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Background: Excessive ethanol consumption results in gastric mucosa damage, which could further develop into chronic gastritis, peptic ulcer, and gastric cancer in humans. Gentiopicroside (GPS), a major active component of Gentianae Macrophyllae radix, was reported to play a critical role in anti-inflammation. In the study, we aimed to investigate the functional role and underlying mechanism of GPS in ethanol-induced gastritis., Methods: A model of gastritis was created by ethanol in C57BL/6 mice. Enzyme-linked immunosorbent assay was used to determine the concentration of TNF-α, IL-1β, IL-8, and IL-10., Results: We found that GPS treatment significantly ameliorated ethanol-induced gastritis in mice, with lower production of pro-inflammatory cytokine TNF-α, IL-1β, and IL-8 and higher levels of anti-inflammatory cytokine IL-10. The anti-inflammatory effect of GPS was further confirmed in vitro in ethanol-treated human gastric mucosal GES cells. Mechanistically, we demonstrated that GPS regulated matrix metallopeptidase expression and pERK1/2 signaling. Knockdown of matrix metallopeptidase 10 (MMP-10) greatly improved cell survival and suppressed inflammatory response in ethanol-treated GES cells. Moreover, inhibition of pERK1/2 signaling using U0126 decreased the expression of MMP-10 in ethanol-induced gastritis. U0126 treatment also suppressed the expression of TNF-α, IL-1β, and IL-8, and enhanced IL-10 expression in mice gastric mucosa., Conclusions: Taken together, our findings suggest that GPS ameliorates ethanol-induced gastritis via regulating MMP-10 and pERK1/2 signaling, which might provide a promising therapeutic drug for ethanol-induced gastritis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus H 2 O 2 , is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox -/- gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox -/- mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.

Gastric cancers are the third leading cause of cancer mortality in the world. Helicobacter pylori causes over 60 % of all stomach cancers. Colonization of the gastric mucosa by H. pylori results in increased DNA damage. Repair of DNA damage may also be reduced by H. pylori infection. Reduced DNA repair in combination with increased DNA damage can cause carcinogenic mutations. During progression to gastric cancer, gastric epithelium goes through stages of increasing pathology. Determining the levels of DNA repair enzymes during progression to gastric cancer could illuminate treatment approaches. Our aim is to determine the level of gastric expression of DNA repair proteins ERCC1 (a nucleotide excision repair enzyme) and PMS2 (a mismatch repair enzyme) in the presence of H. pylori infection at successive stages of gastric pathology and in gastric cancers. We analyzed gastric tissues of 300 individuals, including 30 without dyspepsia, 200 with dyspepsia and 70 with gastric cancers. The presence of H. pylori, gastric pathology and expression of DNA repair proteins ERCC1 and PMS2 were evaluated. Infection by H. pylori carrying the common cagA gene reduced median nuclear expression of ERCC1 and PMS2 to less than 20 % and 15 % of normal, respectively, in all pathologic stages preceding cancer. ERCC1 and PMS2 nuclear expression was 0-5 % of normal in gastric cancers. H. pylori can cause deficiency of ERCC1 and PMS2 protein expression. These deficiencies are associated with gastric pathology and cancer. This reduction in DNA repair likely causes carcinogenic mutations. Substantially reduced ERCC1 and PMS2 expression appears to be an early step in progression to H. pylori-induced gastric cancer., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Helicobacter pylori infection always induces gastritis, which may progress to ulcer disease or cancer. The mechanisms underlying mucosal injury by the bacteria are incompletely understood. Here, we identify a novel pathway for H. pylori -induced gastric injury, the impairment of maturation of the essential transport enzyme and cell adhesion molecule, Na-K-ATPase. Na-K-ATPase comprises α- and β-subunits that assemble in the endoplasmic reticulum (ER) before trafficking to the plasma membrane. Attachment of H. pylori to gastric epithelial cells increased Na-K-ATPase ubiquitylation, decreased its surface and total levels, and impaired ion balance. H. pylori did not alter degradation of plasmalemma-resident Na-K-ATPase subunits or their mRNA levels. Infection decreased association of α- and β-subunits with ER chaperone BiP and impaired assembly of α/β-heterodimers, as was revealed by quantitative mass spectrometry and immunoblotting of immunoprecipitated complexes. The total level of BiP was not altered, and the decrease in interaction with BiP was not observed for other BiP client proteins. The H. pylori -induced decrease in Na-K-ATPase was prevented by BiP overexpression, stopping protein synthesis, or inhibiting proteasomal, but not lysosomal, protein degradation. The results indicate that H. pylori impairs chaperone-assisted maturation of newly made Na-K-ATPase subunits in the ER independently of a generalized ER stress and induces their ubiquitylation and proteasomal degradation. The decrease in Na-K-ATPase levels is also seen in vivo in the stomachs of gerbils and chronically infected children. Further understanding of H. pylori -induced Na-K-ATPase degradation will provide insights for protection against advanced disease. NEW & NOTEWORTHY This work provides evidence that Helicobacter pylori decreases levels of Na-K-ATPase, a vital transport enzyme, in gastric epithelia, both in acutely infected cultured cells and in chronically infected patients and animals. The bacteria interfere with BiP-assisted folding of newly-made Na-K-ATPase subunits in the endoplasmic reticulum, accelerating their ubiquitylation and proteasomal degradation and decreasing efficiency of the assembly of native enzyme. Decreased Na-K-ATPase expression contributes to H. pylori -induced gastric injury.

Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. Kras activation and Pten deletion are observed in intestinal-type gastric cancer, and Cdh1 mutation is associated with diffuse-type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a Tff1-Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomach, Tff1-Cre-mediated recombination was most evident in the pit lineage in the corpus and in entire antral glands; recombination was also observed in a few gastric chief and parietal cells. Outside the stomach, recombination was patchy throughout the intestines, and particularly frequently in the duodenum (Brunner glands), cecum, and proximal colon. In the stomachs of Tff1-Cre;LSL-Kras G12D mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue-positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide-expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Corpus-derived organoids from Tff1-Cre;LSL-Kras G12D mice exhibited accelerated growth and abnormal differentiation with a loss of chief and parietal cell markers. Tff1-Cre;Pten flox/flox mice displayed similar changes to those seen in Tff1-Cre;LSL-Kras G12D mice, both with aberrant ERK activation within 3 months. In contrast, Tff1-Cre;Cdh1 flox/flox mice initially showed signet ring-like cells that were rapidly lost with disruption of the mucosal surface, and later developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in Tff1-Cre;Cdh1 flox/flox mice was completely replaced by squamous epithelium which expanded from the forestomach. Tff1-Cre mice offer an additional useful tool for studying gastric carcinogenesis both in vivo and in vitro. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background & Aims: Chronic gastrointestinal inflammation increases the risk of cancer by mechanisms that are not well understood. Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-binding enzyme that regulates the immune response via catabolization and regulation of tryptophan availability for immune cell uptake. IDO1 expression is increased during the transition from chronic inflammation to gastric metaplasia. We investigated whether IDO1 contributes to the inflammatory response that mediates loss of parietal cells leading to metaplasia., Methods: Chronic gastric inflammation was induced in Ido1 -/- and CB57BL/6 (control) mice by gavage with Helicobacter felis or overexpression of interferon gamma in gastric parietal cells. We also performed studies in Jh -/- mice, which are devoid of B cells. Gastric tissues were collected and analyzed by flow cytometry, immunostaining, and real-time quantitative polymerase chain reaction. Plasma samples were analyzed by enzyme-linked immunosorbent assay. Gastric tissues were obtained from 20 patients with gastric metaplasia and 20 patients without gastric metaplasia (controls) and analyzed by real-time quantitative polymerase chain reaction; gastric tissue arrays were analyzed by immunohistochemistry. We collected genetic information on gastric cancers from The Cancer Genome Atlas database., Results: H felis gavage induced significantly lower levels of pseudopyloric metaplasia in Ido1 -/- mice, which had lower frequencies of gastric B cells, than in control mice. Blood plasma from H felis-infected control mice had increased levels of autoantibodies against parietal cells, compared to uninfected control mice, but this increase was lower in Ido1 -/- mice. Chronically inflamed stomachs of Ido1 -/- mice had significantly lower frequencies of natural killer cells in contact with parietal cells, compared with stomachs of control mice. Jh -/- mice had lower levels of pseudopyloric metaplasia than control mice in response to H felis infection. Human gastric pre-neoplasia and carcinoma specimens had increased levels of IDO1 messenger RNA compared with control gastric tissues, and IDO1 protein colocalized with B cells. Co-clustering of IDO1 messenger RNA with B-cell markers was corroborated by The Cancer Genome Atlas database., Conclusions: IDO1 mediates gastric metaplasia by regulating the B-cell compartment. This process appears to be associated with type II hypersensitivity/autoimmunity. The role of autoimmunity in the progression of pseudopyloric metaplasia warrants further investigation., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Context: Aloe has been used for the prevention and cure of various diseases and symptoms including burns, injuries, oedema and pain., Objective: This study determines the specific inhibitory activity of matrix metalloproteinase (MMP)-9 induced by the low molecular-weight gel fraction of Aloe vera (L.) Burm.f. (lgfAv) on alcohol-induced acute gastric lesions., Materials and Methods: We examined the protective effects of oral (p.o.) administration of lgfAv (molecular weight cutoff <50.0 kDa, 150.0 mg/kg body weight) in a Balb/c mouse model of alcohol-induced acute gastritis for 1 h exposure. By measuring ulcer index, we compared the antiulcerative activity of the fraction. mRNA expression and immunohistochemical analysis of various biomarkers were performed., Results: The lgfAv-treated mice exhibited drastically fewer ulcer lesions than the untreated control mice did. It featured that lgfAv lessened the ulcer lesions than their relevant controls. Moreover, the transcriptional level of MMP-9 was completely alleviated by lgfAv treatment in alcohol-treated gastritis-induced mice., Discussion: The transcriptional level of MMP-9 was significantly alleviated by lgfAv treatment of the model. However, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry experiments revealed that lgfAv treatment in mucosal tissues had the potential to inhibit the mRNA and protein expression levels of MMP-9, respectively. The protein expression of MMP-9 was closely associated with lgfAv-induced gastroprotection against alcohol-induced gastric lesions., Conclusions: The present findings suggest that lgfAv has the potential to alleviate alcohol-induced acute gastric lesions, which is mediated in part, mainly by the suppression of the mRNA expression of MMP-9.

Objective: To assess whether helicobacter pylori was associated with CDX2 expression in intestinal metaplasia, atrophic gastritis, dysplasia and gastric cancer., Study Design: Cross-sectional study., Place and Duration of Study: Department of Pathology, The First Hospital of Jilin University, Changchun, China, from August 2016 to January 2017., Methodology: CDX2 expression was evaluated in 62 gastric antral biopsies; including 32 cases of intestinal metaplasia (IM) and 10 cases each of atrophic gastritis (AG), dysplasia and gastric cancer. Hematoxylin and Eosin staining was used to detect H.pyloriand immunohistochemistry was performed to observe CDX2 in the samples., Results: Of the 62 patients inducted in the study, CDX2 expression was observed in 53 (85.5%). Mean age of these patients was 59 years (s.d.:11.3; range: 38-87) and included 32 males (60.38%) and 21 females (39.62%). However, age and gender were not found to be significantly associated with expression of CDX2 (p >0.05). CDX2 was very frequently expressed in individuals with IM (90.6%). Most of the patients with IM were males (17/29) as compared to females (12/29). However, the difference was not statistically significant (p=0.568). Only 4 out of 29 IM CDX2 positive specimens tested positive for H.pylori(p=1.0)., Conclusion: CDX2 is highly expressed along the atrophic gastritis-metaplasia-dysplasia-cancer sequential. Though CDX2 expression is quite dominant in IM, but its expression is not associated with H.pyloriinfection.

Helicobacter pylori infect millions of people around the world. It occupies a niche in the human gastrointestinal tract characterized by high expression of a repertoire of carbohydrates. ABO and Lewis histo-blood group systems are controlled by genes coding for functional glycosyltransferases which synthesize great diversity of related fucosylated carbohydrate in different tissues, including gastrointestinal mucosa, and exocrine secretions. The structural diversity of histo-blood group carbohydrates is highly complex and depends on epistatic interactions among gene-encoding glycosyltransferases. The histo-blood group glycosyltransferases act in the glycosylation of proteins and lipids in the human gastrointestinal tract allowing the expression of a variety of potential receptors in which H. pylori can adhere. These oligosaccharide molecules are part of the gastrointestinal repertoire of carbohydrates which act as potential receptors for microorganisms, including H. pylori. This Gram-negative bacillus is one of the main causes of the gastrointestinal diseases such as chronic active gastritis, peptic ulcer, and cancer of stomach. Previous reports showed that some H. pylori strains use carbohydrates as receptors to adhere to the gastric and duodenal mucosa. Since some histo-blood group carbohydrates are highly expressed in one but not in others histo-blood group phenotypes it has pointed out that quantitative differences among them influence the susceptibility to diseases caused by H. pylori. Additionally, some experiments using animal model are helping us to understand how this bacillus explore histo-blood group carbohydrates as potential receptors, offering possibility to explore new strategies of management of infection, disease treatment, and prevention. This text highlights the importance of structural diversity of ABO and Lewis histo-blood group carbohydrates as facilitators for H. pylori infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Gastritis is preponderantly characterized by inflammation of the lining epithelial layer and the chronic gastritis is considered as a pre-cancer lesion. For many centuries olive (Olea europaea) leaf has been used for its putative health potential, nonetheless, to date, the gastroprotective effects of olive leaves have not been studied yet. Hence, in this study we investigated whether olive leaf extract (OLE) could protect gastric mucosa against HCl/ethanol-induced gastric mucosal damage in rats. Hcl/ethanol administration caused significant damage to the gastric mucosa, as confirmed by gastric ulcer index and histological evaluation. However, this damage was largely prevented by pre-administering 20mg/kg omeprazole or 100mg/kg OLE. Interestingly, the damage was completely prevented by pre-administering 200 and 300mg/kg OLE. Moreover, OLE attenuated the inflammatory response by decreasing nuclear factor-κB (NF-κB), cycloxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expressions, and down-regulating inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β) in gastric mucosa. The gastroprotective mechanism of OLE involved the promotion of enzymatic and nonenzymatic molecules (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione reduced form), promoting nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, halting lipid peroxidation and preventing the overproduction of nitric oxide. Together, our findings clearly demonstrated that OLE could prevent HCl/ethanol-induced gastritis by attenuating inflammation and oxidant/antioxidant imbalance. Indeed, OLE could potentially be useful as a natural therapy for gastritis., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.

