Malvidin Protects against and Repairs Peptic Ulcers in Mice by Alleviating Oxidative Stress and Inflammation.

Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg-1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.

Association of Clinical Phenotypes in Haploinsufficiency A20 (HA20) With Disrupted Domains of A20.

Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively). Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.

IL-10 produced by macrophages regulates epithelial integrity in the small intestine.

Macrophages (Mϕs) are known to be major producers of the anti-inflammatory cytokine interleukin-10 (IL-10) in the intestine, thus playing an important role in maintaining gastrointestinal homeostasis. Mϕs that reside in the small intestine (SI) have been previously shown to be regulated by dietary antigens, while colonic Mϕs are regulated by the microbiota. However, the role which resident Mϕs play in SI homeostasis has not yet been fully elucidated. Here, we show that SI Mϕs regulate the integrity of the epithelial barrier via secretion of IL-10. We used an animal model of non-steroidal anti-inflammatory drug (NSAID)-induced SI epithelial injury to show that IL-10 is mainly produced by MHCII+ CD64+ Ly6Clow Mϕs early in injury and that it is involved in the restoration of the epithelial barrier. We found that a lack of IL-10, particularly its secretion by Mϕs, compromised the recovery of SI epithelial barrier. IL-10 production by MHCII+ CD64+ Ly6Clow Mϕs in the SI is not regulated by the gut microbiota, hence depletion of the microbiota did not influence epithelial regeneration in the SI. Collectively, these results highlight the critical role IL-10-producing Mϕs play in recovery from intestinal epithelial injury induced by NSAID.

Helicobacter pylori outer membrane vesicles involvement in the infection development and Helicobacter pylori-related diseases.

Helicobacter pylori - (H. pylori) play a role in the pathogenesis of gastritis, gastric and duodenal ulcers as well as gastric cancer. A possible involvement of outer membrane vesicles (OMVs) produced by H. pylori in the distribution of bacterial antigens through the gastric epithelial barrier and their role in the development of local and systemic host inflammatory and immune responses has been suggested. OMVs contain various biologically active compounds, which internalize into host cells affecting signaling pathways and promoting apoptosis of gastric epithelial and immunocompetent cells. OMVs-associated H. pylori virulence factors may strengthen or downregulate the immune responses leading to disease development. This review describes the biological importance of H. pylori OMVs and their role in the course of H. pylori infections, as well as H. pylori related local and systemic effects.

Frequency of Celiac Disease in Children with Peptic Ulcers.

AIM: The aim of the present study is to investigate the frequency of celiac disease in children with peptic ulcers and to compare it with that of non-celiac peptic ulcers in terms of clinical and laboratory values. METHODS: Upper gastrointestinal endoscopy was performed in 1769 patients at the Department of Pediatric Gastroenterology, The Faculty of Medicine, Cukurova University, Turkey, between January 2012 and January 2017. These cases consisted of subjects presenting with various GIS symptoms and indicated for endoscopy (with chronic diarrhea, delayed growth and development, abdominal pains, GIS bleeding, etc.). The levels of immunoglobulin A (IgA) serum anti-tissue transglutaminase antibodies, IgA anti-endomysial antibodies (EMA), and IgA serum were estimated in the patients with peptic ulcers. RESULTS: Celiac disease was diagnosed with serology, endoscopy, and histopathology in 250 (14%) of all cases undergoing endoscopy. Peptic ulcers were diagnosed in 74 patients (4.2%) of all cases undergoing endoscopy. tTGA and EMA (+) levels were determined in 22 (29%) of the 74 patients with peptic ulcers, and then the presence of peptic ulcers was investigated in the upper gastrointestinal system using gastrointestinal endoscopy, followed by histopathological confirmation of celiac disease. HP infection was present in 14 (63%) of the patients with celiac disease and in 23 (44%) of non-celiac peptic ulcers; the difference was not statistically significant (p = 0.12). In the total ulcer group, 10.8% (8/74) of patients with celiac peptic ulcers were negative for HP infection, whereas 21% (8/37) of HP-negative patients with ulcers had celiac disease. CONCLUSION: There exists a high risk of celiac disease in children with peptic ulcers. We thus recommend celiac disease to be investigated, particularly in HP-negative patients with peptic ulcers but with no history of NSAID use.

Downregulated regulatory T cell function is associated with increased peptic ulcer in Helicobacter pylori-infection.

