Search

The interleukin-17 (IL-17) family of cytokines (IL-17A to IL-17F) is involved in many inflammatory diseases. Although IL-17A is recognized as being involved in the pathophysiology of Helicobacter pylori -associated diseases, the role of other IL-17 cytokine family members remains unclear. Microarray analysis of IL-17 family cytokines was performed in H. pylori -infected and uninfected gastric biopsy specimens. IL-17C mRNA was upregulated approximately 4.5-fold in H. pylori -infected gastric biopsy specimens. This was confirmed by quantitative reverse transcriptase PCR in infected and uninfected gastric mucosa obtained from Bhutan and from the Dominican Republic. Immunohistochemical analysis showed that IL-17C expression in H. pylori -infected gastric biopsy specimens was predominantly localized to epithelial and chromogranin A-positive endocrine cells. IL-17C mRNA levels were also significantly greater among cagA -positive than cagA -negative H. pylori infections ( P = 0.012). In vitro studies confirmed an increase in IL-17C mRNA and protein levels in cells infected with cagA -positive infections compared to cells infected with either cagA -negative or cag pathogenicity island (PAI) mutant. Chemical inhibition of IκB kinase (IKK), mitogen-activated protein extracellular signal-regulated kinase (MEK), and Jun N-terminal kinase (JNK) inhibited induction of IL-17C proteins in infected cells, whereas p38 inhibition had no effect on IL-17C protein secretion. In conclusion, H. pylori infection was associated with a significant increase in IL-17C expression in human gastric mucosa. The role of IL-17C in the pathogenesis of H. pylori -induced diseases remains to be determined., (Copyright © 2017 American Society for Microbiology.)

Background: In vitro studies have shown that Helicobacter pylori (H. pylori) infection induces autophagy in gastric epithelial cells. However, prolonged exposure to H. pylori reduces autophagy by preventing maturation of the autolysosome. The alterations of the autophagy-related genes in H. pylori infection are not yet fully understood., Materials and Methods: We analyzed autophagy-related gene expression in H. pylori-infected gastric mucosa compared with uninfected gastric mucosa obtained from 136 Bhutanese volunteers with mild dyspeptic symptoms. We also studied single nucleotide polymorphisms (SNPs) of autophagy-related gene in 283 Bhutanese participants to identify the influence on susceptibility to H. pylori infection., Results: Microarray analysis of 226 autophagy-related genes showed that 16 genes were upregulated (7%) and nine were downregulated (4%). We used quantitative reverse transcriptase polymerase chain reaction to measure mRNA levels of the downregulated genes (ATG16L1, ATG5, ATG4D, and ATG9A) that were core molecules of autophagy. ATG16L1 and ATG5 mRNA levels in H. pylori-positive specimens (n=86) were significantly less than those in H. pylori-negative specimens (n=50). ATG16L1 mRNA levels were inversely related to H. pylori density. We also compared SNPs of ATG16L1 (rs2241880) among 206 H. pylori-positive and 77 H. pylori-negative subjects. The odds ratio for the presence of H. pylori in the GG genotype was 0.40 (95% CI: 0.18-0.91) relative to the AA/AG genotypes., Conclusions: Autophagy-related gene expression profiling using high-throughput microarray analysis indicated that downregulation of core autophagy machinery genes may depress autophagy functions and possibly provide a better intracellular habit for H. pylori in gastric epithelial cells., (© 2017 John Wiley & Sons Ltd.)

