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T Shimosegawa

Publications and source records attributed to T Shimosegawa.

At least 19 recordsLinked to original sources
PubMed2000

The relationship between persistent secretion of RANTES and residual infiltration of eosinophils and memory T lymphocytes after Helicobacter pylori eradication.

Helicobacter pylori (HP)-infected gastric mucosa displays a conspicuous infiltration of mononuclear cells as well as neutrophils. RANTES is a potent chemoattractant peptide for memory T lymphocytes and eosinophils. RANTES protein concentration and the numbers of RANTES-, CD45RO-, and major basic protein (MBP)-positive cells were therefore evaluated in the gastric mucosa from 51 patients with HP-positive chronic gastritis before and after HP eradication and from 22 HP-negative healthy volunteers. RANTES protein concentration was significantly elevated in HP-positive cases and remained high after HP eradication. The numbers of RANTES-, CD45RO-, and MBP-positive cells were significantly increased in HP-positive cases and were well correlated with RANTES protein levels. All tended to decrease after HP eradication, but did not reach the level of HP-negative cases, even at 24 months after HP eradication. It was concluded that persistent expression and secretion of RANTES were closely related to residual infiltration of memory T lymphocytes and eosinophils, for a prolonged period after HP eradication. This seems to be an important mechanism of prolonged gastric mucosal immune response against HP infection, even after HP eradication, and of persistent mucosal damage and atrophy.

Adult↗
PubMed2000

Erythropoietic protoporphyria with severe liver dysfunction and acute pancreatitis.

A case of erythropoietic protoporphyria associated with severe hepatic dysfunction and acute pancreatitis is reported. The patient, a 33-year-old man, was admitted to our hospital complaining of upper abdominal pain, nausea, and vomiting of 3 days' duration. Laboratory tests on admission demonstrated liver dysfunction, anemia, and thrombocytopenia. On the third hospital day, the intensity of the upper abdominal pain increased, concomitantly with elevated levels of serum amylase. Ultrasonography and computed tomography scanning revealed a slightly enlarged pancreas. During this episode, he also complained of various neurological symptoms, including reduced mental alertness, weakness of extremities, constipation, profound sweating, and urinary retention. Porphyrin studies demonstrated markedly elevated erythrocyte and fecal protoporphyrin levels. Laparoscopic findings obtained after the attack subsided were compatible with porphyric liver cirrhosis. We therefore concluded that neurologic disorders and acute pancreatitis could develop in patients with erythropoietic protoporphyria with severe liver dysfunction.

Adult↗
PubMed2000

Ascites of severe acute pancreatitis in rats transcriptionally up-regulates expression of interleukin-6 and -8 in vascular endothelium and mononuclear leukocytes.

The molecular mechanisms that link acute pancreatitis and multiple organ failure remain unknown. We examined the effect of ascitic fluids prepared from rats with experimental necrotizing pancreatitis on the expression of interleukin (IL) -6 and IL-8 in human umbilical vein endothelial cells (HUVEC) and human monocytic THP-1 cells. Incubation of HUVEC or THP-1 cells with the ascitic fluids resulted in a concentration-dependent up-regulation of the cytokine expression with comparable mRNA induction. Electrophoretic mobility shift assay revealed that the ascitic fluids increased the nuclear factor-kappaB (NF-kappaB) and NF-IL6 binding activities. Intraperitoneal injection of ascitic fluids into healthy rats induced the activation of NF-kappaB in the infiltrating leukocytes in the lung. Our results suggested that ascitic fluids may play a role in the pathophysiology of severe acute pancreatitis through the activation of transcription factors and consequent cytokine productions in distant organs.

Animals↗
PubMed2000

Cre-loxP-mediated bax gene activation reduces growth rate and increases sensitivity to chemotherapeutic agents in human gastric cancer cells.

