Pedunculated colonic lipoma.
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Colonic Neoplasms↗
Biomedical subjects
Sunao Kawano
Publications and source records attributed to Sunao Kawano.
Promoter hypermethylation silences cyclooxygenase-2 (Cox-2) and regulates growth of human hepatocellular carcinoma cells.
Cyclooxygenase-2 (COX-2) upregulation is recognized to confer advantage in progression in a wide variety of cancers, with colorectal cancer most intensively investigated. Epidemiologically, chemopreventive effects of COX-2 inhibitors have been proven on numerous cancers, but not on hepatocellular carcinoma (HCC). Although the antiapoptotic feature of COX-2 generally supports cancer cell growth, previous reports have shown that COX-2 expression, upregulated in early HCC, is downregulated in advanced HCC. Therefore, COX-2 downregulation may be somehow advantageous and specific for HCC development. However, its mechanism remains unclear. Since promoter hypermethylation often silences the gene expression, we hypothesized that the epigenetic mechanism might regulate COX-2 expression in HCC. We examined the methylation status of the Cox-2 promoter in six human HCC cell lines (Hep3B, HepG2, SK-Hep1, HuH7, PLC, and FLC-7 cells) using methylation-specific PCR. The promoter was remarkably hypermethylated in Hep3B and FLC-7 cells and moderately in HepG2 and SK-Hep1 cells, but not in HuH7 and PLC cells. In Hep3B cells, coincubation with 5-aza-2'-deoxycytidine, a demethylator, demethylated the promoter and upregulated COX-2 expression as well as prostaglandin E2 production dose dependently. On the other hand, no such effects were observed in HuH7 cells. Additionally, the methylator suppressed growth of Hep3B cells dose dependently, accompanied by cyclin D1 downregulation, and the growth suppression was abrogated by potent COX-2 inhibition with a COX-2 selective inhibitor celecoxib, but these responses were not found in HuH7 cells. These results indicated that cell growth was largely retarded by Cox-2 upregulation via promoter demethylation, rather than the potentially reactivated genes concurrently demethylated by 5-aza-2'-deoxycytidine. In conclusion, promoter hypermethylation transcriptionally silences Cox-2 in HCC cells. Epigenetic alteration of Cox-2, at least in part, modulates the growth of HCC cells.
Azacitidine↗
Gastroesophageal reflux disease related to diabetes: Analysis of 241 cases with type 2 diabetes mellitus.
BACKGROUND AND AIM: We examined the incidence of symptomatic gastroesophageal reflux disease (GERD) in patients with type 2 diabetes mellitus (DM). METHODS: Patients comprised those with DM or chronic hepatitis C (CHC) who visited Osaka Prefectural General Hospital in the same study period. Reflux symptoms were examined using a self-administered questionnaire. A total score of 4 or more was considered an indication of symptomatic GERD. Disease duration, hemoglobinA1c and diabetic complications were assessed. RESULTS: Patients with DM (n=241) or CHC (n=42) were recruited for the study. Of the 241 patients with DM, 100 (41.5%) reported experiencing upper gastrointestinal symptoms, whereas only 9 of 42 (21.4%) patients with CHC reported upper gastrointestinal symptoms (P=0.0137). Sixty-one patients (25.3%) with DM had reflux symptoms but only four patients (9.5%) with CHC reported reflux symptoms. The incidence of symptomatic GERD was significantly higher in patients with DM than in those with CHC (P=0.0219). Patients with DM for less than 5 years had a 2.4-fold higher incidence of GERD than patients with CHC. The incidence tended to rise with increased disease duration. Patients with diabetic complications reported reflux symptoms more frequently. The incidence decreased, however, in DM patients who had these conditions for more than 16 years. CONCLUSIONS: Type 2 diabetes mellitus is a risk factor for symptomatic GERD. In DM patients, use of oral hypoglycemic agents, body mass index, disease duration and the quality of diabetic control influenced the incidence of GERD.
Diabetes Mellitus, Type 2↗
Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway.