BACKGROUND: Helicobacter pylori (H. pylori) chronically colonizes gastric/duodenal mucosa and induces gastroduodenal disease such as gastritis and peptic ulcer and induces vigorous innate and specific immune responses; however, the infection is not removed, a state of chronic active gastritis persists for life if untreated. The objective of this study was to determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis and peptic ulcer and determined the relationship between main virulence factor of H. pylori and Tregs. METHODS AND MATERIALS: A total of 89 patients with gastritis, 63 patients with peptic ulcer and 40 healthy, H. pylori-negative subjects were enrolled in this study. Expression of CD4 and Foxp3 was determined by immunohistochemistry. Antrum biopsy was obtained for detection of H. pylori, bacterial virulence factors and histopathological assessments. TGF-ß1, IL-10 and FOXP3 expressions were determined by real-time polymerase chain reaction (qPCR). RESULTS: The numbers of CD4+ and Foxp3+ T cells as well as the expression of IL-10, TGF-ß1, FOXP3, INF-γ and IL-17A in infected patients were significantly higher than the ones in uninfected patients. Also, the number of CD4+ T cells was independent on the vacuolating cytotoxin A (vacA) and outer inflammatory protein A (oipA), but it was positively correlated with cytotoxin-associated gene A (cagA). Instead, the number of Foxp3+ T cells was dependent on the vacA and oipA, but it was independent on cagA. The number of Foxp3+ T cells and the expression of IL-10, TGF-ß1 and FOXP3 in infected patients with gastritis were significantly higher than the ones in infected patients with peptic ulcer. Moreover, the number of CD4+ T cells and the expression of IL-17A and INF-γ was the lowest in the gastritis patients, however, increased progressively in the peptic ulcer patients. Additionally, the numbers of CD4+ and Foxp3+ T cells as well as the expression of IL-10, TGF-ß1, FOXP3 and INF-γ were positively correlated with the degree of H. pylori density and chronic inflammation. CONCLUSION: Tregs are positively associated with vacA alleles and oipA status of H. pylori and histological grade but negatively associated with peptic ulcer disease.

Role of Regulatory T-cells in Different Clinical Expressions of Helicobacter pylori Infection.

Helicobacter pylori (H. pylori) colonization induces vigorous innate and specific immune responses; however, the infection does not disappear and a chronic active gastritis continues if left untreated. It has been shown that the topographical pattern and immune response of gastritis are the main reasons for the bacteria persistence and the clinical outcome. Gastritis due to H. pylori is caused by a complicated interaction among a variety of T cell subsets. Regulatory T (Treg) cells suppressing the immune response of antigen-specific T-cells have recently been demonstrated to play a key role in chronic inflammation by immunologic tolerance. Treg cells have been identified as the major regulatory component of the adaptive immune response and being involved in H. pylori-related inflammation and bacterial persistence. There have been many controversies over the role of Treg cells in H. pylori infection. Many studies have shown that the local Treg response protects the gastric mucosa from intensified inflammation and tissue damage, and the risk of H. pylori-associated diseases has an inverse correlation with Treg accumulation, even if the decrease in the inflammatory response is recognized by Treg it causes increase in bacterial density. This paper reviews the role of Treg in different clinical expressions of H. pylori infection.

Regulatory T Cells and Myeloid-Derived Suppressor Cells in Patients with Peptic Ulcer and Gastric Cancer.

BACKGROUND: Regulatory T Cells (Tregs) and Myeloid-Derived Suppressor Cells (MDSCs) are two main regulatory cells modulating the immune responses in inflammation and cancer. OBJECTIVE: To investigate and compare Tregs and MDSCs in peptic ulcer and gastric cancer. METHODS: Patients with dyspepsia were selected and divided into three groups of non-ulcer dyspepsia (NUD, n=22), peptic ulcer disease (PUD, n=25), and gastric cancer (GC, n=27) according to their endoscopic and histopathological examinations. Helicobacter pylori infection was diagnosed by rapid urease test and histopathology. The number of peripheral blood CD4+CD25+FoxP3+Tregs and CD14+HLA-DR- MDSCs were determined in all patients, by flow cytometry. The number of FoxP3+ regulatory T cells was also determined by immunohistochemistry (IHC). RESULTS: The percentage of peripheral blood Treg cells in both PUD (0.81 ± 0.39, p<0.001) and GC groups (0.98 ± 0.65, p<0.001) were significantly higher than in NUD group (0.46 ± 0.10). These results were also confirmed by IHC. A significantly higher percentage of MDSCs in patients with PUD (0.73 ± 0.19, p<0.001) and GC (0.73 ± 0.16, p<0.001) was also observed when compared to NUD group (0.46 ± 0.16). There was no difference in the percentages of these two cell types between the PUD and GC groups. The percentages of Tregs and MDSCs in patients with PUD and GC were not significantly correlated. CONCLUSIONS: Both Tregs and MDSCs showed higher frequencies in PUD and GC. These results suggest that immune-modulation by the Tregs and MDSCs may play a role in the pathogenesis of PUD and GC.

