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Biomedical subjects

T Tobe

Publications and source records attributed to T Tobe.

At least 163 records · Page 9Linked to original sources
PubMed1992

Protective effect of nafamostat mesilate on cellular and lysosomal fragility of acinar cells in rat cerulein pancreatitis.

This in vivo and in vitro study demonstrates the protective effects of a new synthetic protease inhibitor--nafamostat mesilate, FUT-175--on increased cellular and lysosomal fragility within acinar cells during the early stage of cerulein-induced acute pancreatitis in rats. FUT-175 prevented hyperamylasemia, pancreatic edema, congestion owing to amylase, and lactic dehydrogenase (LDH) discharge from acini as well as cathepsin-B leakage from lysosomes dose-dependently in doses of 1-10 mg/kg.h. These results suggest that FUT-175 can protect against pancreatitis at subcellular levels in lysosomes and cellular or organelle membranes. Proteases may well play the important role in the pathogenesis of acute pancreatitis, and such a low molecular protease inhibitor may be useful clinically in the treatment of acute pancreatitis.

Amylases↗
PubMed1992

Toxic effects of oxygen-derived free radicals on rat pancreatic acini; an in vitro study.

Isolated pancreatic acini were incubated with either a combination of xanthine and xanthine oxidase which generates superoxide (O2), or hydrogen peroxide (H2O2), and the direct cytotoxic effect of active oxygen species on the pancreatic acini was examined in vitro in the isolated pancreatic acini system of the rat. Both amylase secretion and lactic dehydrogenase discharge were increased dose-dependently by the addition of xanthine and xanthine oxidase, and suppressed by the addition of a superoxide scavenger, superoxide dismutase. In addition, amylase and lectate dehydrogenase discharge was increased dose-dependently by hydrogen peroxide and decreased by catalase. These results suggest that superoxide and hydrogen peroxide directly injure pancreatic acinar cells and that active oxygen species are involved in the pathogenesis of acute pancreatitis.

Amylases↗
PubMed1992

[The cellular and lysosomal fragility of pancreatic acinar cells after ligation of pancreatico-biliary duct in the rat and the protective effects of nafamostat mesilate].

To explore the changes of exorine pancreas in the early stage after ligation of pancreatico-biliary duct (PBD) in rat, we evaluated the changes of serum amylase levels, pancreatic water content as well as the changes of subcellular distribution of cathepsin B in the acinar cells. We also evaluated the lactic dehydrogenase (LDH) discharge from dispersed acini as an index of cellular fragility and cathepsin B leakage from lysosomes as an index lysosomal fragility in vitro study as well as the protective effects of a new synthetic protease inhibitor, nafamostat mesilate (FUT 175) in this model. After ligation of PBD, the serum amylase levels and pancreatic water content, increased significantly compared with those of the control group, but returning to the normal levels at 18 hours. The redistribution of cathepsin B in acinar cells was found and both the cellular and lysosomal fragility increased significantly compared with those of the control groups, shown their peak changes at 12 hours after ligation of PBD. But continuous intravenous administration of FUT 175 (2mg/mg.hr) remarkably attenuated all the parameters. These results indicate the important roles of lysosomal enzyme and lysosomal fragility in the pathogenesis of acute pancreatic injuries in this modes, and the clinical usefulness of FUT 175 in the treatment acute pancreatitis.

Acute Disease↗
PubMed1992

Effect of synthetic protease inhibitors on superoxide (O2-), hydrogen peroxide (H2O2) and hydroxyl radical production by human polymorphonuclear leukocytes.

The effects of clinically used protease inhibitors (aprotinin, nafamostat mesilate, gabexate mesilate) on the production of oxygen-derived free radicals (O2-, H2O2, .OH) by human polymorphonuclear leukocytes were examined. Nafamostat mesilate and gabexate mesilate markedly and dose-dependently inhibited zymosan-stimulated O2- production by human polymorphonuclear leukocytes. However, aprotinin had a slight scavenging effect on O2- produced by the xanthine-xanthine oxidase system. All the protease inhibitors inhibited H2O2 production, but had no significant scavenging effect on H2O2. Nafamostat mesilate and gabexate mesilate slightly inhibited .OH production. These results indicate that the synthetic protease inhibitors nafamostat mesilate and gabexate mesilate inhibit the production of various activated oxygen radicals by human polymorphonuclear leukocytes, and the differences in their inhibitory effects suggest that each synthetic protease inhibitor is specific for a particular oxygen-derived free radical.