Prostaglandin (PG) E(2), a cyclooxygenase (COX) product, and angiotensin II are endogenous and have physiological roles in the body. On the other hand, an inducible isoform of COX (COX-2), insulin-like growth factor (IGF) II, and IGF-I receptor (IGF-IR) are up-regulated in colon carcinoma and might have crucial roles in tumor growth and invasion. The aim of the present study was to investigate the effects of COX-2 inhibitor and drugs blocking the biological activities of angiotensin II [angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)] on IGF-IR expression and tumor growth in vivo. We also investigated the effects of PGE(2), a major COX-2 product, in cancer cells and the effects of angiotensin II on IGF-IR expression and the underlying mechanism of action. In in vivo studies, tumor growth and IGF-IR expression were investigated in Colon 26 cells inoculated into BALB/c mice. In in vitro studies, the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on IGF-IR expression were analyzed in three colon cancer cell lines (Colon 26, HCA-7, and LS174T). IGF-II-induced cell growth and invasion were analyzed in Colon 26 cells in the presence and absence of NSAIDs (indomethacin and celecoxib) and angiotensin II. Celecoxib at the lowest effective dose for suppression of PG production (3 mg/kg) or an ACE inhibitor/ARB alone did not have a significant effect as compared with controls, although a high dose of celecoxib (>20 mg/kg) suppressed tumor growth. On the other hand, combination therapy with these two categories of drugs significantly reduced tumor growth in vivo. Treatment with both celecoxib and an ACE inhibitor/ARB decreased IGF-IR expression levels in inoculated tumor cells. In in vitro studies, NSAIDs reduced IGF-IR expression in a dose-dependent manner in all three cell lines. NSAIDs also inhibited IGF-II-stimulated growth and invasion in a dose-dependent manner. PGE(2) or angiotensin II treatment reversed the NSAID-induced down-regulation of IGF-IR expression, growth, and invasion. PGE(2) and angiotensin II induced Akt phosphorylation, and LY294002 or wortmannin inhibited PGE(2)- or angiotensin II-induced IGF-IR expression, indicating that PGE(2) and angiotensin II both regulate IGF-IR expression by the same Akt/phosphatidylinositol-3 pathway. Thus, combination therapy with NSAIDs and ACE inhibitors targeting IGF-IR might be a novel and potentially promising strategy for the chemoprevention of colon cancer.
Angiotensin II↗
Peptic ulcer recurrence and Helicobacter pylori: evidence from Japan.
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Anti-Bacterial Agents↗
Development of colitis in signal transducers and activators of transcription 6-deficient T-cell receptor alpha-deficient mice: a potential role of signal transducers and activators of transcription 6-independent interleukin-4 signaling for the generation of Th2-biased pathological CD4+ betabetaT cells.
Forbidden CD4(+)betabeta T cells, which produce interleukin (IL)-4 predominantly, are a pathological subset in the development of colitis in T-cell receptor alpha chain (TCRalpha)-deficient mice. Stimulation of naive CD4(+) T cells with IL-4 induces Th2 development via the activation of signal transducers and activators of transcription (STAT) 6. In the present study, we had found that IL-4 enhanced the expression of STAT6 in CD4(+)betabeta T cells isolated from TCRalpha(-/-) mice with colitis, suggesting that the IL-4 signal in the CD4(+)betabeta T cells is mediated by STAT6. To further investigate the role of STAT6 in the development of colitis induced by TCRalpha deficiency, we generated double-deficient mice by crossing TCRalpha(-/-) mice and STAT6(-/-) mice. Surprisingly, STAT6 deficiency did not result in decreased severity of colitis in TCRalpha(-/-) mice. STAT6-deficient CD4(+)betabeta T cells produced IL-4 and intraperitoneal injection of anti-IL-4 monoclonal antibody in the nondiseased TCRalpha(-/-) and STAT6 double-deficient mice prevented the colitis formation, thus indicating that the cells differentiated into the Th2 phenotype have the ability to mediate the development of the colitis in the absence of STAT6.
Animals↗
Combination therapy of ecabet sodium and cimetidine compared with cimetidine alone for gastric ulcer: prospective randomized multicenter study.