Background/aims: The aim of this study was to evaluate the effect of the synthetic S-allyl-L-cysteine (SAC) PMK-S005 on gastric acid secretion, inflammation, and antioxidant enzymes in aging rats., Methods: The rats were divided into four groups at 31 weeks of age and were continuously fed a diet containing a vehicle control, PMK-S005 (5 or 10 mg/kg), or lansoprazole (5 mg/kg). Gastric acid secretion and connective tissue thickness of the lamina propria were evaluated at 74 weeks and 2 years of age. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and COX-2 levels were measured by using enzyme-linked immunosorbent assays (ELISAs) or Western blot assays. Levels of antioxidant enzymes, including heme oxyganase 1 (HO-1) and, Nad(p)h: quinone oxidoreductase 1 (NQO-1), were also measured., Results: As the rats aged, gastric acid secretion significantly decreased, and the connective tissue of the lamina propria increased. However, 74-week-old rats in the PMK-S005 group exhibited greater levels of gastric acid secretion than those of the control and lansoprazole groups. The increase of TNF-α, IL-1β, and COX- 2 expression in 74-week and 2-year-old control rats were inhibited by PMK-S005. In addition, the decrease in HO-1 and NQO-1 protein expression that occurred with aging was inhibited by PMK-S005 in the 74-week-old rats., Conclusions: These results suggest that PMK-S005 has therapeutic potential as an antiaging agent to ameliorate age-related gastric acid secretion, inflammation, and oxidative stress in the stomach.

Ethnopharmacological Relevance: Xanthium strumarium L. (Asteraceae) has traditionally been used to treat bacterial infections, nasal sinusitis, urticaria, arthritis, chronic bronchitis and rhinitis, allergic rhinitis, edema, lumbago, and other ailments. However, the molecular mechanisms by which this plant exerts its anti-inflammatory effects are poorly characterized. Here we studied the immunopharmacological activities of the methanolic extract of the aerial parts of this plant (Xs-ME) and validated its pharmacological targets., Materials and Methods: To evaluate the anti-inflammatory activity of Xs-ME, we employed lipopolysaccharide (LPS)-treated macrophages and an HCl/EtOH-induced mouse model of gastritis. We also used HPLC to identify the potentially active anti-inflammatory components of this extract. The molecular mechanisms of its anti-inflammatory activity were studied by kinase assays, reporter gene assays, immunoprecipitation analysis, and overexpression of target enzymes., Results: The production of nitric oxide (NO) and prostaglandin E2 (PGE2) were both suppressed by Xs-ME. Moreover, orally administered Xs-ME ameliorated HCl/EtOH-induced gastric lesions. Furthermore, this extract downregulated the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and reduced the nuclear levels of NF-κB. Signaling events upstream of NF-κB translocation, such as phosphorylation of AKT and the formation of PDK1-AKT signaling complexes, were also inhibited by Xs-ME. Moreover, Xs-ME suppressed the enzymatic activity of PDK1. Additionally, PDK1-induced luciferase activity and Akt phosphorylation were both inhibited by Xs-ME. We also identified the polyphenol resveratrol as a likely active anti-inflammatory component in Xs-ME that targets PDK1., Conclusion: Xs-ME exerts anti-inflammatory activity in vitro and in vivo by inhibiting PDK1 kinase activity and blocking signaling to its downstream transcription factor, NF-κB., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

OBJECTIVE To compare expression, activity, and fecal concentration of intestinal alkaline phosphatase (IAP) between healthy dogs and dogs with chronic enteropathy (CE). ANIMALS 9 healthy university-owned Beagles and 109 healthy client-owned dogs (controls) and 28 dogs with CE (cases). PROCEDURES Cases were defined as dogs with persistent (> 3 weeks) gastrointestinal signs that failed to respond to antimicrobials and anti-inflammatory doses of prednisolone or dietary trials, did not have mechanical gastrointestinal abnormalities as determined by abdominal radiography and ultrasonography, and had a diagnosis of lymphoplasmacytic enteritis or eosinophilic gastroenteritis on histologic examination of biopsy specimens. Duodenal and colonic mucosa biopsy specimens were obtained from the 9 university-owned Beagles and all cases for histologic examination and determination of IAP expression (by real-time quantitative PCR assay) and activity (by enzyme histochemical analysis). Fecal samples were obtained from all dogs for determination of fecal IAP concentration by a quantitative enzyme reaction assay. RESULTS For dogs evaluated, IAP expression and activity were localized at the luminal side of epithelial cells in the mucosa and intestinal crypts, although both were greater in the duodenum than in the colon. Active IAP was detected in the feces of all dogs. Intestinal alkaline phosphatase expression and activity were lower for cases than for controls, and fecal IAP concentration for dogs with moderate and severe CE was lower than that for dogs with mild CE. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that dogs with CE had impaired IAP expression and activity. Additional research is necessary to elucidate the role of IAP in the pathogenesis of CE.

Unlabelled: We aimed to study MLH1 and MGMT methylation status in Helicobacter pylori-associated chronic gastritis in Egyptian patients with and without gastric cancer. 39 patients were included in our study. They were divided into 2 groups; patients without (group I) and with gastric adenocarcinoma (group II). Patients were subjected to clinical examination, abdominal ultrasound and upper endoscopy for gastric biopsy. Biopsies were subjected to urease test, histological examination, and DNA purification. H. pylori, Braf, Kras, MLH1 and MGMT methylation were assessed by quantitative PCR. DNA sequencing was performed to assess Braf and Kras genes mutation. qPCR of H. pylori was significantly higher in patients with adenocarcinoma (group II) than those without adenocarcinoma (group I); with a p < 0.001 as well as in patients with age above 50 years with a p value = 0.008. By applying logistic regression analysis it was reported that the H. pylori qPCR is a significant predictor to the adenocarcinoma with OR = 1.025 (95 % CI: 1. 002-1.048), with sensitivity of 90 % and specificity of 100 %. Adenocarcinoma patients had a significantly higher mean age and levels of H. Pylori, Braf, K-ras, methylated MGMT and methylated MLH1 than those of gastritis patients. DNA sequence analysis of Braf (codon 12) and Kras (codon 600) had genes mutation in gastric adenocarcinoma versus chronic gastritis., Conclusion: H. pylori may cause epigenetic changes predisposing the patients to cancer stomach. Estimation of H. pylori by qPCR can be a good predictor to adenocarcinoma. Braf and Kras genes mutation were reveled in gastritis and adenocarcinoma patients.

Human gastric diseases have shown significant changes in the activity and expression of superoxide dismutase (SOD) isoforms. The aim of this study was to detect Mn-SOD activity and expression in the tissue of gastric mucosa, primarily in chronic gastritis (immunohistochemical Helicobacter pylori-negative gastritis, without other pathohistological changes) and to evaluate their possible connection with pathohistological diagnosis. We examined 51 consecutive outpatients undergoing endoscopy for upper gastrointestinal symptoms. Patients were classified based on their histopathological examinations and divided into three groups: 51 patients (archive samples between 2004-2009) with chronic immunohistochemical Helicobacter pylori-negative gastritis (mononuclear cells infiltration were graded as absent, moderate, severe) divided into three groups. Severity of gastritis was graded according to the updated Sydney system. Gastric tissue samples were used to determine the expression of Mn-SOD with anti-Mn-SOD Ab immunohistochemically. The Mn-SOD expression was more frequently present in specimens with severe and moderate inflammation of gastric mucosa than in those with normal mucosa. In patients with normal histological finding, positive immunoreactivity of Mn-SOD was not found. Our results determine the changes in Mn-SOD expression occurring in the normal gastric mucosa that had undergone changes in the intensity of chronic inflammatory infiltrates in the lamina propria., (© 2016 APMIS. Published by John Wiley & Sons Ltd.)

