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Biomedical subjects

T Toyota

Publications and source records attributed to T Toyota.

At least 19 recordsLinked to original sources
PubMed1999

Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats.

We have recently reported that steady-state gastric mucosal blood flow (GMBF) is decreased in streptozotocin (STZ) diabetic rats, and that their GMBF response to burn-stress is impaired, probably via a nitric oxide (NO)-mediated mechanism. Accordingly, this study was designed to investigate the relation of aldose reductase (AR) and NO synthase to the regulation of GMBF during chronic hyperglycemia. STZ rats were treated with or without chronic oral administration of an AR inhibitor, epalrestat (EPA) and/or an NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). GMBF was measured by laser-Doppler velocimetry (LDV). In the STZ rats, GMBF after a 24-h fasting period was decreased significantly 4 weeks after the onset of diabetes and this was accompanied by an increase in the gastric ulcer index (UI) (a measure of the length of gastric erosions and ulcers). Chronic oral administration of EPA to the STZ rats dose-dependently inhibited the increased UI and the decreased GMBF after the fasting stress, whereas chronic oral administration of L-NAME further increased the UI and further decreased the GMBF. EPA administered in combination with L-NAME to the STZ rats reduced the effects of L-NAME, but the effects did not reach significance. These results suggest that EPA protects the gastric mucosa of diabetic rats, by preventing the decrease in GMBF that is, at least in part, caused by NO-related mechanisms.

Aldehyde Reductase↗
PubMed1999

Specific induction of adhesion molecules in human vascular endothelial cells by rat experimental pancreatitis-associated ascitic fluids.

The molecular mechanisms that link acute pancreatitis (AP) and multiple organ failure remain unknown. To clarify the role of endothelial activation, we examined the effects of ascitic fluids from rats with experimental pancreatitis on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs). Necrotizing hemorrhagic pancreatitis was induced with sodium taurocholate. Six and 24 h later, peritoneal exudates were collected, centrifuged and HUVECs were treated with the supernatants. The expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was quantified by enzyme-linked immunosorbent assay. Induction of mRNA was assessed by reverse-transcriptase polymerase chain reaction. The activation of transcription factors was examined by electrophoretic mobility shift assay. The expression of ICAM-1 in the tissues was examined immunohistochemically. ICAM-1 and VCAM-1, but not E-selectin expression was upregulated with comparable mRNA induction. Nuclear factor kappaB was activated, while activator protein-1 binding activity was not altered. Immunohistochemically, enhanced ICAM-1 expression was observed in the pancreas and lung, but not in the liver. Ascitic fluids may contain soluble factors responsible for the transcriptional activation of endothelial adhesion molecules, and ICAM-1 may play roles in the pathogenesis of complicated AP.

Animals↗
PubMed1999

Co-expression of Bcl-2 protein and vascular endothelial growth factor in hepatocellular carcinomas treated by chemoembolization.

AIMS/BACKGROUND: Transcatheter arterial chemoembolization (TAE) of hepatocellular carcinoma (HCC) causes anoxia. Escape of cancer cells from anoxic injury may be enhanced by induction of proteins which provide resistance to apoptosis. METHODS: We examined HCCs immunohistochemically for Bcl-2, vascular endothelial growth factor (VEGF), p53, and Ki67. The staining intensity for VEGF, a protein induced by anoxia, was assessed morphometrically with a computer-assisted image-analyzer. RESULTS: The frequency of Bcl-2 positive cells was higher in HCCs that had undergone TAE (TAE HCC) than that in HCCs that had not undergone TAE (41.75+/-15.06 vs. 1.01+/-0.79 cells/1000 cells, p = 0.0173). The frequency of p53- or Ki67-positive cells was not increased after TAE. Of 12 TAE HCCs, 7 had Bcl-2 positive HCC cells and 6 had clusters of Bcl-2 positive cells. In contrast, 2 of 11 HCCs that had not undergone TAE had only a few, sporadically distributed, Bcl-2-positive cells. The staining intensity for VEGF was higher in Bcl-2 positive than in Bcl-2 negative areas (1.208+/-0.091 vs. 1.071+/-0.017, p = 0.0222). Furthermore, the VEGF staining intensity in Bcl-2 positive areas of TAE HCCs was higher than in Bcl-2 negative areas (1.296+/-0.126 vs. 1.066+/-0.024, p = 0.0186), while in HCCs that had not undergone TAE the staining intensity was similar. CONCLUSIONS: TAE of HCC can induce Bcl-2 expression, possibly through anoxic stress.