Dysregulation of apoptosis may be closely related to the development of cancer and its chemoresistance. Overexpression of Bax, an inducer of apoptosis, has led to increased cell death in a variety of cancer cell lines. In this study, we investigated the effect of Bax overexpression in two gastric cancer cell lines, MKN-28 and MKN-45, using a Cre-loxP-mediated inducible expression system. After induction of bax, both cell lines showed decreased proliferation, partially due to increased cell death. Furthermore, Bax-expressing MKN-28 cells were more sensitive to cisplatin. These results indicate that up-regulation of the bax gene may provide a novel strategy for the treatment of gastric cancer.

Adenoviridae↗
PubMed2000

Activation of adenosine A1-receptor pathway induces edema formation in the pancreas of rats.

BACKGROUND & AIMS: Adenosine has been shown to modulate various pathophysiologic conditions through receptor-mediated mechanisms. However, the role of adenosine in the pathogenesis of acute pancreatitis has not been described. We examined the effect of adenosine-receptor stimulation or inhibition on the pathologic changes of the pancreas. METHODS: Rats received intraperitoneal injections of selective agonists of A1, A2a, and A3 adenosine receptors: 2-chloro-N(6)-cyclopentyladenosine (CCPA), CGS-21680 (CGS), or 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-D-ribofuranuronamide (IB-MECA), respectively. Serum amylase activity and pathologic changes of the pancreas were evaluated. The effects of a specific A1-receptor antagonist (FK-838) on the pathologic findings of cerulein- and taurocholate-induced pancreatitis were also examined. RESULTS: Administration of a selective A1 agonist induced hyperamylasemia and morphologic changes in the pancreas characterized by interstitial edema and leukocyte infiltration; neither A2a nor A3 agonist produced such changes. Treatment with an A1-receptor antagonist significantly attenuated the outcome induced by A1 agonist stimulation. In addition, the A1-receptor antagonist significantly ameliorated pancreatic edema in both pancreatitis models, although it did not improve the acinar cell damage of the pancreas or the increase of serum amylase. CONCLUSIONS: Activation of the adenosine A1-receptor pathway may have an important role in the pathogenesis of acute pancreatitis.

Acute Disease↗
PubMed2000

Fas-mediated cholangiopathy in the murine model of graft versus host disease.

Bile-duct injury observed in hepatic graft versus host disease (GVHD) is regarded as an immune-mediated injury, although its precise mechanism is unclear. However, recent studies have suggested the involvement of Fas-mediated cell death in this immune-mediated cholangiopathy. In this study, we first showed the constitutive expression of Fas receptor by cholangiocytes in situ from normal BALB/c mice, which was upregulated in GVHD mice. Also, we confirmed the Fas protein expression in the isolated cholangiocytes from normal BALB/c mice by immunocytochemistry and immunoblotting. Furthermore, the addition of agonistic Fas antibody-(Jo2)-induced cholangiocyte apoptosis confirmed by DNA-ladder formation and annexin V staining. Cholangiocytes from Fas-deficient mice (MRL lpr/lpr) did not show Jo2-induced apoptosis. Interferon-gamma augmented Fas expression and Fas-mediated cell death, respectively. Following these observations, experimental GVHD was induced by transfer of splenocytes from B10.D2 mice to irradiated (800 rad) BALB/c mice. Liver-infiltrating lymphocytes from the recipient showed dose-dependent cytotoxicity against (51)Cr-labeled cholangiocytes isolated from BALB/c mice. Moreover, the addition of blocking Fas-Fc fusion protein reduced this cytotoxicity to 44.7%. Finally, administration of this Fas-Fc protein to the BALB/c mice, which had been adoptively transferred with splenocytes of B10.D2 mice, prevented the development of hepatic GVHD in vivo. These results showed the involvement of Fas-mediated cell death in cholangiopathy observed in GVHD, and a soluble Fas-Fc protein may have a therapeutic potential for hepatic GVHD.

Animals↗
PubMed2000

Nitric oxide decreases endothelial activation by rat experimental severe pancreatitis-associated ascitic fluids.