Objectives: This study was done in order to investigate the effect of CYP2C19 genetic polymorphism on the cure rate of children who received proton pump inhibitors (PPI)-based triple therapy for treating Helicobacter pylori (H. pylori) infection., Methods: Participants included 100 children with H. pylori-positive gastritis diagnosed by endoscopy and biopsy in addition to H. pylori stool antigen test. Cure rate was assessed after 1 month of completion of a triple treatment course for 14 days. CYP2C19 polymorphism was analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method., Results: Results showed that cases with a CYP2C19 genotypic status consistent with the heterozygote extensive metabolizers (HetEMs) had a higher cure rate of H. pylori when compared with the homozygote extensive metabolizers (HomEMs) although it was statistically nonsignificant (84.6 vs. 69.2). In addition, the poor metabolizers (PMs) had a higher cure rate compared with those of the HomEMs which was also statistically nonsignificant (77.8 vs. 69.2). The cure rate was also higher among both the groups of HetEMs and PMs combined together compared to the HomEMs (OR = 2.15, p > 0.05). Comparing cases regarding their age, gender, and severity of H. pylori gastritis revealed a better cure rate in the age group >10 years, in females and in mild and moderate cases than other cases although statistically nonsignificant., Conclusion: The higher cure rate of H. pylori infection using the triple therapy for 2 weeks among HetEMs and PMs cases compared to the HomEMs might warrant a need for a therapy augmentation or modification for the HomEMs.

Background & Aims: The gastric cancer-causing pathogen Helicobacter pylori up-regulates spermine oxidase (SMOX) in gastric epithelial cells, causing oxidative stress-induced apoptosis and DNA damage. A subpopulation of SMOX(high) cells are resistant to apoptosis, despite their high levels of DNA damage. Because epidermal growth factor receptor (EGFR) activation can regulate apoptosis, we determined its role in SMOX-mediated effects., Methods: SMOX, apoptosis, and DNA damage were measured in gastric epithelial cells from H. pylori-infected Egfr(wa5) mice (which have attenuated EGFR activity), Egfr wild-type mice, or in infected cells incubated with EGFR inhibitors or deficient in EGFR. A phosphoproteomic analysis was performed. Two independent tissue microarrays containing each stage of disease, from gastritis to carcinoma, and gastric biopsy specimens from Colombian and Honduran cohorts were analyzed by immunohistochemistry., Results: SMOX expression and DNA damage were decreased, and apoptosis increased in H. pylori-infected Egfr(wa5) mice. H. pylori-infected cells with deletion or inhibition of EGFR had reduced levels of SMOX, DNA damage, and DNA damage(high) apoptosis(low) cells. Phosphoproteomic analysis showed increased EGFR and erythroblastic leukemia-associated viral oncogene B (ERBB)2 signaling. Immunoblot analysis showed the presence of a phosphorylated (p)EGFR-ERBB2 heterodimer and pERBB2; knockdown of ErbB2 facilitated apoptosis of DNA damage(high) apoptosis(low) cells. SMOX was increased in all stages of gastric disease, peaking in tissues with intestinal metaplasia, whereas pEGFR, pEGFR-ERBB2, and pERBB2 were increased predominantly in tissues showing gastritis or atrophic gastritis. Principal component analysis separated gastritis tissues from patients with cancer vs those without cancer. pEGFR, pEGFR-ERBB2, pERBB2, and SMOX were increased in gastric samples from patients whose disease progressed to intestinal metaplasia or dysplasia, compared with patients whose disease did not progress., Conclusions: In an analysis of gastric tissues from mice and patients, we identified a molecular signature (based on levels of pEGFR, pERBB2, and SMOX) for the initiation of gastric carcinogenesis., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Helicobacter pylori is one of the most common causes of chronic gastritis. With the development of the disease cellular inflammatory infiltrates composed of lymphocytes, plasma cells, and macrophages are formed in epithelium and lamina propria of the stomach. These cells are capable of secreting a number of active substances, including inducible nitric oxide synthase (iNOS). We examined the relationship between H. pylori and secretion of iNOS by cells of inflammatory infiltrates in chronic gastritis by light microscopy and immunohistochemistry. The data obtained indicate that stimulation of H. pylori immune system cells of the host organism during development of chronic gastritis causes increase in number of macrophages and lymphocytes in the inflammatory infiltrate of the gastric mucosa. This is accompanied with increased expression of inducible NO-synthase with excess free radicals in the tissues, which leads to secondary alterations and exacerbates the inflammation with impaired regeneration processes.

Human and animals studies support the idea that there is a gender-related co-morbidity of pain-related and inflammatory gastrointestinal (GI) diseases with psychological disorders. This co-morbidity is the evidence for the existence of GI-brain axis which consists of immune (cytokines), neural (vagus nerve) and neuroendocrine (HPA axis) pathways. Psychological stress causes disturbances in GI physiology, such as altered GI barrier function, changes in motility and secretion, development of visceral hypersensitivity, and dysfunction of inflammatory responses. Whether GI inflammation would exert impact on psychological behavior is not well established. We examined the effect of experimental gastritis on anxiety- and depression-like behaviors in male and female Sprague-Dawley rats, and evaluated potential mechanisms of action. Gastritis was induced by adding 0.1% (w/v) iodoacetamide (IAA) to the sterile drinking water for 7 days. Sucrose preference test assessed the depression-like behavior, open field test and elevated plus maze evaluated the anxiety-like behavior. IAA treatment induced gastric inflammation in rats of either gender. No behavioral abnormality or dysfunction of GI-brain axis was observed in male rats with IAA-induced gastritis. Anxiety- and depression-like behaviors were apparent and the HPA axis was hyperactive in female rats with IAA-induced gastritis. Our results show that gastric inflammation leads to anxiety- and depression-like behaviors in female but not male rats via the neuroendocrine (HPA axis) pathway, suggesting that the GI inflammation can impair normal brain function and induce changes in psychological behavior in a gender-related manner through the GI-to-brain signaling.

Aim: To compare matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in gastric ulcer (GU) and chronic superficial gastritis (CSG)., Methods: This study enrolled 63 patients with GU and 25 patients with CSG. During upper gastroduodenal endoscopy, we took samples of gastric mucosa from the antrum and ulcer site from patients with GU, and samples of antral mucosa from patients with CSG. Mucosal biopsy tissues were cultured for 24 h, and the culture supernatant was measured for levels of MMP-9 and TIMP-1. After receiving eradication therapy for Helicobacter pylori (H. pylori) and 8 wk proton-pump inhibitor therapy for GU, follow-up endoscopy examination was performed after 6 mo and whenever severe symptoms occurred., Results: Levels of MMP-9 and TIMP-1 at the ulcer site or in the antrum were significantly higher in GU than CSG patients. MMP-9 levels at the ulcer site were significantly higher than in the antrum in GU patients, and had a significantly positive correlation with TIMP-1. MMP-9 levels were significantly higher in H. pylori-positive than H. pylori-negative GU and CSG patients. Levels of MMP-9 or TIMP-1 at the ulcer site were associated with the histological severity of activity and inflammation. About 57 GU patients were followed up, and seven had GU recurrence. H. pyloriinfection and MMP-9 levels were risk factors for the recurrence of GU adjusted for age and sex by multiple logistic regression analysis., Conclusion: MMP-9 may perform an important function in gastric ulcer formation and recurrence.

Background: CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of IL-17 in inflammatory response to H. pylori colonization has been indicated. We investigated the influence of IL17A polymorphisms, -197 G > A (rs2275913) and *1249 C > T (rs3748067), on the methylation of DAPK and CDH1., Methods: Gastric mucosal samples were obtained from 401 subjects without malignancies. Methylation status of gene was determined by MSP. The genotyping of IL17A was performed by PCR-SSCP., Results: Methylations of DAPK and CDH1 were seen in 196 and 149 of all 401 subjects, respectively. Overall, *1249 T carrier was associated with a decreased risk for DAPK methylation, whereas -197 G > A was not. In the subjects older than 60 years old, *1249 T carrier was more strongly associated with gene methylation and -197 A carrier tended to be associated with an increased risk for CDH1 methylation. When evaluating by inflammation promoting haplotype (-197 mutant carrier with *1249 homozygote), this haplotype had a more strongly increased risk for both DAPK and CDH1 methylations in comparatively older subjects. Both atrophy and metaplasia scores were significantly increased with age in -197 A carrier or *1249 CC homozygote, whereas were not in -197 GG homozygote or *1249 T carrier. PG I/II ratio was more significantly decreased in -197 A carrier than in GG homozygote under influence of H. pylori infection., Conclusions: In -197 A allele carrier with *1249 CC homozygote, the methylations of both DAPK and CDH1 may be increased gradually, but more rapidly than the other genotypes, with age and altered gastric mucosal structure induced by H. pylori infection.