Adult↗
PubMed1992

Effect of intraarterial active oxygen species on the rat pancreas.

To explore the role of active oxygen species in the development and progression of acute pancreatitis, we studied the direct toxic effect on the rat pancreas of active oxygen species: superoxide anions generated by xanthine/xanthine oxidase (X/XO), and hydrogen peroxide (H2O2). After a continuous injection of X (10(-3)M, 0.9 ml/hour)/XO (1 U/ml, 0.3 ml/hour) into the celiac artery supplying the pancreas, hemorrhages and extensive edema developed in the pancreas. The amylase and lipase concentrations in the peritoneal fluid rose to 10.3 and 13.8 times the control values, respectively. The subsequent infusion of superoxide dismutase (SOD, 3600 U/hour) into the external jugular vein completely suppressed hemorrhages, and reduced edema and the amylase and lipase concentrations in the peritoneal fluid. After continuous injection of H2O2 (100 microM, 1.2 ml/hour), via the celiac artery, marked hemorrhages and edema appeared in the pancreas, and the amylase and lipase concentrations in the peritoneal fluid were 11.1 and 17.3 times higher than the control values, respectively. These abnormalities were significantly suppressed by the intravenous infusion of catalase (10 mg/kg/hour) or gabexate mesilate (10 mg/kg/hour). These results indicate that active oxygen species have a direct toxic effect on the pancreas and that free radicals may play an important role in the development of acute pancreatitis.

Amylases↗
PubMed1992

[Interdigestive and postprandial pancreatic exocrine secretion and cholecystokinin release in dogs].

Interdigestive and postprandial pancreatic exocrine secretion and cholecystokinin (CCK) release were investigated in 5 mongrel dogs with chronic gastric and pancreatic fistulas in this study. The rapidly exaggerated postprandial pancreatic exocrine secretions were shown to be directly correlated to the rapid CCK release after meal. Corresponding to the previous studies, in the interdigestive state, pancreatic exocrine secretion showed cyclic changes which would be abolished by intravenous administration of atropine sulfate. However, we failed to demonstrate any significant correlation between plasma CCK levels and periodic pancreatic exocrine secretions during the interdigestive state through CCK radioimmunoassay. Furthermore, intravenous administration of atropine sulfate did not change the plasma CCK levels significantly in the interdigestive state. Having reviewed the literature, we thought that the periodic pancreatic exocrine secretion during the interdigestive state might be related to motilin release and cholinergic enteropancreatic reflex.

Animals↗
PubMed1992

Experimental hybrid islet transplantation: application of polyvinyl alcohol membrane for entrapment of islets.

In this study, we first examined in vitro a polyvinyl alcohol membrane to be used to contain hybrid islet cells, and second we tested a bioartificial pancreas with entrapment of pancreatic islets in polyvinyl alcohol membrane in rats with experimentally induced diabetes. The permeability of the polyvinyl alcohol membrane to different substances was studied in a two-cell chamber system. Glucose, insulin, and nutrients passed through the membrane easily, whereas the passage of immunoglobulin G was completely prevented, indicating that this membrane could be effective in protecting the bioartificial pancreas from immunorejection. Approximately 2,000 islets collected from three Sprague-Dawley rats were enclosed in a mesh-reinforced polyvinyl alcohol tube and transplanted into the peritoneal cavity of six Wistar rats with streptozotocin-induced diabetes. Their nonfasting serum glucose levels were significantly decreased for at least 12 days. Six diabetic rats receiving intraperitoneal transplantation of free islets without the tube showed a slight but significant decrease in nonfasting serum glucose levels for only 3 days. One diabetic rat with transplantation of the bioartificial pancreas had a significant and sustained decrease in nonfasting glucose levels from pretransplanted levels of 440-500 mg/dl to a mean value of 162 +/- 13 mg/dl for over 3 months without immunosuppression. The bioartificial pancreas was then removed, and glucose levels gradually increased to over 500 mg/dl. The results of the present study suggest that a bioartificial pancreas with entrapment of islets in a polyvinyl alcohol membrane could be a promising therapeutic approach to diabetes mellitus.