Background: The prevalence of gastroesophageal reflux disease (GERD) has increased in Japan since the end of the 20th century due to changes in environmental factors, such as a decreased infection rate of Helicobacter pylori and increased ability of acid secretion in the Japanese population. In 2013, the Japanese health insurance system started to cover eradication treatment for all patients infected with H. pylori to prevent gastric cancer, suggesting we may soon be able to completely eradicate this infection in Japan. Re-clarification of the clinical characteristics of GERD in Japan is therefore required in time covering the eradication for all patients infected with H. pylori., Summary: In Japan, more than half of GERD patients exhibit non-erosive reflux disease, and a majority of erosive esophagitis (RE) cases have mild severity of GERD (Los Angeles classification of grades A and B). The prevalence of RE in H. pylori-positive patients is relatively low (4.1%) compared to the general Japanese population (7.6-10.6%). In multivariate analysis to evaluate a risk of RE development, a risk in H. pylori-positive patients is elevated in those with mild gastric mucosal atrophy (C-I and C-II according to the Kimura-Takemoto classification, OR 12.14, 95% CI 1.28-115.26, p = 0.03) or with hiatal hernia (OR 5.24, 95% CI 1.80-15.22, p < 0.01). Here, we provide a comprehensive review of GERD in Japan, including associations between GERD and H. pylori infection, low-dose-aspirin-induced GERD, and pharmacological treatment for GERD., Key Messages: The recent decrease in the rate of H. pylori infection and increase in the proportion of elderly persons might have increased the prevalence of GERD in Japan., (© 2016 S. Karger AG, Basel.)

Background: Patients with duodenal ulcer have a reduced risk of developing gastric cancer compared to those without. Recently, the prostate stem cell antigen (PSCA) rs2294008 C>T polymorphism was found to be associated with different pathogenesis of duodenal ulcer and gastric cancer developments. However, whether PSCA rs2294008 C>T polymorphism is associated with severity of gastric mucosal atrophy is unclear. We examined the influence of the PSCA rs2294008 C>T polymorphism on susceptibility to H. pylori-related diseases and the relationships between PSCA polymorphism and gastric mucosal atrophy., Methods: PSCA rs2294008 C>T polymorphism was assessed in H. pylori-positive Japanese patients (n = 488) with noncardia gastric cancer (n = 193), gastric ulcer (n = 84), duodenal ulcer (n = 61), and atrophic gastritis (n = 150), as well as in H. pylori-negatives (n = 266)., Results: Frequency of PSCA rs2294008 C/C genotype in duodenal ulcer was 36.1%, which was significantly higher than those with gastric cancer (12.4%), gastric ulcer (19.0%), gastritis (10.7%), and H. pylori-negatives (19.5%) (p < .001). Compared with duodenal ulcer, having the T allele significantly increased the risk of gastric cancer (OR: 3.97, 95% CI: 2.02-7.80; p < .001), gastric ulcer (2.40, 1.13-5.10; p = .023), and gastritis (4.72, 2.26-9.86; p < .001). Mean pepsinogen (PG) I/PG II ratio in T allele carriers (2.17 ± 0.75) was significantly lower than that in C/C genotype (3.39 ± 1.27, p < .001)., Conclusions: The PSCA rs2294008 C>T polymorphism is associated with differing susceptibilities to H. pylori-associated diseases. The PSCA rs2294008 C>T polymorphism may be acting through induction of gastric mucosal atrophy, finally leading to development of gastric ulcer and gastric cancer in PSCA rs2294008 T allele carriers, but not duodenal ulcer., (© 2014 John Wiley & Sons Ltd.)

Anti-platelet drug-induced gastric mucosal injury correlates with intragastric pH. Our aim was to investigate prophylaxis effects of famotidine, one of the representative histamine-2 receptor antagonists (H2RA), on gastric mucosal injury induced by dual therapy with low-dose aspirin and clopidogrel in relation to Helicobacter pylori (H. pylori) infection and CYP2C19 genotypes. This study was conducted for 20 healthy Japanese volunteers (10 H. pylori-positive and 10-negative subjects) with 100 mg aspirin plus 75 mg clopidogrel (AC) once-daily dosing and AC plus 20 mg famotidine twice-daily dosing (ACH). Mucosal injury was endoscopically assessed on day 3 and 7 and 24-hour intragastric pH and antiplatelet-function test was performed on day 7. Median pH in ACH was similar between CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM)/poor metabolizer (PM) and was significantly higher in H. pylori-positive than negative subjects (P < .05). Mucosal injury with ACH significantly decreased in both day 3 and 7 compared with AC, irrespective with H. pylori and CYP2C19 genotypes (P < .05). Although antiplatelet effect of clopidogrel in EM was significantly higher than that in IM/PM, the additional famotidine did not affect the effect. Anti-platelet drug-induced gastric injury was alleviated by famotidine without attenuation of anti-platelet functions irrespective of H. pylori and CYP2C19 genotypes., (© 2014, The American College of Clinical Pharmacology.)