The Gastric Mucosa from Patients Infected with CagA+ or VacA+ Helicobacter pylori Has a Lower Level of Dual Oxidase-2 Expression than Uninfected or Infected with CagA-/VacA- H. pylori.

BACKGROUND: Helicobacter pylori (H. pylori) is a well-recognized gastroduodenal pathogen and class I carcinogen. Dual oxidase-2 (DUOX2), a member of NADPH oxidase family, has several critical physiological functions, including thyroid hormone biosynthesis and host mucosal defense. AIM: To investigate the effect of H. pylori infection on DUOX2 gene expression in human stomach. MATERIALS AND METHODS: The biopsies were obtained from patients who underwent endoscopic diagnosis. The patient serum was assayed for two virulence factors of H. pylori, CagA IgG and VacA. The inflammation in gastric mucosa was analyzed with histology. Real-time quantitative PCR was used to detect the expression of three members of NADPH oxidase, NOX1, NOX2, and DUOX2, as well as lactoperoxidase (LPO) in the gastric mucosa. NOX2, DUOX2, and myeloperoxidase (MPO) protein levels were quantified by Western blots or immunohistochemistry. RESULTS: The H. pylori-infected gastric mucosa had more severe inflammation than uninfected samples. However, the expression of DUOX2 mRNA and protein was lower in gastric mucosa of patients with H. pylori infection compared to the uninfected. Among the H. pylori-infected patients, those having CagA IgG or VacA in the serum had lower DUOX2 expression levels than those infected with H. pylori without either virulence factor. The NOX2 and MPO levels were higher in those patients infected with H. pylori irrespective of the virulence factors than those uninfected patients. NOX1 and LPO mRNA were undetectable in the gastric mucosa. CONCLUSION: CagA+ or VacA+ H. pylori in the stomach of patients may suppress DUOX2 expression to promote its own survival. Increased NOX2 could not eliminate H. pylori infection.

Frequency of γδ T Cells and Invariant Natural Killer T Cells in Helicobacter Pylori-infected Patients with Peptic Ulcer and Gastric Cancer.

To clarify the effect of γδ T cells and invariant Natural Killer T (iNKT) cells in pathophysiology of dyspeptic disorders, number of these two cells in patients with non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), and gastric cancer (GC) were compared.Patients with dyspepsia were divided into three groups of NUD, PUD, and GC according to their endoscopic and histopathological examinations. Helicobacter pylori infection was diagnosed by rapid urease test and histopathology. The number of peripheral blood CD3+TCRγδ(+) T cells and CD3+Va24Ja18+ iNKT cells were determined by flow cytometry. Immunohistochemistry (IHC) was also used for identifying the TCRγδ+ cells.Forty two patients with NUD (31.6%), 44 with PUD (33.1%), and 47 with GC (35.3%) were included in the study. The frequency of CD3+TCRγδ(+) T cells in peripheral blood of patients with GC (2.71±0.25) was significantly lower than that in NUD (3.97±0.32, p<0.05) and PUD groups (3.87±0.32, p<0.05). However, there was no significant difference in CD3+TCRγδ(+) T cell percentage between the NUD and PUD groups. The frequency of TCRγδ(+) lymphocytes was significantly lower in tissue samples from patients with GC (4.81±0.53) than in NUD (11.09±1.09, p<0.0001) and PUD groups (11.11±1.01, p<0.0001). Also, we could not find any significant difference in the percentage of mucosal TCRγδ+ cells between the NUD and PUD groups. The results showed no significant difference in iNKT cells percentage among the three groups of patients.The results suggest that decreasing number of γδ T cells may be related to development and progression of gastric cancer.

Peptic ulcer disease in Helicobacter pylori-infected children: clinical findings and mucosal immune response.