Background/aims: The risk of gastric cancer is increased in patients with intestinal metaplasia. Cyclooxygenase-2 activity is crucial for gastric cancer cell survival and proliferation. We aimed to assess cyclooxygenase-2 expression in patients with intestinal metaplasia or chronic active gastritis and in patients with or without a family history of gastric cancer, i.e. a first-degree relative with gastric cancer., Materials and Methods: One hundred and six patients with histologically proven intestinal metaplasia, chronic active gastritis or normal gastric mucosa were included. Immunohistochemical staining was performed using the immunoperoxidase method., Results: Cyclooxygenase-2 expression was detected in 23.1% of normal gastric mucosa, 70.6% of chronic active gastritis, and 90.5% of intestinal metaplasia patients. Cyclooxygenase-2 expression was significantly higher in intestinal metaplasia than in chronic active gastritis (p=0.018). Cyclooxygenase-2 expression was significantly more severe in the intestinal metaplasia group when compared to the chronic active gastritis group (p=0.017). Severe cyclooxygenase-2 expression (>60% of cells) was more frequent in the intestinal metaplasia group. Cyclooxygenase-2 expression was higher in the Helicobacter pylori-positive group when compared to the Helicobacter pylori-negative group (80.3% vs 57.1%, respectively; p=0.012). Cyclooxygenase-2 expression did not significantly differ according to presence of a first-degree relative with gastric cancer., Conclusions: Patients with intestinal metaplasia demonstrated increased presence and severity of cyclooxygenase-2 expression. Our findings suggest that cyclooxygenase-2 plays an important role in the stepwise process that eventually leads to gastric cancer. There was no statistically significant difference between the patients with and without a first-degree relative with a history of gastric cancer in terms of cyclooxygenase-2 expression.

Poly (ADP-ribose) polymerase 1 (PARP1), which plays a critical role in the base excision DNA repair mechanism, and matrix metallopeptidase 2 (MMP2), a member of the matrix metalloprotease family, are involved in tumor formation and metastasis, respectively. In the present study, the possible association of single nucleotide polymorphisms (SNPs) and gene-gene interaction between PARP1 and MMP2 with the increased incidence of gastric cancer (GC) development and lymph node metastasis (LNM) was investigated in a Korean population. Samples were obtained from 326 patients with chronic gastritis and 153 patients with GC and genotyped using the GoldenGate® method. The PARP1 rs1136410 genotype showed a significant association with the frequency of LNM of GC (odds ratio [OR] = 2.19, p = 0.02), LNM stage (p = 0.035), and tumor invasion (p = 0.035). The allele frequency of MMP2 rs243865 was not associated with the development of GC or with the development of LNM of GC. Epistasis between the PARP1 SNP and the MMP2 SNP was associated with the development of LNM of GC. The combination of the MMP2 rs243865 CC genotype and the PARP1 rs1136410 CC or CC+CT genotypes showed a high risk of LNM of GC (OR = 2.47, p = 0.01; OR = 2.28, p = 0.01, respectively). In summary, PARP1 is associated with the risk of LNM of GC and the stage of LNM and tumor invasion. Epistasis between PARP1 rs1136410 and MMP2 rs243865 increased the risk of LNM of GC.

We investigated the tumor suppressor activity and regulatory mechanism of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in gastric cancer; 15-PGDH expression was lost in 70.1% of malignant human gastric tissues, but was preserved in normal and metaplastic gastritis. KATO III and SNU-719 cells were transfected with pcDNA3.1-empty vector or an expression vector encoding wild-type 15-PGDH. In TUNEL assays apoptotic cell numbers were increased in KATO-PGDH-WT cells compared with control. We found that EGFR and ERK1/2 inhibitors clearly increased the expression of 15-PGDH in KATO III cells. Our findings demonstrate both downregulation and a tumor suppressor activity of 15-PGDH in gastric cancer.

Background: Helicobacter pylori causes gastritis and is the most important risk factor of peptic ulcer disease and gastric cancer. In chronic adulthood H. pylori infection some matrix metalloproteinases (MMPs), which are proteolytic metalloendopeptidases regulated by tissue inhibitors of metalloproteinases (TIMPs), are upregulated. Our aim was to determine circulating levels of MMPs and their regulators TIMP-1, human neutrophil elastase (HNE) and myeloperoxidase (MPO) in childhood H. pylori infection., Design and Methods: Twenty-six H. pylori positive and 34 H. pylori negative children whose H. pylori status was verified by histological examination of gastric biopsies were included. Serum samples were analysed by enzyme-linked immunosorbent assay., Results: Significantly decreased serum levels of TIMP-1 were detected in H. pylori-infected children (median, 97.50 ng/mL) as compared to H. pylori-negative children (median, 118.5 ng/mL, p = 0.003). However, there were no significant differences in serum levels of MMP-2, -7, -8, -9, and their regulators HNE and MPO between H. pylori-positive and -negative children., Conclusions: Differing from the recent findings in adulthood H. pylori infection, only circulating TIMP-1 levels were significantly different between H. pylori-positive and -negative children. Whether this reflects the first sign of a proteolytic cascade later leading to increased levels of MMPs remains to be shown.

Objective: To determine whether clinically normal dogs have lesions in the pylorus and duodenum and to examine the expression of cyclooxygenase (COX) isoforms in the pylorus and duodenum of these dogs., Animals: 27 clinically normal dogs., Procedures: Physical examination was performed on clinically normal dogs from animal shelters and research projects; the dogs were then euthanized. After the dogs were euthanized, the pylorus and duodenum were photographed and scored for gross appearance of lesions. Samples were obtained for histologic evaluation and determination of COX expression via western blot analyses. Tissues from the pylorus and duodenum were categorized as normal, inflamed, or eroded on the basis of histologic analysis. Each histologic category of tissue was then evaluated to determine the correlation with gross appearance and COX expression., Results: Of the 27 dogs, 5 had unremarkable histologic findings in the pylorus and duodenum. Inflammation was found in the pylorus of 10 dogs and in the duodenum of 5 dogs. Epithelial erosion was detected in the pylorus of 1 dog and in the duodenum of 3 dogs. Gross appearance was not significantly correlated with histologic appearance. Expression of COX-1 was not upregulated by inflammation, whereas COX-2 expression was increased by inflammation or erosion., Conclusions and Clinical Relevance: Dogs that appear to be clinically normal may have underlying gastroduodenal lesions associated with upregulation of COX-2. Because of the inability to determine this during routine physical examination, practitioners should be aware of this potential situation when prescribing COX inhibitors.