To clarify the roles of nitric oxide (NO) in acute pancreatitis (AP), we examined the effects of NO on the endothelial activation induced by ascitic fluids from rats with experimental severe AP. Necrotizing hemorrhagic pancreatitis was induced in male Wistar rats with sodium taurocholate. Six hours later, peritoneal exudates were collected, centrifuged, and human umbilical vein endothelial cells were treated with the supernatants. Then (a) the mRNA level of endothelial-type NO synthase (ecNOS) was examined by reverse transcription-polymerase chain reaction; (b) effects of an NO donor, sodium nitroprusside (SNP) and an inhibitor of NOS, N(omega)-nitro-L-arginine (L-NNA) on the ascitic fluids-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin-8 were assessed by enzyme-linked immunoassay; (c) nuclear translocation of nuclear factor-kappa B (NF-kappaB) was examined by electrophoretic mobility shift assay; and (d) effects of SNP and L-NNA on the adhesion of U937 cells to endothelial monolayer were assessed. The ecNOS mRNA level was decreased by the ascitic fluids; ascitic fluids-induced expression of adhesion molecules and interleukin-8 as well as the nuclear translocation of NF-kappaB were attenuated by SNP, whereas L-NNA augmented them; and the effects on the endothelial activation were paralleled by the altered adhesion of U937 cells to endothelium. The ability of NO to limit endothelial activation and inhibit leukocyte adhesion might contribute to its antiinflammatory properties in AP.

Acute Disease↗
PubMed2000

Changes in gastric acid secretion assayed by endoscopic gastrin test before and after Helicobacter pylori eradication.

BACKGROUND: It remains controversial whether or not Helicobacter pylori infection causes altered gastric acid secretion. A novel test for evaluating gastric acid secretion (endoscopic gastrin test; EGT) has recently been developed. AIM: To investigate by EGT the effects of H pylori eradication on the state of gastric acid secretion in patients with peptic ulcer. METHODS: Twenty six patients with duodenal ulcer and 33 with gastric ulcer, for all of whom H pylori infection had been documented, were studied by EGT, histological examination of gastric mucosa, and measurement of plasma gastrin levels before and one and seven months after H pylori eradication. RESULTS: In patients with duodenal ulcer, the mean EGT value before H pylori eradication was higher than that in H pylori negative controls, but it had decreased significantly seven months after the treatment. In contrast, the mean EGT value of patients with gastric ulcer before H pylori eradication was lower than that in H pylori negative controls, but it had increased one month after the treatment; this was followed by a slight decrease at seven months. In both groups, mean EGT values seven months after the treatment were not significantly different from the mean control value. CONCLUSIONS: The reduced acid secretion in gastric ulcer patients and gastric acid hypersecretion in duodenal ulcer patients were both normalised after the clearance of H pylori.

Adult↗
PubMed1999

The T3(b) gene promoter directs intestinal epithelial cell-specific expression in transgenic mice.

Although a few promoters that direct intestinal epithelial cell-specific expression in transgenic animals have been reported, they are not necessarily appropriate for transgenic studies in terms of activity and tissue specificity. Here, we examined the tissue specificity of transgene expression directed by the 2.8-kb promoter region of the T3(b) gene, which encodes one of the non-classical major histocompatibility complex class I molecules. The transgene was expressed exclusively in the epithelial cells of the small and large intestines at high levels. The results indicate that the T3(b) promoter is useful for directing transgene expression specifically in intestinal epithelial cells.

Animals↗
PubMed1999

Telomere shortening and the clinicopathologic characteristics of human colorectal carcinomas.

BACKGROUND: It has been reported that shortening of telomeres and strong activation of telomerase occur frequently in colorectal carcinomas. In the current study, the authors examined the correlations between the telomere length of colorectal carcinomas and their clinicopathologic characteristics as well as the activity of telomerase to clarify whether telomere length might represent the biologic behavior of tumors and the mode of tumor development. METHODS: Telomere length was examined by Southern blot analysis in 61 invasive colorectal carcinomas and corresponding normal mucosas. Telomerase activity was assayed by the telomeric repeat amplification protocol with minor modifications. RESULTS: Shortening of the telomere was detected in 38 (62.3%) and elongation in 3 (4. 9%) of the 61 carcinomas. The telomere shortening occurred more frequently in nonulcerating polypoid carcinomas than in ulcerating carcinomas (P = 0.0373) and also occurred more frequently in ascending colon carcinomas than in sigmoid colon or rectal carcinomas (P = 0.0259 and P = 0.0407, respectively). However, no significant correlation was found between the activity of telomerase and the length of telomere. CONCLUSIONS: The results of this study indicate that telomere length may represent the biologic behavior of individual tumors and possibly the mode of development of colorectal carcinomas.