Carcinoma, Hepatocellular↗
PubMed1999

Inhibition of nuclear factor-kappaB activation improves the survival of rats with taurocholate pancreatitis.

BACKGROUND: Death in the early stages of severe acute pancreatitis is frequently the result of multiple organ dysfunction, but its mechanism is not clear. AIMS: To investigate the state of nuclear factor-kappaB (NF-kappaB) in macrophages of rats with lethal pancreatitis, and to assess the effectiveness of pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB, on the pathology and mortality. METHODS: Taurocholate pancreatitis was produced in rats, and the severity of the disease, the mortality, and activation of NF-kappaB in peritoneal and alveolar macrophages were compared in rats receiving pyrrolidine dithiocarbamate (PDTC) treatment and those that were not. RESULTS: Taurocholate pancreatitis produced massive necrosis, haemorrhage, and severe leucocyte infiltration in the pancreas as well as alveolar septal thickening in the lung. NF-kappaB was activated in peritoneal and alveolar macrophages six hours after pancreatitis induction. Pretreatment with PDTC dose-dependently attenuated the NF-kappaB activation and improved the survival of the rats, although it did not affect the early increase in serum amylase and histological findings. CONCLUSIONS: Early blockage of NF-kappaB activation may be effective in reducing fatal outcome in severe acute pancreatitis.

Acute Disease↗
PubMed1999

11Beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor in human fetal development.

11Beta-Hydroxysteroid dehydrogenase type II (11betaHSD2) confers specificity on the mineralocorticoid receptor (MR) by converting biologically active glucocorticoids to inactive 11-keto metabolites. The biological significance of 11betaHSD2 activity during fetal development is currently being explored, but the temporal and spatial distributions of the enzyme and receptor have not been examined. We therefore examined their distributions during various stages of human fetal development using immunohistochemistry. Both 11betaHSD2 and MR immunoreactivity were detected in the distal convoluted and collecting tubules of the kidney from early in gestation. Fetal skin, intermediate layer of the epidermis, peridermal cells, and hair follicles were positive for both 11betaHSD2 and MR. Weak 11betaHSD2 and MR immunoreactivity was detected in the superficial ciliated epithelium of the esophagus, the deep layer of gastric epithelial cells, and the superficial epithelium of the small intestine. Columnar epithelium in the terminal bronchiolar budding component of fetal lung and tracheal and bronchial ciliated epithelium were also positive for MR and 11betaHSD2 from early gestation. Colonic epithelium and pancreatic exocrine duct cells, which demonstrated marked immunoreactivity of both MR and 11betaHSD2 in the adult, did not express MR and 11betaHSD2 until very late in gestation. These results imply that mineralocorticoid action in the upper fetal gastrointestinal tract, kidney, skin, and lung is facilitated by 11betaHSD2 and is involved in water and electrolyte transport between fetus and amniotic fluid as well as fetal urine production.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

[Current concept of the pathogenesis of autoimmune type 1 diabetes mellitus].

In type 1 diabetes, the beta cell is selectively destroyed by T lymphocytes in a genetically susceptible individual. Susceptible HLA-class II molecules which have low binding affinity with putative beta cell antigens may fail in induction of self-tolerance. beta cell-reactive T cells may expand and infiltrate around the islet (benign insulitis) by stimulation with environmental factors through molecular mimicry and/or beta cell antigens per se. Benign insulitis may develop to destructive insulitis under overexpression of Th1 cytokines, which may be affected by non-MHC genes. Immune interventions to shift a cytokine balance to Th2 dominance in the insulitis lesion may be most realistic approach to suppress development of type 1 diabetes after the induction of autoimmunity.

Animals↗
PubMed1999

[Sulfonylurea drug--a new sulfonylurea drug for type 2 diabetes].