Background: Angiotensin II contributes to the pathogenesis of inflammation induced by ischemia-reperfusion (I/R) in various organs. Angiotensin II increases vascular permeability that initiates the inflammatory process and leads to the migration of inflammatory cells into the tissue. The aim of the present study was to investigate the effect of angiotensin II on ischemia-reperfusion induced expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in rat stomachs exposed to ischemia-reperfusion., Methods: Wistar rats were randomly separated into five groups: sham operated, I/R, I/R plus candesartan (an AT1 receptor antagonist), I/R plus PD123319 (an AT2 receptor antagonist), and I/R plus captopril (an angiotensin-converting enzyme inhibitor). Candesartan (1mg/kg/d), PD123319 (3mg/kg/d), and captopril (20mg/kg/d) were given subcutaneously twice a day for 5 d before I/R. The rats were submitted to gastric ischemia by clamping the celiac artery for 30min followed by 24h reperfusion., Results: Candesartan decreased the neutrophil accumulation, iNOS expression, and increased NOx level, COX-2 expression in the gastric tissue exposed to I/R compared with I/R group. PD123319 did not change the neutrophil accumulation, iNOS expression, PGE(2), or NOx levels, but increased the expression of COX-2 in the gastric tissue exposed to I/R. However, captopril did not play any role in I/R induced change in gastric mucosa., Conclusions: The results suggest that Angiotensin II via angiotensin II type 1 receptor increases the accumulation of neutrophils and iNOS expression and plays a significant role in mediating inflammation in gastric mucosa exposed to I/R., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background & Aims: The gastric epithelium genome undergoes extensive epigenetic alterations during Helicobacter pylori-induced gastritis. Expression of the gene encoding the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) might be reduced via hypermethylation of its promoter in patients with H pylori gastritis. We characterized expression of MGMT and its epigenetic regulation via CpG methylation in gastric tissue from patients with H pylori gastritis and investigated the effects of H pylori infection eradication on MGMT expression., Methods: Gastric biopsy samples were collected from patients with H pylori gastritis before and after eradication and from H pylori-negative control subjects. AGS cells were cocultured with H pylori to study the effects of H pylori infection on MGMT RNA, protein expression, and CpG methylation., Results: CpG methylation of MGMT was more frequent in the gastric mucosa of patients with H pylori gastritis (69.7%) than in those without (28.6%, P = .022). MGMT methylation was significantly reduced after H pylori eradication (from 70% to 48% of cases, P = .039), and mean levels of CpG methylation decreased from 12.6% to 5.7% (P = .025), increasing MGMT expression. MGMT methylation was significantly associated with CagA-positive H pylori (P = .035). H pylori reduced MGMT protein and RNA levels and induced MGMT CpG methylation in gastric AGS cells., Conclusions: H pylori gastritis, particularly in patients infected with H pylori CagA-positive strains, is associated with hypermethylation of MGMT and reduced levels of MGMT in the gastric epithelium. MGMT promoter methylation is partially reversible after eradication of H pylori infection. These data indicate that DNA repair is disrupted during H pylori gastritis, increasing mutagenesis in H pylori-infected gastric mucosa., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: To examine the rate of Helicobacter pylori infection and the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in gastric mucosa with intestinal metaplasia or dysplasia, and explore their correlations in precancerous gastric lesions., Methods: A total of 172 patients were included in the study. H. pylori infection was evaluated by hematoxylin-eosin and modified Giemsa staining. The expression of COX-2 and VEGF proteins was detected by immunohistochemistry., Results: The rates of H. pylori infection in gastric mucosal dysplasia (DYS), intestinal metaplasia in gastric mucosa (IM), chronic atrophic gastritis (CAG) and chronic superficial gastritis (CSG) patients were significant differences (P = 0.001). The average optical density (AOD) values of COX-2 staining in CSG, CAG, IM and DYS patients were 13.81 +/- 5.53, 45.28 +/- 21.44, 73.67 +/- 26.02 and 91.23 +/- 45.11, respectively, with significant differences among CSG, CAG and IM patients (P = 0.037, 0.001 and 0.047 for CSG vs CAG, CSG vs IM and CAG vs IM, respectively). The expression level of VEGF in DYS patients was significantly higher than those in other patients (P = 0.001, 0.001 and 0.001 for DYS vs CSG, DYS vs CAG and DYS vs IM, respectively). The expression levels of COX-2 in H. pylori-positive IM, CAG and DYS patients were significantly higher than those in H. pylori-negative counterparts (P = 0.043, 0.009, 0.001, respectively). Additionally, the expression level of COX-2 was positively correlated with that of VEGF with the aggravation of gastric mucosal lesions (r = 0.640, P = 0.006)., Conclusion: H. pylori infection might be able to induce the expression of COX-2 in precancerous gastric lesions, which in turn upregulates the expression of VEGF.

Aim: To assess expression of matrix metalloproteinases 2 (MMP2) and MMP9 in gastric cancer, superficial gastritis and normal mucosa, and to measure metalloproteinase activity., Methods: MMP2 and MMP9 mRNA expression was determined by quantitative real-time polymerase chain reaction. Normalization was carried out using three different factors. Proteins were analyzed by quantitative gelatin zymography (qGZ)., Results: 18S ribosomal RNA (18SRNA) was very highly expressed, while hypoxanthine ribosyltransferase-1 (HPRT-1) was moderately expressed. MMP2 was highly expressed, while MMP9 was not detected or lowly expressed in normal tissues, moderately or highly expressed in gastritis and highly expressed in cancer. Relative expression of 18SRNA and HPRT-1 showed no significant differences. Significant differences in MMP2 and MMP9 were found between cancer and normal tissue, but not between gastritis and normal tissue. Absolute quantification of MMP9 echoed this pattern, but differential expression of MMP2 proved conflictive. Analysis by qGZ indicated significant differences between cancer and normal tissue in MMP-2, total MMP-9, 250 and 110 kDa bands., Conclusion: MMP9 expression is enhanced in gastric cancer compared to normal mucosa; interpretation of differential expression of MMP2 is difficult to establish.

Unlabelled: Backgroud: Helicobacter pylori (Hp) rarely proliferates in patients with fundic gland polyps (FGPs). We recently found that FGPs express lysozyme, one of the natural defence substances against infection. We aimed to assess the degree of lysozyme expression in a cohort of consecutive FGPs., Materials and Methods: A total of 153 gastric biopsies were investigated: 93 with FGPs, 30 with normal mucosa (Nm), 15 with Hp-induced chronic gastritis (Hp-gastritis) and 15 with chronic gastritis without Hp infection (non-Hp-gastritis). Sections were stained with anti-lysozyme (muramidase)., Results: Lysozyme was slightly to moderately expressed in the surface and foveolar pits, being markedly expressed in the neck glands in Nm, in non-Hp and Hp-gastritis. The ratio of lysozyme neck glands-foveoli was higher in non-Hp than in Nm and even higher in Hp-gastritis. In FGPs, lysozyme was markedly expressed in the surface, the foveolar pits and the cells that partly or entirely covered the microcysts., Discussion and Conclusion: While the moderate expansion of the lysozyme-producing cells of the neck glands in Hp-gastritis might be insufficient to eradicate these bacteria, the overproduction of lysozyme in the epithelium covering FGP could be an explanation for the lack of Hp proliferation in these patients.

Helicobacter pylori-induced gastritis is the strongest singular risk factor for gastric adenocarcinoma. Matrix metalloproteinase-7 (MMP-7) is a proteolytic enzyme that can modify the intestinal microbial replicative niche as well as affect tumorigenesis, and H. pylori stimulates expression of MMP-7 in gastric epithelial cells in vitro. Utilizing a transgenic murine model of H. pylori-mediated injury, our experiments now show that gastric inflammation is increased within the context of MMP-7 deficiency, which involves both Th1- and Th17-mediated pathways. Enhanced gastritis in H. pylori-infected mmp-7-/- mice is strongly linked to accelerated epithelial cellular turnover. However, more severe inflammation and heightened proliferation and apoptosis are not dependent on MMP-7-mediated bacterial eradication. Collectively, these studies indicate that H. pylori-mediated induction of MMP-7 may serve to protect the gastric mucosa from pathophysiologic processes that promote carcinogenesis.