OBJECTIVES: Peptic ulcer disease (PUD) is highly prevalent among adults but less common in children. Helicobacter pylori infection, the main cause of PUD, is, however, acquired extremely early in life. The aim of the study was to analyze clinical characteristics of children with PUD in a country with a high prevalence of the disease and to evaluate which host factors could determine this clinical outcome. METHODS: Children referred for upper gastrointestinal (GI) endoscopy with suspicion of peptic diseases were included prospectively during an 8-year period. Antral biopsies were performed to determine H pylori presence and mucosal cytokines profile. RESULTS: A total of 307 children between 3 and 18 years old were enrolled. Of the total, 237 children (46% boys) with complete data were included. H pylori infection was confirmed in 133 (56.1%) participants. Duodenal ulcer (DU) was diagnosed in 32 patients (13.5%); among them 29 were infected with H pylori (90.6%). Infected children had a nodular appearance of the gastric mucosa more often than noninfected children. Noninfected children had fewer lymphoid follicles and less inflammatory infiltrate than infected children. Only mucosal polymorphonuclear cell infiltration was more intense in DU-infected children as compared with non-DU-infected children. DU-infected children had higher levels of mucosal interferon-γ than noninfected and non-DU-infected patients. Non-DU-infected children had also higher levels of mucosal interleukin-10 than noninfected patients (P < 0.05). CONCLUSIONS: PUD in children, especially DU, is strongly associated with H pylori infection in developing countries. There is no distinctive clinical presentation of children with PUD. T-helper cytokine balance may influence clinical outcomes in children.

Immune responses to Helicobacter pylori infection.

Helicobacter pylori (H. pylori) infection is one of the most common infections in human beings worldwide. H. pylori express lipopolysaccharides and flagellin that do not activate efficiently Toll-like receptors and express dedicated effectors, such as γ-glutamyl transpeptidase, vacuolating cytotoxin (vacA), arginase, that actively induce tolerogenic signals. In this perspective, H. pylori can be considered as a commensal bacteria belonging to the stomach microbiota. However, when present in the stomach, H. pylori reduce the overall diversity of the gastric microbiota and promote gastric inflammation by inducing Nod1-dependent pro-inflammatory program and by activating neutrophils through the production of a neutrophil activating protein. The maintenance of a chronic inflammation in the gastric mucosa and the direct action of virulence factors (vacA and cytotoxin-associated gene A) confer pro-carcinogenic activities to H. pylori. Hence, H. pylori cannot be considered as symbiotic bacteria but rather as part of the pathobiont. The development of a H. pylori vaccine will bring health benefits for individuals infected with antibiotic resistant H. pylori strains and population of underdeveloped countries.

CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa.

BACKGROUND: Helicobacter pylori-induced peptic ulceration is less likely to occur in patients with a strong gastric anti-inflammatory regulatory T cell (Treg) response. Migration of Tregs into the gastric mucosa is therefore important. OBJECTIVE: To identify the homing receptors involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the relevant chemokine responses. DESIGN: Gastric biopsy samples and peripheral blood were donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified gastric biopsy chemokine concentrations. Flow cytometry was used to characterise homing receptors on CD4(+)CD25(hi) Tregs. H pylori wild-type and isogenic mutants were used to investigate the signalling mechanisms behind CCL20 and IL-8 induction in gastric epithelial cell lines. Transwell assays were used to quantify Treg migration towards chemokines in vitro. RESULTS: CCL20, CXCL1-3 and IL-8 concentrations were significantly increased in gastric biopsy samples from H pylori-infected patients. CCR6 (CCL20 receptor), CXCR1 and CXCR2 (IL-8 and CXCL1-3 receptors) were expressed by a higher proportion of peripheral blood Tregs in infected patients. Most gastric Tregs expressed these receptors. H pylori induced CCL20 production by gastric epithelial cells via cag pathogenicity island (cagPAI)-dependent NF-κB signalling. Foxp3(+), but not Foxp3(-), CD4 cells from infected mice migrated towards recombinant CCL20 in vitro. CONCLUSIONS: As well as increasing Treg numbers, H pylori infection induces a change in their characteristics. Expression of CCR6, CXCR1 and CXCR2 probably enables their migration towards CCL20 and IL-8 in the infected gastric mucosa. Such qualitative changes may also explain how H pylori protects against some extragastric inflammatory disorders.

Is there any relationship between Le(b) antigen expression and Helicobacter pylori infection?