Aged↗
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

Crohn's disease is associated with novel polymorphisms in the 5'-flanking region of the tumor necrosis factor gene.

BACKGROUND & AIMS: Tumor necrosis factor (TNF) is considered to play an important role in the pathogenesis of Crohn's disease (CD). Recently, 3 polymorphisms in the 5'-flanking region of the TNF gene at positions -1031, -863, and -857, which are related to high transcriptional promoter activity, have been identified in the Japanese population. In an effort to understand potential genetic association with CD, we evaluated patients diagnosed with CD and ulcerative colitis (UC) in the presence of other novel polymorphisms. METHODS: Blood samples were obtained from 103 patients with CD and 76 patients with UC. Polymorphisms in the TNF gene at their respective positions were analyzed by direct sequencing, and the allele frequencies were compared with those determined previously in a healthy Japanese population. RESULTS: Allele frequencies of -1031C, -863A, and -857T in normal controls were 16.0%, 14.0%, and 17.7%, respectively. Polymorphic allele frequencies at positions -1031, -863, and -857 were 24.3%, 21.8%, and 27.2% in CD and 11.8%, 11.2%, and 11.8% in UC, respectively. The frequencies at all 3 positions were significantly higher in CD patients than in UC patients or healthy controls. Among the subgroups of CD, small bowel disease showed the highest frequencies. CONCLUSIONS: Although the findings need to be confirmed in other populations with larger numbers of patients, TNF gene polymorphisms -1031C, -863A, and -857T are positively associated with CD; they may influence not only the susceptibility to CD but also the disease location.

Adult↗
PubMed1999

Helicobacter pylori-dependent ceramide production may mediate increased interleukin 8 expression in human gastric cancer cell lines.

BACKGROUND & AIMS: Helicobacter pylori adheres to gastric epithelial cells, activates nuclear factor kappaB (NF-kappaB), and stimulates interleukin (IL)-8 production, but the responsible molecular mechanisms remain largely unknown. Because several studies have shown that sphingolipids are involved in a number of signaling pathways, including NF-kappaB activation, we investigated the possible role of sphingolipids in the regulation of IL-8 expression in Kato III and AGS cells. METHODS: IL-8 production in the conditioned media was quantified by enzyme immunoassay. Induction of messenger RNA (mRNA) was assessed by Northern blot analysis. Activation and binding activity of transcription factors were examined by luciferase assay and electrophoretic mobility shift assay, respectively. Intracellular levels of ceramide were quantified by diacylglycerol kinase assay. RESULTS: A cell-permeable ceramide analogue (C2-ceramide) increased IL-8 expression with comparable mRNA induction. This effect was mimicked by sphingomyelinase, but not by phospholipase A2 or phospholipase C. C2-ceramide induced IL-8 gene transcription mainly through activation of NF-kappaB because mutation of the NF-kappaB-binding site completely abrogated the induction of luciferase activity. Direct contact of live H. pylori with epithelial cells increased the intracellular concentration of ceramide. CONCLUSIONS: The results suggest a novel role of the sphingomyelin-ceramide pathway, at least in part through NF-kappaB, in IL-8 production induced by H. pylori infection in gastric epithelial cells.

Ceramides↗
PubMed1999

Cell damage and proliferation in human gastric mucosa infected by Helicobacter pylori--a comparison before and after H pylori eradication in non-atrophic gastritis.