Immunological responses in the host can result in different disease outcomes of Helicobacter pylori-induced gastritis. Prostaglandin E2 derived from cyclooxygenase (COX) and prostaglandin E synthase contribute to gastric protection. Recently, prostaglandin D2 was shown to be involved in host immunity by chemotactic activity through chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), but its role in H. pylori-induced gastritis has not been clarified. We determined the expression levels of mRNAs for haematopoietic PGD synthase (H-PGDS) and lipocalin-type PGDS (L-PGDS), MIP-1 alpha, IFN-gamma, IL-4, and CDX2 in H. pylori-induced gastritis mucosa by quantitative RT-PCR. We found that L-PGDS was constitutively expressed in the epithelium of the glandular base. L-PGDS, but not H-PGDS, was induced on fibroblasts close to infiltrating cells in the H. pylori-infected gastric mucosa. These fibroblasts co-expressed COX-2. The level of L-PGDS mRNA expression decreased as gastritis became more severe. In most of the H. pylori-infected gastric mucosa, CCR5(+) cells had more actively infiltrated than had CRTH2(+) cells. However, the expression level of IFN-gamma was lower in the mucosa of the CRTH2(+) cells-dominantly infiltrating group than that of the less CRTH2-infiltrating group. Exogenously added PGD2 decreased the H. pylori-induced expression of IFN-gamma in peripheral blood mononuclear cells in vitro. The data suggest that PGD2 derived from the gastric mucosa and fibroblasts plays protective roles against inflammatory changes in H. pylori-induced gastritis.

Objectives: In this study, we analysed the expression of chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) genes in human gastric mucosa biopsies to establish the function of the corresponding enzymes in patients with gastritis associated or not with Helicobacter pylori infection., Methods: All 27 patients who took part in this study suffered from dyspeptic symptoms and postprandial pain, and sought to undergo gastroscopy. Antral and corpus biopsy specimens were taken to analyse stomach inflammation and detect H. pylori. RNA was extracted from antral gastric biopsies and expression of genes for CHIT1 and AMCase was analysed by quantitative real-time PCR., Results: In human inflamed gastric mucosa, CHIT1 and AMCase genes were expressed on average at a very low level (approximately 10 pg), and a correlation was shown among expression of CHIT1 gene and both positivity to the H. pylori test (P = 0.016) and gastric mucosa inflammation (P = 0.026). No correlation was found among AMCase gene expression and presence of H. pylori and inflammation., Conclusion: In this study, we showed the presence of CHIT1 and AMCase mRNA in gastric mucosa and the correlation with the presence of H. pylori was significant only for CHIT1 but not for AMCase expression. This study has shown for the first time that CHIT1 mRNA is present in gastric mucosa and confirms the participation of such an enzyme in the human immune response to inflammation in general, and to H. pylori infection in particular.

Selective COX-2 inhibitor, celecoxib, delays the healing of gastric ulcers by inhibiting prostaglandins synthesis. Therefore, the effect of celecoxib on normal and acid-challenged gastric mucosa was studied. Wistar rats were distributed into four groups: group-1 (vehicle treated), group-2 (celecoxib treated), group-3 (given 0.6N HCl) and group-4 (HCl+celecoxib treated). The gastric mucosa was assessed histopathologically and by evaluating gastric adherent mucus. To assess the role of oxidative stress, the levels of free radicals and antioxidants were measured. The histopathological examination showed mild inflammation in group-2, moderate inflammation in group-3 and severe inflammation in group-4. The results showed an increase in malondialdehyde and a decrease in gastric adherent mucus, nitrite, reactive thiols and glutathione in groups-2-4 as compared to control group. Activity of superoxide dismutase, catalase and glutathione-s-transferase was increased in all the groups except the group-1. The present study suggested that celecoxib aggravated the gastric damage caused by acid which may be mediated by altering the balance between free radicals and antioxidants.

The authors examined gastric biopsy specimens in 40 children aged 7 to 15 years: 30 children with the clinical diagnosis of chronic Helicobacter pylori (HP)-associated chronic gastritis (CG) and 10 children with functional dyspepsia (FD). In HP-associated CG, the gastric mucosa (GM) showed higher levels of matrix metalloproteinases (MMP) and their tissue inhibitor in the antral and fundal stomach than those in FD. There was an increased exposure of the markers MMP-9 and MMP-2, which was most evident in the fundal GM and correlated with the activity of inflammation. The significant elevation of TIMP-1 suggests that compensatory reactions are tense and may cause GM remodeling with enhanced collagen generation. The increased synthesis and activation of MMP-9 and MMP-2 can stimulate the realization of ulcerogenic properties of these metalloproteinases. The findings revealed the points of application of target drugs to some links of the pathogenesis of HP-associated CG in children.

Background/aims: Many patients who undergo distal gastrectomy develop remnant gastritis. The diagnosis of remnant gastritis is commonly established endoscopically. This report describes the correlation between endoscopic and histological findings of inflammatory changes in the remnant gastric mucosa., Methodology: Ninety-seven patients who underwent curative distal gastrectomy for gastric cancer, with radical lymphadenectomy, were studied. Endoscopy was performed 12 weeks after surgery. Patients with marked redness, erosion, or edema of the gastric remnant, as seen by endoscopy, were judged to have remnant gastritis, and were divided into group P (positive) and group N (negative). Histological remnant gastritis was evaluated with the neutrophil infiltration score based on the updated Sydney System for endoscopically taken biopsies. Cyclooxygenase (COX)-2 expression was evaluated immunohistochemically., Results: There was no difference in neutrophil infiltration or COX-2 expression scores between the patients in groups P and N. There was a significant correlation between neutrophil infiltration score and COX-2 expression score (p<0.001)., Conclusions: Endoscopic diagnosis of remnant gastritis was not correlated with histological findings. Histological remnant gastritis had significant correlation with COX-2 expression score, which was induced by inflammation. Therefore, proper diagnosis of remnant gastritis should be based on histological examination.

Aim: To evaluate the expression of eNOS and CD34 in gastric mucosa of Helicobacter pylori (H. pylori) positive diabetic patients, in correlation with glycaemic control and diabetic autonomic neuropathy (DAN)., Methods: We prospectively studied 49 diabetic type 2 patients (29 women, mean age 65.32+/-8.56 years) and 30 control subjects (15 women, mean age 58.47+/-12.40) that underwent endoscopy. Biopsies from the body and antrum were evaluated for H. pylori-gastritis, eNOS and angiogenic marker CD34 expression. Statistical analysis in correlation with mean glycosylated haemoglobin (HbA1c) of the last 3 years, and DAN was performed., Results: The two groups were matched for age (p=0.144), sex (p=0.335), H. pylori-infection (p=0.617) and degree of gastritis (p=0.78). eNOS and CD34 attenuated expression correlated with diabetes mellitus (DM) in the corpus (p=0.009 and 0.02, respectively). eNOS and CD34 expression was upregulated in H. pylori-positive controls but not in H. pylori-positive diabetic patients (p=0.010 and 0.007 for the corpus and p=0.036 and 0.047 for the antrum, respectively). eNOS expression correlated with good glycaemic control (GGC) in the gastric corpus (p<0.001) and antrum (p=0.0037) and with absence of DAN (p=0.009 and 0.036, respectively for the corpus and antrum)., Conclusion: Chronic glycaemic control affects eNOS expression and angiogenesis in the gastric mucosa of patients with type 2 DM. eNOS expression is not upregulated in H. pylori-positive diabetic patients.

A procedure has been developed for simultaneous determination of the activities of alpha-D- and beta-D-mannosidase in the biological fluids from the quantity of free 4-nitrophenol. The latter is released via enzymatic degradation of substrates of 4-nitrophenyl-alpha-D-mannose and 4-nitrophenyl-beta-D-mannose in individual incubation tests.

