Cell-surface Toll-like receptors (TLRs) initiate innate immune responses, such as inducible nitric oxide synthase (iNOS) induction, to microorganisms' surface pathogens. TLR2 and TLR4 play important roles in gastric mucosa infected with Helicobacter pylori (H. pylori), which contains lipopolysaccharide (LPS) as a pathogen. The present study investigates their physiological roles in the innate immune response of gastric epithelial cells to H. pylori-LPS. Changes in the expression of iNOS, TLR2, and TLR4, as well as downstream activation of mitogen-activated protein kinases and nuclear factor-kappaB (NF-kappaB), were analyzed in normal mouse gastric mucosal GSM06 cells following stimulation with H. pylori-LPS and interferon-gamma. Specific inhibitors for mitogen-activated protein kinases, NF-kappaB, and small interfering RNA for TLR2 or TLR4 were employed. The immunohistochemistry of TLR2 was examined in human gastric mucosa. H. pylori-LPS stimulation induced TLR2 in GSM06 cells, but TLR4 was unchanged. TLR2 induction resulted from TLR4 signaling that propagated through extracellular signal-related kinase and NF-kappaB activation, as corroborated by the decline in TLR4 expression on small interfering RNA treatment and pretreatment with inhibitors. The induction of iNOS and the associated nitric oxide production in response to H. pylori-LPS stimulation were inhibited by declines in not only TLR4 but also TLR2. Increased expression of TLR2 was identified in H. pylori-infected human gastric mucosa. TLR4 signaling initiated by H. pylori-LPS and propagated via extracellular signal-regulated kinase and NF-kappaB activation induced TLR2 expression in gastric epithelial cells. Induced TLR2 cooperated with TLR4 to amplify iNOS induction. This positive correlation may constitute a mechanism for stimulating the innate immune response against various bacterial pathogens, including H. pylori-LPS.

The endoscopic recognition of linear furrows, concentric rings, and white exudates is important in the diagnosis of eosinophilic esophageal inflammation. In a subset of patients this condition improves clinicopathologically with PPI treatment, and typical EoE, as strictly defined by unresponsiveness to PPI, appears to be a rather rare condition.

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Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori–induced expression of the intestinal epithelial–specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-κB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-κB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-κB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori–induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori–infected patients to limit their risks of accumulating precancerous gastric lesions.

Atrophic gastritis (AG) is a well-recognized high-risk condition for developing gastric cancer (GC). Gastrin 17 (G17), a hormone secreted from antral G cells, regulates gastric acid secretion, and its serum level is a possible indicator of antral atrophy. Serum pepsinogen is well established as the indicator of AG involving the corpus. Here we investigated whether serum PG and G17 levels would be useful for determining the topographic pattern of AG and estimating the risk of GC. Enrolled were 122 Japanese patients with early GC (114 well-to moderate-differentiated cancers and 8 poorly-differentiated cancers). In addition, 178 subjects without GC were recruited as control from those undergoing endoscopic examination (non-GC group). All subjects were histologically assigned to the following four groups: non-AG, antrum-predominant AG, corpus-predominant AG, and multifocal AG, affecting the antrum and corpus. Serum concentrations of pepsinogen and G17 were determined using ELISA. Multifocal AG was more frequent in the GC group than in the adjusted non-GC group, and had the highest risk of GC (OR 25.1). Serum G17 was significantly decreased with the exacerbation of antral atrophy in the coexistence of corpus atrophy. Serum biomarker profiles showed that the low levels of pepsinogen and G17 could discriminate between multifocal AG and other types of AG, but not with pepsinogen level alone. Serologically defined multifocal AG had the highest cancer risk among other serologically defined AG groups (OR 26.9). In conclusion, the low serum levels of pepsinogen and G17 are predictive of extensive gastric atrophy with high-risk of early GC.

We demonstrated for the first time that scheduled EBD combined with oral agent tranilast might be effective and safe for improving the efficacy of stricture dilation after esophageal ESD.

This prospective study showed that continuation of antithrombotics did not increase the bleeding risk after upper gastrointestinal endoscopic biopsy.

The integrity of gastric mucosa during endotoxemia is maintained by the balance of inflammatory mediators, such as prostanoids originated from cyclooxygenase-2 (COX-2) and nitric oxide (NO) from inducible nitric-oxide synthase (iNOS). Thus, we elucidated in vivo cross talk between prostanoids and NO in gastric mucosa during endotoxemia, using an iNOS-specific inhibitor, N-(3-(aminomethyl)benzyl)acetamidine (1400W); a nonspecific COX inhibitor, indomethacin; and a COX-2-specific inhibitor, N-(2-[cyclohexyloxy]-4-nitrophenyl)methanesulfonamide (NS-398). Gastric mucosal NO and prostaglandin E2 (PGE2), a predominant product of COX, expressed as mean Ϯ S.D. of five rats per group, were assayed by electron paramagnetic resonance spectrometry and enzyme immunoassay technique, respectively. The levels of NO and PGE2 increased gradually up to 6 h after administration of bacterial lipopolysaccharide (LPS) (NO: control, 0.35 Ϯ 0.16; 6 h, 13.3 Ϯ 3.3 nmol/g tissue/30 min; and PGE2: control, 288 Ϯ 16; 6 h, 806 Ϯ 15 pg/g tissue). Pretreatment with 1400W decreased the increase in NO level without any effect on the PGE2 level (NO, 4.0 Ϯ 0.4 nmol/g tissue/30 min; PGE2, 788 Ϯ 26 pg/g tissue). In contrast, treatment with indomethacin and NS-398 inhibited not only PGE2 level but also NO level in a dose-dependent manner without any significant effect on both iNOS and COX protein and mRNA expression. These results demonstrate that in the LPStreated rat gastric mucosa, PGE2 enhances the release of NO after activation of iNOS, although NO produced by iNOS does not stimulate the release of PGE2 by COXs. The effect of COX activity on iNOS-NO pathway can be important in the regulation of gastric mucosal integrity in inflammatory states.