BACKGROUND AND AIM: Little is known about the clinical efficacy of co-therapy of ecabet sodium, a mucoprotective agent, and a histamine H2-receptor antagonist. The aim of the present study was to assess its additive benefit in combination with cimetidine for gastric ulcer. METHODS: In this prospective randomized study, after gastric ulcer was confirmed by endoscopy, 200 patients in 47 hospitals received either ecabet sodium 1 g b.i.d and cimetidine 400 mg b.i.d. (EC), or cimetidine 400 mg b.i.d. alone (C) for 8 weeks. Healing was examined by endoscopy at 4 and 8 weeks. RESULTS: Of the intention-to-treat (ITT) population (EC, 103; C, 97), 181 patients comprised the per protocol (PP) analysis (EC, 93; C, 88). At 4 weeks, healing rates were significantly higher in the EC group (60%) than in the C group (36%) ( p < 0.01). At 8 weeks, those by the ITT and PP analyses were 82% (EC) versus 58% (C), and 90% (EC) versus 64% (C), respectively ( p < 0.01 and p < 0.001). Symptom relief rates (EC vs C) at 2, 4 and 8 weeks were 73%versus 47% ( p < 0.01), 89%versus 66% ( p < 0.001), and 97%versus 73% ( p < 0.001), respectively. Significant additive effects of ecabet sodium were observed in patients aged 60 years or older, with solitary and medium to large ulcer, and without smoking or drinking habits. No adverse effects were critical. CONCLUSION: Ecabet sodium significantly augmented gastric ulcer healing and symptom relief by cimetidine, especially in the elderly.
Abietanes↗
Gastrin enhances gastric mucosal integrity through cyclooxygenase-2 upregulation in rats.
Gastrin, PGs, and growth factors have important roles in maintaining gastrointestinal mucosal integrity. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in PG synthesis. This study aimed to clarify the mechanisms of gastric mucosal protection by gastrin. Fasted rats were administered subcutaneous gastrin 17 with or without gastrin receptor antagonist YM022 pretreatment. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and COX-2 expression were examined using Western blot analysis. Another series of experiments investigated 1) PGE(2) levels in gastric mucosa, 2) the protective action of gastrin against gastric damage by acidified ethanol, 3) the effects of a specific HB-EGF-neutralizing antibody on gastrin-induced COX-2 expression, and 4) the effects of a specific COX-2 inhibitor NS-398 on PGE(2) synthesis and the mucosal protection afforded by gastrin. Gastrin dose-dependently increased HB-EGF, COX-2 expression, and PGE(2) levels and reduced gastric damage. However, pretreatment with YM022 dose-dependently abolished such effects of gastrin. A specific HB-EGF- neutralizing antibody and an EGF receptor inhibitor decreased gastrin-induced COX-2 expression. NS-398 blocked gastrin-induced PGE(2) synthesis and mucosal protection. In conclusion, this study demonstrates that gastrin enhances gastric mucosal integrity through COX-2, which is partially mediated by HB-EGF, and PGE(2) upregulation in rats.
Animals↗
Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis.
Cyclooxygenase-2 (COX-2) was recently reported (M. Tsujii and R. N. DuBois, Cell, 83: 493-501, 1995) to affect the metastatic potential of cells. Previous studies (M. Fukuda, Cancer Res., 56: 2237-2244, 1996) indicated that sialyl Lewis antigen expression is correlated with hematogenous metastasis of colon cancer. In the present study, we investigated the interaction between COX-2 activity, expression of sialyl Lewis antigens, in vitro cancer cell adhesion to endothelial cells, and in vivo metastatic potential. Effects of COX-2 activity and prostaglandin E(2) on cell adhesion, expression of sialyl Lewis antigens, and glycosyltransferase genes were determined in Caco-2-m (COX-2 low level), Caco-2-COX-2 (programmed to overexpress COX-2), and HT-29 (COX-2 high level) cells. Metastatic spread of these cells to the liver was also investigated. Caco-2-COX-2 cells had increased SPan-1 levels and increased adherence to endothelial cells via SPan-1 compared with Caco-2-m cells. HT-29 cells expressed sialyl Lewis a and adhered to endothelial cells via sialyl Lewis a. Treatment with a COX-2 inhibitor, celecoxib, decreased SPan-1 and sialyl Lewis a expression and adherence to endothelial cells. beta 3Gal-T5 and ST3Gal III and IV expression was inhibited by celecoxib and was enhanced by prostaglandin E(2) treatment. Caco-2-COX-2 and HT-29 cells metastasized to the liver, whereas Caco-2-m cells did not. Pretreatment with celecoxib reduced the metastatic potential as well as anti-sialyl Lewis antibodies. Our results indicate a direct link between COX-2 and enhanced adhesion of carcinoma cells to endothelial cells, and enhanced liver metastatic potential via accelerated production of sialyl Lewis antigens. COX-2 inhibitors may suppress metastasis.
Animals↗
Influences of Helicobacter pylori on gastric angiogenesis and ulcer healing in mice.