The incidence of diabetes mellitus has been increased year by year and now 5-6 millions are diabetic patients in Japan. Studies of DCCT and UKPDS concluded that tight control of diabetes was benefit for prevention of diabetic complications in type 1 and type 2 diabetes, respectively. New type of sulfonylurea (glimepiride) has been developed by Hoechst Marion Roussel company which continues clinical trials in Japan. Grimepiride is an insulin sparing sulfonylurea drug for the treatment of type 2 diabetes patients whose high blood glucose cannot be controlled by diet and exercise alone. In Europe and United State glimepiride has been used as a monotherapy or in combination with insulin. Glucose control was effectively observed in type 2 diabetics including obese and hypertensive patients by the drug. Mechanism of sulfonylurea which stimulates insulin release is supposed by binding to a regulatory subunit of plasma membrane ATP-sensitive K+ (KATP) channel. The consequent closure of KATP channel leads to depolarization, opening of voltage-dependent Ca2+ channels, Ca2+ influx, and a rise in intracellular [Ca2+], resulting in insulin secretion. However, it has been suggested that sulfonylurea may have an additional action on secretion, independent of changes in intracellular [Ca2+] but dependent on the activity of protein kinase C (PKC). It is controversial whether or not sulfonylurea is a risky drug to the process of diabetic macroangiopathy, by suppressing KATP channels in the heart.

Diabetes Mellitus, Type 2↗
PubMed1999

[Inflammatory bowel disease and pregnancy: clinical study of mutual influence, clinical course and treatment].

We studied the clinical courses of 70 pregnancies in 47 women with ulcerative colitis (UC) and 18 pregnancies in 12 women with Crohn's disease (CD) retrospectively. We concluded as follows. 1. Pregnancy has less influence on the course of UC. 2. The patients with UC who kept remission for more than 1 year before conception have less risk of relapse and severity during pregnancy. 3. The patients with active UC at the time of conception tend to worsen during pregnancy. The patients whose onset of UC is during pregnancy tend to worsen. 4. UC has a little influence on the course of pregnancy except severe active disease. 5. It is not obtained that pregnancy becomes a relapsing factor of CD. 6. CD during pregnancy has little influences on the course of pregnancy, if it is remitted. 7. Salazosulfapyridine and corticosteroids therapy has less influence on the fetus and the course of pregnancy.

Adrenal Cortex Hormones↗
PubMed1998

Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients.

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD+ and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P </= 0.05). Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies (P </= 0.04-0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 (P </= 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera (P </= 0.05). These results strongly suggest that the presence of anti-CD38 autoantibodies in NIDDM patients can be one of the major causes of impaired glucose-induced insulin secretion in NIDDM.

ADP-ribosyl Cyclase↗
PubMed1998

Studies of 13C-urea breath test for diagnosis of Helicobacter pylori infection in Japan.

In recent years Helicobacter pylori infection has been implicated in the etiology of a variety of upper gastrointestinal diseases. The aim of this multi-center trial was to search for the cut-off value of the simple 13C-urea breath test (13C-UBT) for diagnosis of H. pylori infection, and to examine the sensitivity and specificity of 13C-UBT for culture, the rapid urease test (CLO test), histology, and serological tests. Two hundred and forty-eight patients participated in this study after giving their informed consent. Endoscopic biopsy specimens were taken from gastric antrum and corpus for culture (190 patients), CLO test (222 patients), and histology (98 patients). A serological test was carried out for all patients. H. pylori infection was established when culture was positive or more than two of the tests, histology, CLO test, and serological test, were positive, and non-infection status was established when the all tests more than two tests were negative. After baseline breath samples were taken, the patients (who had fasted) were given 100mg of 13C-urea in 100ml water while sitting; they washed out the mouth with water. They were then placed in the left lateral decubitus position for 5 min, and additional breath samples were taken 10, 20, 30, 45, and 60 min after urea administration, with patients in the sitting position. One hundred and sixty-five of the 248 patients were infected, 48 were not infected, and H. pylori infection status was not evaluated in 35 by endoscopic and serological tests. Breath samples at 20 min were employed to determine the cut-off value. Using the receiver operating characteristic (ROC) curve, we determined the cut-off value for a positive UBT at 2.5 delta per thousand. The sensitivities of UBT for culture, CLO test, histology, and serological test were 98.4%, 98.6%, 100.0%, and 92.5%, and the specificities were 78.8%, 82.5%, 83.3%, and 87.3%, respectively. The cut-off value of 13C-UBT for the diagnosis of H. pylori infection was 2.5 delta per thousand; this test is a simple and noninvasive method for the diagnosis of this infection and has high sensitivity and specificity.

Adult↗
PubMed1998

The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation.

The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q10 (CoQ10) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ10-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ10 for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ10-DM group was significantly higher than that in the control-DM group. CoQ10 therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ10 treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ10 treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ10 on MIDD.