Aim: To study the value of serum biomarker tests to differentiate between patients with healthy or diseased stomach mucosa: i.e. those with Helicobacter pylori (H pylori) gastritis or atrophic gastritis, who have a high risk of gastric cancer or peptic ulcer diseases., Methods: Among 162 Japanese outpatients, pepsinogen I (Pg I) and II (Pg II) were measured using a conventional Japanese technique, and the European GastroPanel examination (Pg I and Pg II, gastrin-17 and H pylori antibodies). Gastroscopy with gastric biopsies was performed to classify the patients into those with healthy stomach mucosa, H pylori non-atrophic gastritis or atrophic gastritis., Results: Pg I and Pg II assays with the GastroPanel and the Japanese method showed a highly significant correlation. For methodological reasons, however, serum Pg I, but not Pg II, was twice as high with the GastroPanel test as with the Japanese test. The biomarker assays revealed that 5% of subjects had advanced atrophic corpus gastritis which was also verified by endoscopic biopsies. GastroPanel examination revealed an additional seven patients who had either advanced atrophic gastritis limited to the antrum or antrum-predominant H pylori gastritis. When compared to the endoscopic biopsy findings, the GastroPanel examination classified the patients into groups with "healthy" or "diseased" stomach mucosa with 94% accuracy, 95% sensitivity and 93% specificity., Conclusion: Serum biomarker tests can be used to differentiate between subjects with healthy and diseased gastric mucosa with high accuracy.

Background: The local angiotensin II system (LAS) has numerous functions, including the regulation of growth and differentiation in the gastrointestinal tract. Angiotensin II (AngII) may be generated by angiotensin-I-converting enzyme (ACE) or mast cell chymase (CMA1) and plays an important role in inflammatory processes, although opinions differ as to which AngII-generating enzyme is primarily associated with AngII-mediated effects. ACE inhibitors have been shown to have a protective or healing effect on gastric ulcers and colitis in animal models, which could be related to the local expression of ACE., Methods: The localisation of ACE and CMA1 was examined immunohistochemically in Helicobacter pylori gastritis, non-H. pylori gastritis, gastric ulcers and non-lesional gastric tissues. Using real-time qRT-PCR, ACE- and CMA1-mRNA expression in gastric cell lines were examined and changes in ACE levels after exposure to H. pylori or cytokines (IL-1beta, IL-6, IL-8, TNF, TGFbeta1) were quantified., Results: ACE and CMA1 were not expressed in the non-lesional foveolar epithelium. Cytoplasmic staining for ACE in fundic chief cells, and apical membranous expression of ACE in the mucin-secreting cells of the antral and pyloric region was observed. ACE was found in endothelial cells of the gastric ulcer granulation tissue and CMA1 was strongly expressed in mast cells. ACE but not CMA1 was expressed in the MKN28, N87 and MKN45 gastric cell lines, and ACE mRNA expression was regulated by both H. pylori and the cytokines., Conclusions: ACE in the gastric mucosa and the microvasculature of granulation tissue may represent a novel therapeutic target for the promotion of healing processes in gastritis and ulceration using ACE inhibitors or AT1R antagonists.

Chronic gastritis was morphologically verified in 119 patients. The count of parietal cells per 100 epitheliocytes of fundic glands was estimated. The sizes of parietal cells were measured by the morphometric computer program Videotest. For the diagnosis of autoimmune chronic gastritis (ACG), the level of antibodies to H+K+ATPase of gastric parietal cells in the patients' serum was determined by enzyme immunoassay. Childhood ACG has been found to be characterized by hyperplasia and structural changes of parietal cells with their preserved total count. The specific features of adult ACG include a significant reduction in the number of parietal cells, their sizes depending on the level of antiparietal autoantibodies, and marked ultrastructural changes as impairments in the differentiation and destruction of cytoplasm, organelles, and cell membrane.

Objectives: The present study examined the cross-talk between prostanoids and nitric oxide (NO) in human gastric biopsies during Helicobacter pylori infection., Subjects and Methods: A pool of 1 or 2 biopsies per patient (11 H. pylori positive and 9 H. pylori negative) were incubated in the medium with/without drugs, 1400W and NS-398, inhibitors of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Levels of NO and prostaglandin E(2) (PGE(2)), predominant products of activity of NOS and COX enzymes, were measured in the medium whereas the expressions of iNOS and COX protein, examined by Western blotting, were measured in the biopsies., Results: The 11 patients with H. pylori infection showed a marked expression of COX-2 and iNOS proteins and high levels of PGE(2) and NO, as a consequence of iNOS and COX-2 activation, while proteins were absent and the level of nitrite and PGE(2) was low in the 9 noninfected patients. The COX-2 inhibitor decreased both NO and PGE(2). The iNOS-specific inhibitor decreased NO but did not have any effect on the increase in gastric mucosal PGE(2). Both inhibitors had no effect on the protein level of these two enzymes., Conclusions: The data showed that COX-2 inhibitor might modulate the iNOS pathway, suggesting that COX-2 activity and/or its products may be related to the functional activation of iNOS but not to the expression of iNOS protein., (Copyright 2009 S. Karger AG, Basel.)

Background: Helicobacter pylori causes chronic gastritis, peptic ulcer disease, and is the most important risk factor for non-cardia gastric cancer, and has been shown to upregulate matrix metalloproteinases (MMPs) in infected gastric mucosa. MMPs are proteolytic enzymes regulated by tissue inhibitors of metalloproteinases (TIMPs)., Aims: We set up this study to find out whether H. pylori gastritis induces systemic MMP response., Methods: Serum samples were collected from patients undergoing gastroscopy; 26 patients had H. pylori gastritis and 18 were H. pylori-negative controls with normal gastric mucosa. Serum MMP levels were analysed by enzyme-linked immunosorbent assay., Results: Significantly elevated serum levels of collagenase-2 (MMP-8), gelatinase B (MMP-9), neutrophil elastase (NE), and myeloperoxidase (MPO), and reduced serum levels of gelatinase A (MMP-2) and TIMP-1 were demonstrated in patients with H. pylori gastritis as compared to H. pylori-negative controls. No significant differences were shown in serum matrilysin-1 (MMP-7) levels., Conclusions: For the first time, we show enhanced MMP-8 response in H. pylori infection together with other neutrophil degranulation products (MMP-9, MPO, NE). Elevated circulating neutrophil degranulation product levels in serum of H. pylori-positive patients reflect accelerated proteolysis and oxidative stress, and may contribute to extraintestinal sequelae, such as cardiovascular diseases.

The Purpose of the Study: To study role of E2 and F2alpha prostaglandins in development of erosive-ulcerative lesions of gastrointestinal tract., Materials and Methods: were examined patients with mucosal erosive-ulcerative and inflammatory lesions of gastrointestinal tract, as well as patients with osteoarthritis who received selective and non selective NSAIDs. Determination of E2 and F2alpha endogenous PG group was investigated with help of immunefuoration method with help of R&D Systems, Inc. Control group was 15 healthy patients., Results: in presented work you can find that there is relationship between degree of reduction of PG level and severity of gastrointestinal mucosal lesion area. The lowest values of PGE2 and PG F2alpha observed in patients with gastric ulcer disease, especially during exacerbation. Patients with low PG synthesis in body increases likelihood of gastropathy as to reception of non-selective COX inhibitors, and at receiving selective COX-2 inhibitors.

To identify the role of eicosanoid-mediated pathways for gastric carcinogenesis, the expression of enzymes (COX-1, COX-2, 5-LOX) and receptors (BLT-1, CysLTR(1)) were immunohistochemically studied in H. pylori positive patients with a risk gastritis phenotype and either successful or unsuccessful eradication (n=12, each; followed up for a median of 5 years). Gastric cancer risk index improved significantly after successful eradication (p<0.001). Semiquantitative immunohistochemistry revealed distinct significant changes in the expression patterns for COX-2, CysLTR1, COX-1 and BLT-1 depending on the eradication outcome, whereas 5-LOX expression was not altered. These results suggest an involvement of the COX-LOX pathway in gastric carcinogenesis.