BACKGROUND AND AIMS: Helicobacter pylori infection is associated with peptic ulcers; however, it is unclear whether the bacterium delays ulcer healing. We investigated the influence of H. pylori on ulcer healing in mice. We also examined the influence of H. pylori infection on angiogenesis. METHODS: An acetic acid ulcer was made in male BALB/c mice. Three days later (day 0), the animals were inoculated with H. pylori SS1 strain. The healing process of the ulcer was examined macroscopically and microscopically on days 0, 6 and 9. The index of angiogenesis was also determined using carmine dye injection. RESULTS: On day 0, angiogenesis began at the ulcer margin while the mucosal epithelia had not yet regenerated. On days 6 and 9, angiogenesis and epithelial regeneration developed and ulcer size reduced. These phenomena were significantly suppressed in mice infected with H. pylori. CONCLUSION: Helicobacter pylori infection significantly suppressed angiogenesis and delayed ulcer healing. These results indicate that H. pylori plays an important role in ulcer healing.
Acetic Acid↗
Randomized comparative study of omeprazole and famotidine in reflux esophagitis.
BACKGROUND: Although proton pump inhibitors (PPI) and H2-receptor antagonists (H2-RA) are routinely used in the treatment of reflux esophagitis (RE), no consensus has been reached yet as to whether the first-choice drug should be PPI or H2-RA. In this study, the effects of omeprazole (OMP) and famotidine (FAM) on RE have been examined in a randomized comparative study. METHODS: Protocols of OMP 20 mg once daily or FAM 20 mg twice daily for 8 weeks were allocated to 56 cases with RE at random, using an envelope randomization method. Their efficacy in achieving healing was examined endoscopically and a relief from subjective symptoms was compared. RESULTS: Patient's background such as sex, age, recurrence, hiatal hernia, smoking and drinking habits, and complications, and the severity of esophagitis at the time of enrolment were not significantly different between the two groups. Healing in the OMP group and the FAM group was observed in 72 and 32% (P = 0.025) of patients at week 4 and 95 and 53% (P = 0.003) of patients at week 8, respectively. Subjective symptoms were relieved more frequently in the OMP group (at week 2, 67% compared with 29%, P = 0.005; at week 4, 95% compared with 55%, P = 0.009), but this superiority was not significant at week 8 (94% compared with 65%, P = 0.085). No serious adverse events occurred. CONCLUSIONS: Omeprazole provided quicker healing and a greater relief from subjective symptoms than did FAM in the treatment of RE, and was considered more suitable as a first-choice drug.
Aged↗
Tumor necrosis factor alpha stimulates invasion of Src-activated intestinal cells.
BACKGROUND & AIMS: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis-related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. METHODS: A cell line derived from intestinal epithelia was transfected with a v-src- or v-H-ras-expressing vector. The effect of TNF-alpha on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of beta-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. RESULTS: TNF-alpha altered the colony morphology of src-, but not ras-expressing cells. TNF-alpha increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-alpha led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. CONCLUSION: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-alpha leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates.
Agar↗
Lansoprazole induces mucosal protection through gastrin receptor-dependent up-regulation of cyclooxygenase-2 in rats.
Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.
2-Pyridinylmethylsulfinylbenzimidazoles↗
[Ammonia and monochloramine generated by urease in Helicobacter pylori cause gastric mucosal injury].
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Ammonia↗
[Neutrophil-endothelium interaction].
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Anti-Inflammatory Agents, Non-Steroidal↗
[Dual therapy for Helicobacter pylori resistance to anti microbial agents].
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2-Pyridinylmethylsulfinylbenzimidazoles↗
[Epidemiology of peptic ulcer disease in the aged in Japan].
The population in Japan is now decreasing, however, the population older than 65 years old is increasing remarkably in the recent years. The old people with peptic ulcer may hospitalize for longer period than that of younger. The serious complications such as bleeding, perforation and obstruction may affect the period of hospitalization. In 1983, Helicobacter pylori was found and identified. The eradication of Helicobacter pylori causes a decrease of ulcer recurrence and the lower prevalence rate of Helicobacter pylori in the younger people may decrease the incidence of peptic ulcer in the near feature. Thus, the people older than 65 years old with a high risk for peptic ulcer will increase, although the infection rate of Helicobacter pylori will decrease. The actual number of peptic ulcer in the old people may decrease, however, the percentage of old people with peptic ulcer against total population may increase, although it is very difficult to predict the incidence of peptic ulcer diseases in the future.
Aged↗