Adult↗
PubMed1998

Inhibitory effect of troglitazone on diabetic neuropathy in streptozotocin-induced diabetic rats.

Free-radical scavengers and inhibitors of tumour necrosis factor-alpha (TNF-alpha) such as N-acetylcysteine and pentoxifylline have been shown to inhibit the development of peripheral neuropathy in streptozotocin(STZ)-induced diabetic rats. In this study we examined the effect of troglitazone, an anti-diabetic thiazolidinedione, on diabetic neuropathy, since it also is a free-radical scavenger and a TNF-alpha inhibitor. Rats were fed powder chow mixed with troglitazone at 0.5% and 0.125% ad libitum. Although blood glucose concentrations were remarkably higher and body weight lower in diabetic than in nondiabetic rats, troglitazone had no effect on these throughout the 24-week experiment. Serum lipoperoxide concentrations, tibial nerve lipoperoxide content and serum TNF-alpha activity induced by lipopolysaccharide was increased in diabetic rats, but inhibited in troglitazone-treated rats. Motor nerve conduction velocity (MNCV) of the tibial nerve slowed in diabetic rats, compared with that in nondiabetic rats. On the other hand, the slowed MNCV was (p < 0.05-0.01) inhibited after weeks 12 and 16 of the experiment in diabetic rats treated with high and low doses of troglitazone, respectively. Morphometric analysis showed that troglitazone suppressed the decrease of the myelinated fibre area (p < 0.05), axon/myelin ratio (p < 0.01) and fascicular area (p < 0.05) and suppressed the increase of myelinated fibre density (p < 0.001) in diabetic rats. These results indicate that troglitazone has a beneficial effect on peripheral neuropathy in STZ-induced diabetic rats irrespective of blood glucose concentrations.

Animals↗
PubMed1998

Telomere shortening in the colonic mucosa of patients with ulcerative colitis.

Telomere length in human somatic cells gradually decreases with the number of cell divisions and is regarded as a marker of somatic cell turnover. Mucosal cells of the affected colon show rapid turnover in individuals with active ulcerative colitis (UC). Telomere length was determined by Southern blot analysis of terminal restriction fragments (TRFs) from the colonic mucosa of 17 patients with UC in remission, two of whom showed dysplasia, and 17 control subjects without colitis. For each individual, mean TRF length was compared between rectal mucosa and unaffected cecal mucosa. The mean TRF length of the rectal mucosa was significantly less than that of cecal mucosa in UC patients (7.87 +/- 0.36kb versus 8.77 +/- 0.21 kb; P = 0.0015, Wilcoxon signed rank test), whereas no significant difference was detected in the control subjects. The extent of telomere shortening was 10.6 +/- 3.35% in UC patients, compared with 0.8 +/- 0.64% in noncolitis controls (P = 0.0024, Mann-Whitney U-test). Four UC patients, two of whom had dysplasia, showed telomere shortening of more than 20% in the rectal mucosa. These observations suggest that telomere shortening in the colonic mucosa of individuals with UC may represent the history of mucosal inflammation during disease of long duration, and that it may contribute to aneuploidy in UC.

Adolescent↗
PubMed1998

Profiles of cytokines produced by CD4-positive T lymphocytes stimulated by anti-CD3 antibody in patients with chronic hepatitis C.

Helper T cells (Th) are classified as type 1 (Th1) and type 2 (Th2) according to the cytokines they produce; interferon-gamma is produced by Th1, and interleukin-4 by Th2. We counted the circulating CD4-positive Th cells that produce interferon-gamma or interleukin-4 with an enzyme-linked immunospot assay. CD4-positive T cells isolated from patients with chronic hepatitis B (n = 10), chronic hepatitis C (n = 16), and healthy subjects (n = 10) were stimulated with anti-CD3 antibody in vitro. The number of interferon-gamma-producing Th cells was significantly lower in patients with chronic hepatitis C than in healthy subjects (P = 0.0024), whereas in patients with chronic hepatitis B, the number was similar to that in healthy subjects (P = 0.8530). The number of interleukin-4-producing Th cells was significantly higher in patients with chronic hepatitis C (P = 0.0010) and chronic hepatitis B (P = 0.0089) than in healthy subjects. In chronic hepatitis C, the number of interferon-gamma-producing Th cells was increased after incubation of the cells with interferon-alpha (P = 0.008) or with recombinant interferon-gammala (P = 0.024), but not with interferon-beta (P = 0.051). The number of interleukin-4-producing Th cells was decreased after incubation with interferon-alpha (P = 0.0004), with interferon-beta (P = 0.003), and with recombinant interferon-gammala (P = 0.0004). Changes in the numbers of interferon-gamma- or interleukin-4-producing Th cells in vitro were more evident in sustained responders to interferon therapy than in non-responders. These results suggest that Th2 cells are the predominant cell type in chronic hepatitis C, and that their activity may be suppressed by the administration of interferon.