Animals↗
PubMed1992

[Immunohistochemical and ultrastructural study on the islet of autotransplanted pancreas in dogs].

This study was conducted to clarify the quantitative and qualitative changes of the islet cells of Langerhans in the autotransplanted pancreas. The left lobe of the canine pancreas was autotransplanted to the left iliac fossa with pancreatic duct left open to the peritoneal cavity. Fibrosis of transplanted pancreas progressed after transplantation. B-cell ratio was decreased significantly (p less than 0.01) whereas A-cell ratio and D-cell ratio showed no significant changes. Ultrastructural study revealed the increase of collagen/bundle, degranulation of B-cells and well preservation of A-cell granules at 3 weeks after operation. B-cells with dark cytoplasm were found at 7 weeks after operation which indicate the dysfunction of B-cells. In contrast, clusters of immature B-cells appeared on some sections obtained from the pancreas 14 weeks after autotransplantation. On the other hand, K-values were decreased significantly 7 weeks after operation (p less than 0.05). sigma BS (integrated response value of serum glucose level during IVGTT) was increased significantly (p less than 0.01) in addition to the decrease of K-values (p less than 0.01) at 11 weeks after operation. It proved that any indices at 14 weeks after operation showed no significant changes from the control group. It might be possible to speculate that relatively well preservation of glucose tolerance at 14 weeks after operation is associated with some clusters of immature B-cells observed ultrastructurally.

Animals↗
PubMed1992

Tax protein of human T-cell leukemia virus type I is required for maintenance of the transformed phenotype.

We have isolated and characterized revertants of a clonal cell line (40MRatcl-1) of human T-cell leukemia virus type I Tax-transformed Rat1 cells. The 40MRatcl-1 cells contain a single copy of tax gene, form large colonies in soft agar, elicit tumors rapidly in nude mice and revert to the normal phenotype at low frequency. From one of its subclones (B7) bearing pSV2gpt DNA as a marker gene, four morphologically reverse-transformed cell lines were isolated. They display contact inhibition at confluency, lose the ability to form colonies in soft agar, fail to form tumors in nude mice and restore the transformed phenotype similar to that of 40MRatcl-1 cells by transfection with the tax-expression plasmid. Southern blot analysis revealed that they have lost the tax gene. Our results indicate that transformation of Rat1 cells by Tax is not the consequence of secondary mutations of cellular genes and that tax functions are directly required for establishment and maintenance of the transformed phenotype.

Animals↗
PubMed1992

[Morphometric study on islet of Langerhans in relation to glucose tolerance in chronic obstructive pancreatitis due to pancreatoduodenal cancer].

Twenty one specimens of the pancreas in the patients who underwent pancreatoduodenectomy or total pancreatectomy for pancreatoduodenal cancer were divided into 4 groups according to the extent of fibrosis (Grade 0-Grade III). Islet cells of serial sections were stained immunohistochemically with calculation of the proportion of B-cells, A-cells, D-cells and PP-cells in the islets of Langerhans. In the pancreatic tissue with the most severe fibrosis (Grade III), B-cell ratio was significantly decreased (p less than 0.01), whereas A-cell ratio was significantly increased (p less than 0.01). Based on the data of oral glucose tolerance test (OGTT) and insulin response test, some indices were calculated (delta IRI/delta BS, sigma IRI/sigma BS, sigma delta IRI/sigma delta BS). In Grade III, sigma delta IRI/sigma delta BS was significantly decreased. A significant positive correlation was observed between B-cell ratio and both delta IRI/delta BS or sigma delta IRI/sigma delta BS, whereas a significant negative correlation was seen between A-cell ratio and sigma delta IRI/sigma delta BS. The present study first demonstrates the significant correlation between the endocrine secretory function of the islets and quantitative changes of the endocrine cells of islets in chronic obstructive pancreatitis due to pancreatoduodenal cancer. The present data strongly suggest that it is possible to estimate the degree of fibrosis and quantitative changes of the islet cells in the patients with pancreatoduodenal cancer by means of calculating the above mentioned indices, especially sigma delta IRI/sigma delta BS.