Introduction: The antiplatelet effects of low-dose aspirin (LDA) vary between individuals. Here, we investigated the relationship between the incidence of LDA-induced mucosal injury, antiplatelet effects of LDA, and intragastric pH., Methods: We evaluated gastric injury severity and platelet function using the VerifyNow® System before and after administration of 100 mg aspirin for 7 days to 18 young healthy subjects (study 1). We investigated whether injury was correlated with platelet function and gastric juice pH in 45 patients with cardiovascular disease administered LDA daily (study 2)., Results: In study 1, platelet aggregation was attenuated by LDA to different degrees. Although 55.6% of subjects (10/18) developed gastric injury of modified Lanza score (MLS) ≥ 3, no significant difference in platelet function was detected between the mild (n = 8, MLS: 0-2) and severe injury groups (n = 10, MLS: 3-5). In study 2, the severity of LDA-induced injury was associated with gastric juice pH, but not with antiplatelet effects of LDA., Discussion: In contrast to gastric juice pH, the antiplatelet effect had no correlation with the severity of gastric mucosal injury. Monitoring gastric acidity, rather than platelet function, may be useful for predicting the risk of gastric injury during LDA treatment., (© 2013 S. Karger AG, Basel.)

Background & Aims: Low doses of aspirin can injure the gastric mucosa. It is not clear whether other drugs such as the antiplatelet agent clopidogrel also cause gastric mucosal injury or exacerbate aspirin-induced injury, or whether proton pump inhibitors prevent damage., Methods: Twenty Japanese subjects with different CYP2C19 genotypes were randomly assigned to groups that were given a low dose of aspirin (100 mg; A), clopidogrel (75 mg; C), low dose of aspirin and clopidogrel (AC), or low dose of aspirin in combination with clopidogrel and rabeprazole (10 mg; ACR) once daily for 7 days. Subjects underwent gastroduodenoscopy and platelet tests on days 3 and 7; gastric mucosal damage was assessed by using the modified Lanza score (MLS). We performed 24-hour intragastric pH monitoring on day 7 of each regimen. We also analyzed the effects of the AC regimen on 30 patients with different CYP2C19 genotypes., Results: Subjects in groups A, C, and AC had significantly higher levels of gastric mucosal damage on days 3 and 7, compared with baseline. The median MLS for the AC group was similar to that of the A group. Helicobacter pylori-negative subjects in the ACR group with different CYP2C19 genotypes had significant differences in MLS, intragastric pH, and platelet function. Gastric mucosal injury was inhibited equally among H pylori-positive subjects in the ACR group. Rabeprazole did not appear to affect platelet function or intragastric pH in subjects given clopidogrel., Conclusions: Clopidogrel and low doses of aspirin cause a similar degree of gastric mucosal damage. Rabeprazole prevented this damage without reducing the antiplatelet function of clopidogrel. However, its prophylactic effect varies with CYP2C19 genotype in H pylori-negative subjects., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The preventive effects of lansoprazole and famotidine on low-dose aspirin-induced gastric mucosal injury in relation to gastric acidity were compared in healthy Japanese volunteers. Fifteen Helicobacter pylori-negative volunteers with different CYP2C19 genotypes were randomly administered aspirin 100 mg, aspirin plus famotidine 20 mg twice daily, or aspirin plus lansoprazole 15 mg once daily for 7 days each in a crossover fashion. Gastroscopy for the evaluation of mucosal injury based on modified Lanza score (MLS) and 24-hour intragastric pH monitoring were performed on day 7 of each regimen. Aspirin induced gastric mucosal injury (median MLS = 3). Lansoprazole significantly decreased MLS to 0, which was significantly lower than that by famotidine (MLS = 1) (P < .05). Medians of pH 3 holding time and mean 24-hour pH values with the lansoprazole regimen were significantly higher than those with famotidine (P < .05). No significant differences in MLS were observed among the different CYP2C19 genotype groups in any of the treatment regimens. In this 7-day study, lansoprazole appeared to be more protective than famotidine against low-dose aspirin-induced mucosal injury but a larger well-controlled study is necessary to establish a definitive clinical benefit.