Adult↗
PubMed1998

Duodenal gastrinoma--clinical features and usefulness of selective arterial secretin injection test.

Duodenal gastrinoma is recognized as a relatively common cause of Zollinger-Ellison syndrome, but its clinical and biological features are not well known. Here we report a case of duodenal gastrinoma with lymph node metastasis which was confirmed by pathology examinations. Hypergastrinemia and gastric acid hypersecretion were documented, but the secretin test showed negative results. An enlarged peripancreatic lymph node lying close to the pancreas head was the only positive finding on preoperative imaging studies. The results of the selective arterial secretin injection (SASI) test suggested that the primary tumor was located in the gastrinoma triangle. Finally, surgical exploration was carried out and a submucosal tumor, approximately 15 mm in size, was detected by intraoperative palpation at the posterior wall of the proximal portion of the duodenum. Intraoperative pathology examination demonstrated metastases to regional lymph nodes. The present case calls attention to the unique features of duodenal gastrinomas, which differ from those of pancreatic origin: a highly malignant potential for its small size, and submucosal location in the proximal duodenum. The SASI test is recommended for assessing the location of a primary lesion if it cannot be identified by various conventional imaging studies.

Diagnosis, Differential↗
PubMed1998

Endogenous glucocorticoids decrease the acinar cell sensitivity to apoptosis during cerulein pancreatitis in rats.

BACKGROUND & AIMS: We recently showed that activation of the hypothalamus-pituitary-adrenal axis may mitigate the progress of acute pancreatitis. To clarify the mechanism, the role of endogenous glucocorticoids in pancreatic acinar cell death was examined. METHODS: The occurrence of apoptosis was studied in adrenalectomized or sham-operated rats with or without cerulein-induced pancreatitis. The effects of RU38486, a glucocorticoid-receptor antagonist, on the survival of cultured acinar cells (AR42J) were also examined. RESULTS: Adrenalectomy caused increases in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) of acinar nuclei depending on the time after adrenalectomy but not of other cell types in the pancreas and in other digestive organs. Electron microscopy showed the characteristic features of apoptosis in the TUNEL-labeled acinar cells. In cerulein pancreatitis of adrenalectomized rats, the TUNEL-labeled acinar nuclei increased remarkably depending on the time after cerulein infusion. Replacement of glucocorticoids blocked the occurrence of apoptosis in these experiments. RU38486 induced dose dependently the apoptosis of AR42J cells. CONCLUSIONS: These results provide evidence that endogenous glucocorticoids are an important factor for acinar cell survival. Endogenous glucocorticoids may protect acinar cells by decreasing their sensitivity to the induction of cell death during acute pancreatitis.

Acute Disease↗
PubMed1998

Anti-angiogenic effect of TGFbeta in aqueous humor.

Neovascularization is mediated by various factors in ocular tissues. Recent studies have emphasized the role of vascular endothelial growth factor in the induction of angiogenesis. We have previously reported that aqueous humor (AH) suppressed vascular endothelial cell growth and angiogenesis. We speculated that the anti-angiogenic effect of AH is mediated by transforming growth factor beta (TGFbeta). In order to clarify the presence of TGFbeta in bovine AH, we applied it on the heparin-sepharose affinity column and prepared two fractions (bound and unbound fractions). We measured TGFbeta concentration in each fraction and examined how the anti-TGFbeta antibody decreased the inhibitory effect of AH on human umbilical vein endothelial cell growth and on in vitro angiogenesis. We found the presence of TGFbeta2, but not TGFbeta1, in the heparin bound fraction, and the inhibitory effect was detected in the heparin-bound fraction. Anti-TGFbeta antibody completely and dose-dependently extinguished the inhibitory effect of AH. We propose that the inhibitory effect of AH on endothelial cell growth and in vitro angiogenesis are both mediated by TGFbeta2. Our results indicate TGFbeta2 is normally present in AH and protects the eye tissue against abnormal neovascularization.

Animals↗