Alimentary Pharmacology & Therapeutics Symposium Series最新文献

Summary

Background

Recent studies in models of inflammatory bowel disease have demonstrated that heme oxygenase-1 (HO-1) induction, or its by-products in this process such as carbon monoxide (CO), plays an important role in the intestinal inflammation. However, the distribution of HO-1 in intestinal mucosa and the concentration of intestinal luminal CO in humans have not yet been investigated.

Aim

To detect the HO-immunopositive cells in the intestine of normal subjects and in patients with ulcerative colitis (UC) and to measure intestinal luminal CO gas contents using gas chromatography.

Materials and Methods

The expression of HO-1 in the intestine was determined using immunohistochemistry. Human colonic gas was collected using colonoscopy from healthy volunteers and patients with UC. Analysis of intestinal luminal gas was performed using a newly developed portable gas chromatograph.

Results

Immunopositive staining for HO-1 was localized in the inflammatory cells, mainly mononuclear cells, and the number of cells that accepted stain was greater in patients with UC. CO level in the intestinal lumen significantly increased in patients in the active stage of UC.

Conclusion

These findings indicate that the HO-CO system is induced in UC.

Summary

Background

Many recent studies have indicated the importance of heat shock proteins for cell survival under stress conditions. Some heat shock proteins are known to be involved in cytoprotection against environmental stresses, through their function as ‘molecular chaperones’.

Aim

To examine the biological characteristics of HSP70 gene-transfected gastric mucosal cells.

Materials and methods

Complimentary DNA of human HSP70 gene was transfected to RGM-1 cells (rat gastric mucosal cell line) and HSP70 highly-expressing cells were selected and cloned. A single clone (7018-RGM-1), which highly expressed HSP70 compared with RGM-1, was used in this study. Cytoprotective ability against H₂O₂ or ethanol was analysed by WST-assay and LDH-release. Wound restoration of artificially created wounds was also compared between RGM-1 and 7018-RGM-1 cells.

Results

We successfully cloned HSP70 highly-expressing gastric mucosal cells, which expressed a level of HSP70 equal to 350% of that of RGM-1 cells. Over-expression of HSP70 clearly enhanced cytoprotective ability against H₂O₂ or ethanol-induced cell damage. Wound restoration was enhanced in 7018-RGM-1 cells compared with RGM-1 cells.

Conclusion

Our results suggested that expression of HSP70 might play important roles not only in cytoprotection but also in mucosal wound restoration, mediated by the molecular chaperone function of HSP70.

Summary

Background

Many reports have described coinfection of Helicobacter pylori and other bacteria in the gastric mucosa in humans. However, relatively few have reported the relation of coinfection with pathological characteristics.

Aim

To culture and identify bacteria other than H. pylori from the gastric mucosa of 64 patients undergoing scheduled gastric biopsy for various gastric conditions. The relation of coinfection with the pathological changes was also investigated.

Methods

From colonies showing characteristics different to those of H. pylori, bacteria were identified by the 16S rRNA gene sequence using FASTA. Cluster analysis was performed using GENETYX-MAC and a phylogenetic tree was constructed using the UPGMA method. The correlation of pathological observation and the existence of identified bacteria and H. pylori were also analysed.

Results

Forty-eight per cent of patients were positive to H. pylori, and 27% were positive to Neisseria species. Coinfection of the two bacterial existences was significantly linked. DNA sequencing studies revealed these Neisseria strains to coincide mostly with Neisseria subflava. With regard to the interaction of pathological characteristics, Neisseria and H. pylori coinfection was closely related to lymph follicle formation.

Conclusions

Coinfection of H. pylori and N. subflava was found to be closely related to lymph follicle formation.

Summary

Background

Increase in interleukin-8 in the oesophageal mucosa has been associated with the pathogenesis of reflux oesophagitis.

Aim

To assess the effect of bile acids on the interleukin-8 expression in normal human oesophageal epithelial cells and to determine its molecular mechanisms.

Methods

Human oesophageal epithelial cells were stimulated with unconjugated bile acids, conjugated bile acids and inflammatory cytokines. Protein and mRNA of interleukin-8 were measured by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. In addition, we examined protein kinases and transcription factors involved in interleukin-8 synthetic pathways using protein kinase inhibitors and luciferase expression vectors, respectively.

Results

Unconjugated bile acids induced interleukin-8 production from human oesophageal epithelial cells stronger than conjugated bile acids. However, conjugated bile acids in acidic media resulted in remarkable increase of interleukin-8 production compared with those in neutral-pH media. Mutation of the binding site of NF-kB, AP-1 and NF-IL6 abrogated the induction of luciferase activities by 100%, 70% and 30%, respectively. Inhibitor of protein kinase A, protein kinase C or p38 mitogen-activated protein kinase attenuated the production of interleukin-8 by cholic acid.

Conclusions

These results indicate that bile acids induce interleukin-8 expression from oesophageal epithelial cells mainly via the activation of NF-kB as well as AP-1.

Summary

Background

There is little evidence of changes in genetic variations in gastric intestinal metaplasia (GIM) after the eradication of Helicobacter pylori (H. pylori).

Aim

To investigate the effects of H. pylori eradication on genetic GIM variability in patients with and without gastric cancer in a one-year prospective study.