Helicobacter pylori (HP) is believed to be involved in the transition from normal gastric mucosa to atrophic gastritis and intestinal metaplasia. Infection with the organism is one of the risk factors for development of intestinal-type gastric adenocarcinoma, possibly through altered cell turnover. Medical eradication of HP is widely performed for the treatment of peptic ulcers and other upper gastrointestinal disorders. Eradication of HP may affect altered cell turnover of the gastric mucosa caused by the infection, but there are few reports comparing sterilized mucosa with HP-infected and non-infected mucosa. In this study, we examined cell damage using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), in situ nick translation (ISNT), and cell proliferation by Ki 67 immunohistochemistry staining in gastric mucosa before and after HP eradication and in non-infected gastric mucosa. We then compared these findings using endoscopic gastric biopsy specimens. Labeling indices of TUNEL (2.46 +/- 1.22), ISNT (1.13 +/- 0.42), and Ki67 (21.8 +/- 6.14) in tissue from which HP had been eradicated were significantly lower than those of HP-infected mucosa (6.36 +/- 2.26, 4.00 +/- 1.62, 45.8 +/- 5.35, for TUNEL, ISNT, and Ki67, respectively). There were no significant differences between formerly infected and non-infected mucosa (TUNEL: 2.26 +/- 0.69, ISNT: 1.29 +/- 0.63, Ki67: 23.5 +/- 8.20). These results indicate that medical HP eradication results in decreased cell proliferation and damage, restoring the condition seen in non-infected mucosa. Thus, HP eradication may be effective, not only in the treatment of gastric ulcers or gastric symptoms, but also in the prevention of gastric carcinoma.

Anti-Bacterial Agents↗
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

11C-methionine uptake to the pancreas and its secretion: a positron emission tomography study in humans.

The aim of this study was to investigate the uptake of [11C-methyl]-L-methionine (11C-methionine) in the human pancreas by analyzing dynamic positron emission tomography (PET) images and the duodenal aspirate. A double-lumen tube was inserted in the duodenum and dynamic PET was performed in seven healthy volunteers for 110 min after intravenous (i.v.) injection of 11C-methionine during the continuous i.v. administration of secretin (125 ng/kg/h) and cerulein (30 ng/kg/h). For the calculation of the radioactivity in the pancreas, the regions of interest were set on the PET images. Radioactivity was measured in 10-min fractions of duodenal juice. After i.v. injection, 11C-methionine accumulated in the pancreas within a few minutes, and the radioactivity plateaued during the study. The radiolabeled proteins in the duodenal juice increased linearly 30 min after 11C-methionine injection, but the relative rates of radioactivity in the protein precipitate to the total count in the duodenal juice were 44-48%. From these findings, it was concluded that 11C-methionine accumulation in the pancreas is very rapid after the i.v. administration, and only a part of methionine uptake to the pancreas is incorporated into secretory proteins. The pancreatic 11C-methionine uptake detected by PET may represent a new aspect of exocrine pancreatic function that has not been expressed by the conventional intubation method.

Adult↗
PubMed1999

Ascitic fluid of experimental severe acute pancreatitis modulates the function of peritoneal macrophages.

Although the pathophysiology of acute pancreatitis appears to be greatly influenced by the production of ascites, little is known about the mechanism. To investigate the effects of pancreatitis-associated ascitic fluid (PAAF) on macrophage function, we examined the effects of PAAF obtained from a rat model of severe acute pancreatitis on the ability of peritoneal macrophages to produce tumor necrosis factor-alpha (TNF-alpha). In addition, we compared the responses of PAAF-treated and PAAF-untreated macrophages to lipopolysaccharide (LPS) by evaluating their TNF-alpha production and nuclear factor-kappaB (NFkappaB) activation. Incubation of peritoneal macrophages with the PAAF led to the rapid and prolonged activation of NF-kappaB and to TNF-alpha production. Pyrrolidine dithiocarbamate, a potent inhibitor of NF-kappaB activation, attenuated the macrophage TNF-alpha production by PAAF. Macrophages produced TNF-alpha in response to LPS, but the cytokine production was significantly reduced when macrophages were pretreated with PAAF. The suppression of TNF-alpha production by PAAF pretreatment accompanied the impairment of NF-kappaB activation in response to LPS. These results indicate that the PAAF of severe acute pancreatitis may play important roles in the pathologic course of this disease through its effects on macrophage function.

Amylases↗