Blood Glucose↗
PubMed1992

[Measurement of small bowel transit time in dogs with acetaminophen and indocyanine green].

We developed an experimental method to measure the gastric and the small bowel transit times in dogs without using X-ray nor radioisotopes. The dog with the ileostomy was given food containing acetaminophen (APAP) and indocyanine green (ICG), then we sampled blood and ileal contents of the dog. We could measure the gastric transit time by detecting plasma APAP and the small bowel transit time by detecting ICG in the intestinal contents. Using this experimental system, we examined the times after feeding milk or solid meal. The gastric transit time after taking solid meal was longer than that after taking milk, but this difference was not significant, and the small bowel transit time after taking solid meal was significantly shorter than that after taking milk.

Acetaminophen↗
PubMed1992

Hepatectomy accelerates the growth of transplanted liver tumor in mice.

To study the effect of hepatectomy on the growth of liver tumor, Shionogi Carcinoma 42, a mammary tumor, was transplanted into the liver of mice which had undergone 40% hepatectomy. The liver tumor and the number of pulmonary metastases in hepatectomized mice were significantly larger than those in nonhepatectomized mice. Responses to lectins and IL-2, subpopulations, and cytotoxicity to YAC-1 and P815 cells of splenocytes were assessed to evaluate immunological status. At the initial phase after hepatectomy and tumor transplantation into the remaining liver, NK activity transiently increased, and function of B and T cells, especially of helper T cells, decreased, while B-cell function recovered beyond normal levels in a later phase. These results suggest that liver may play an important immunological role and that the immunological modification after hepatectomy may be responsible for the accelerated growth of liver tumor. Accordingly, some adjuvant immunotherapy may be recommended for the prevention of recurrence after hepatectomy for liver tumor.

Alanine Transaminase↗
PubMed1992

Gastrin release from antral G cells stimulated with secretin.

Recently, gastrinoma cells were demonstrated to release gastrin when directly stimulated by secretin both in vivo and in vitro. In this study, the reaction of antral G cells was investigated. Secretin was injected into the right gastroepiploic artery in canines, and into the common hepatic artery during a selective arteriography in patients without gastrinomas. G cells obtained from the antrum of rats were attached to 0.45-microns filters and irrigated with medium containing secretin. The serum gastrin concentration increased rapidly in significant amounts and very quickly after an intraarterial injection of secretin, both in humans and in dogs. The rate of gastrin release from the rat antral G cells in vitro increased significantly when the medium contained secretin. In conclusion, secretin stimulated gastrin release from antral G cells both in vivo and in vitro.

Analysis of Variance↗
PubMed1991

Pancreatic lysosomal enzyme secretion via gut-hormone-regulated pathway in rats.

To explore the secretory profiles of lysosomal enzyme in pancreatic juice, we stimulated the secretion of lysosomal enzyme by intravenous pancreatic secretagogues and intraduodenal instillation of liquid meals in rats. Lysosomal hydrolases, such as cathepsin B, are secreted from the apices of pancreatic acinar cells via a hormone-regulated pathway, as in the secretion of pancreatic digestive enzymes. The intravenous infusion of the cholecystokinin analogue caerulein, or the intraduodenal administration of nutrients results in a closely related secretion of both amylase and cathepsin B from the apices of acinar cells, suggesting that they are discharged from the same presecretory compartment (zymogen granules). Lysosomal enzymes appear to enter into the secretory compartment as a result of malsorting, but the cause of this anomaly is not known. We found small amounts of lysosomal enzymes colocalized with digestive enzymes within zymogen granules in normal acinar cells and in normal pancreatic juice, suggesting some physiological roles of lysosomal enzymes in pancreatic ducts. Furthermore, lysosomal enzymes appear to play important roles in the pathogenesis of pancreatic disease, such as pancreatitis, from both inside and outside the pancreas, since cathepsin B can probably activate trypsinogen.

Amylases↗