Methods

We analysed microsatellite instability (MSI) and loss of heterozygosity (LOH) in GIM. Subjects included Gr. A (n = 39): chronic gastritis, and Gr. B (n = 53): intestinal-type early gastric cancer patients who underwent endoscopic mucosal resection (n = 25) and surgical resection (n = 28).

Results

The frequency of incidence of MSI in GIM was 10.3% and 28.3% for Gr. A and Gr. B, respectively. Gr. B showed a significantly (p = 0.03) higher incidence rate than Gr. A for MSI, but not for LOH. The frequency of MSI declined in both groups post-eradication, and patients that were positive for MSI before treatment were negative after H. pylori eradication. Unfortunately, however, GIM scores did not decline significantly post-treatment for either group.

Conclusions

MSI in GIM may be associated with gastric carcinogenesis. H. pylori eradication reduced MSI during the one-year post-treatment period, although no histological improvement in GIM was observed. These changes in MSI may explain the decrease in gastric cancer incidence after the eradication of H. pylori.

Summary

Background

Patients with Obstructive Sleep Apnea Syndrome (OSAS) often experience gastroesophageal reflux disease (GERD).

Aim

To investigate gastric motility and autonomic nervous activity during sleep apnea.

Methods

The subjects of this study were 20 individuals with OSAS who experienced 10 or more sleep apnoea events per hour, as measured with a portable sleep polygraph. A percutaneous electrogastrography (EGG) and fast Fourier transformation analysis was carried out on the results. The mean amplitude was compared for bradygastria, normogastria and tachygastria. Spectral analysis of heart rate variability was performed, and low-frequency (LF) power, high-frequency (HF) power and the LF/HF ratio were measured. Oesophagogastroduodenal endoscopy was performed on each subject, and the presence of reflux oesophagitis (RE) was diagnosed according to the Los Angeles (LA) grade classification. Moreover, questionnaire for the diagnosis of reflux disease (QUEST) was carried out.

Results

Normogastria was significantly decreased, and brady-, tachygastria, or both were increased during sleep apnea (P < 0.01). There was no significant relation between LA grade classification of RE and severity of OSAS. The LF/HF ratio was significantly higher during sleep apnea for patients with RE and OSAS, but the opposite for those with RE without OSAS. Decreased percutaneous arterial oxygen saturation and normogastria were independent risk factors for the severity of RE.

Conclusions

The present study suggested that, in addition to decreased pressure on the pleural cavity, factors affecting the development of RE might include abnormal gastric motility, low oxygen, and increased sympathetic nervous activity during sleep apnea.

Summary

Background

Controversy exists concerning the efficacy of acid suppressants in the regression of Barrett's oesophagus.

Aim

To evaluate the effect of proton pump inhibitors on cyclooxygenase-2 expression, cellular proliferation and apoptosis in Barrett's oesophagus with different mucin phenotypes.

Methods

Four hundred and sixty-six biopsy samples of Barrett's oesophagus from 358 non-treatment patients and 81 from 61 chronic proton pump inhibitor users were immunohistochemically examined using anti-cyclooxygenase-2 protein, anti-proliferating cell nuclear antigen and anti-single stranded DNA antigens in both mucin phenotypes of Barrett's oesophagus.

Results

Prevalence of the cyclooxygenase-2 expression pattern did not significantly differ between the non-treatment and proton pump inhibitor users. In those using proton pump inhibitors, significant suppression of the proliferating cell nuclear antigen index was found in Barrett's oesophagus with the gastric-predominant mucin phenotype, but not with the intestinal-predominant mucin phenotype. Apoptosis indices in chronic proton pump inhibitor users did not significantly differ between the two mucin phenotypes.

Conclusions

Proton pump inhibitors suppress cellular proliferation in Barrett's oesophagus with the gastric-predominant mucin phenotype but not in that with the intestinal-predominant mucin phenotype. This finding may at least partly explain the ongoing controversy surrounding the notion that all cases of Barrett's oesophagus respond to acid-suppressive therapy.

Summary

Background

The loss of sonic hedgehog is an early change that occurs in the mucosa prior to neoplastic transformation and correlates with the type of intestinal metaplasia. Aberrant expression of CDX has also been shown to correlate with the development of intestinal metaplasia.

Aim

To examine CDX2 expression in the non-cancerous mucosa of patients with gastric cancer and compared it to CDX2 expression in controls with intestinal metaplasia.

Methods

Sixty patients who had undergone endoscopic mucosal resection for early gastric cancer and 60 gender- and age-matched controls were studied. Two specimens each were obtained from the greater and lesser curves of the corpus and from the greater curve of the antrum. Expression of CDX2 and sonic hedgehog were evaluated by immunostaining.

Results

Gastric cancer was associated with a higher frequency of incomplete intestinal metaplasia (OR = 8.3; 95%CI, 3.7–18.9, P < 0.001). CDX2 negatively correlated with sonic hedgehog expression, however, multivariate analysis revealed that CDX2 correlated with the intestinal metaplasia scores. Sonic hedgehog indices were lower and CDX2 staining in the corpus lesser curve was higher in the cancer group than in the controls. Sonic hedgehog indices in the corpus decreased and CDX2 indices in both areas increased in patients in the ascending order of those without intestinal metaplasia, those with complete intestinal metaplasia and those with incomplete intestinal metaplasia (P < 0.001).

Conclusions

Loss of sonic hedgehog expression and aberrant expression of CDX2 correlates with the type of intestinal metaplasia and may play a role in carcinogenesis.