl may release endogenous NO and PGs, both of which in turn inhibit acid secretion and unmask luminal alkalinization due to HCO3- flux in the damaged portion.

Animals↗
PubMed1995

Irritant and protective action of urea-urease ammonia in rat gastric mucosa. Different effects of ammonia and ammonium ion.

The effects of urea-urease-ammonia on the rat gastric mucosa were examined and compared with those of NH4OH and NH4Cl. The mucosal application of urea with urease produced a reduction in potential difference (PD) in a dose-related manner for urea, and a significant drop was observed by > 0.1% urea in the presence of 100 units urease. Such PD reduction was also observed when the mucosa was exposed to either NH4OH (> 0.03%) or NH4Cl (> 1%); delta PD (20 mV) caused by 0.3% NH4OH and 3% NH4Cl was equivalent to that induced by 0.5% urea+urease (100 units). The combined oral administration of urea (approximately 6%) and urease (100 units) did not induce any macroscopic damage in the gastric mucosa. NH4Cl given orally had no or little effect on the mucosa at any dose levels even at 10%, while NH4OH given orally caused hemorrhagic lesions in the mucosa at the dose of > 0.3%. In contrast, both urea+urease and NH4Cl given prior to HCl/ethanol protected the gastric mucosa against damage in a dose-related manner, and a significant effect was obtained by urea at > 0.5% and by NH4Cl at > 1%. NH4OH was also effective in reducing the severity of HCl/ethanol-induced gastric lesions at lower dose (0.3%). The protective effect of urea+urease was attenuated significantly by prior administration of indomethacin or coadministration of hydroxyurea, while that of NH4Cl or NH4OH was mitigated by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗
PubMed1995

Pharmacological aspects of acid secretion.

The secretion of gastric acid is regulated both centrally and peripherally. The finding that H2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic stimulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, and histamine release is inhibited by somatostatin or by the H3-receptor ligand, R-alpha-methyl histamine. The parietal cell has a muscarinic, M3, receptor responsible for [Ca]i regulation. Blockade of muscarinic receptors by atropine can be as effective as H2-receptor blockade in controlling acid secretion. However, general effects on muscarinic receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+,K(+)-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an alpha,beta heterodimer, present in cytoplasmic membrane vesicles of the resting cell and in the canaliculus of the stimulated cell. It has been shown that acid secretion by the pump depends on provision of K+Cl- efflux pathway becoming associated with the pump. As secretion occurs only in the canaliculus, this K+Cl- pathway is activated only when the pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and extracytoplasmic domain. These result in changes in sidedness and affinity for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump inhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytoplasmic loops between the fifth and sixth transmembrane and the seventh and eighth transmembrane segments of the alpha subunit of the H+,K(+)-ATPase, forming disulfide derivatives. This inhibits ATP hydrolysis and H+ transport, resulting in effective, long-lasting regulation of acid secretion. Therefore, this class of acid pump inhibitor is significantly more effective and faster acting than the H2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segments of the alpha subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectively than receptor antagonists and provide shorter acting but complete inhibition of acid secretion.

Amino Acid Sequence↗