INTRODUCTION: Helicobacter pylori infection is one of the main causes of peptic ulcer. There are some blood groups acting as receptors for the pathogen. Based on this view and previous attempts, we tried to examine the relationship between Lewis blood group and H. pylori infection. MATERIALS AND METHOD: Blood and saliva samples were collected from 60 patients with established peptic ulcer induced by H. pylori. Secretory status of each patient was determined by both direct agglutination and saliva tests. RESULTS: Seventy-two percent of the patients were secretor and expressed Lewis B antigen. This rate in control group was 61%. Statistical analysis showed no significant difference between the two groups. CONCLUSION: This study did not find any correlation between Le(b) antigen expression and presence of H. pylori-induced peptic ulcer. It is now recommended that other factors like Lewis(x) and sialyl Lewis(x) should be investigated in binding, colonization and virulence of H. pylori infection in the future.

A role for altered phagosome maturation in the long-term persistence of Helicobacter pylori infection.

The vigorous host immune response that is mounted against Helicobacter pylori is unable to eliminate this pathogenic bacterium from its niche in the human gastric mucosa. This results in chronic inflammation, which can develop into gastric or duodenal ulcers in 10% of infected individuals and gastric cancer in 1% of infections. The determinants for these more severe pathologies include host (e.g., high IL-1ß expression polymorphisms), bacterial [e.g., cytotoxicity-associated gene (cag) pathogenicity island], and environmental (e.g., dietary nitrites) factors. However, it is the failure of host immune effector cells to eliminate H. pylori that underlies its persistence and the subsequent H. pylori-associated disease. Here we discuss the mechanisms used by H. pylori to survive the host immune response and, in particular, the role played by altered phagosome maturation.

Increased numbers of Foxp3-positive regulatory T cells in gastritis, peptic ulcer and gastric adenocarcinoma.

AIM: To determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis, peptic ulcers and gastric cancer. METHODS: This study was a retrospective analysis of gastric antrum biopsy specimens from healthy controls (n = 22) and patients with gastritis (n = 30), peptic ulcer (n = 83), or gastric cancer (n = 32). Expression of CD4, CD25 and Foxp3 was determined by immunohistochemistry in three consecutive sections per sample. RESULTS: Compared with healthy controls, there was an increased number of CD25(+) and Foxp3(+) cells in patients with gastritis (P = 0.004 and P = 0.008), peptic ulcer (P < 0.001 and P < 0.001), and gastric cancer (P < 0.001 and P < 0.001). The ratio of CD25(+)/CD4(+) or Foxp3(+)/CD4(+) cells was also significantly higher in all disease groups (P < 0.001, respectively). The number of CD4(+), CD25(+), and Foxp3(+) cells, and the ratio of CD25(+)/CD4(+) and Foxp3(+)/CD4(+) cells, were associated with the histological grade of the specimens, including acute inflammation, chronic inflammation, lymphoid follicle number, and Helicobacter pylori infection. The number of CD4(+), CD25(+) and Foxp3(+) cells, and the ratio of CD25(+)/CD4(+) and Foxp3(+)/CD4(+) cells, were negatively associated with intestinal metaplasia among gastritis (P < 0.001, P < 0.001, P < 0.001, P = 0.002 and P = 0.002) and peptic ulcer groups (P = 0.013, P = 0.004, P < 0.001, P = 0.040 and P = 0.003). CONCLUSION: Tregs are positively associated with endoscopic findings of gastroduodenal diseases and histological grade but negatively associated with intestinal metaplasia in gastritis and peptic ulcer groups.

Reduced small-intestinal injury induced by indomethacin in interleukin-17A-deficient mice.

BACKGROUND AND AIMS: The pathogenesis of enteropathy induced by non-steroidal anti-inflammatory drugs (NSAIDs) is still unclear, and there are no established treatments. Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has been associated with the development of chronic inflammatory diseases, including autoimmune diseases. To define the role of IL-17A in small intestinal injury and inflammation, we studied the effects of indomethacin administration in mice with targeted deletions of the IL-17A gene. METHODS: Male C57BL/6 (wild-type) and homozygous IL-17A(-/-) C57BL/6 mice were subjected to this study. Indomethacin (10 mg/kg) was subcutaneously administered to induce small-intestinal damage. Indomethacin-induced lesions in the small intestine were evaluated by measuring the injured area and by histopathology. Also assessed were myeloperoxidase (MPO) activity, as an index of neutrophil accumulation, and intestinal mRNA expression for inflammatory cytokines. RESULTS: The area of macroscopic ulcerative lesions, the MPO activity and the mRNA expression of inflammatory-associated chemokines, such as keratinocyte chemoattractant (KC), monocyte chemotactic protein-1 (MCP-1), and granulocyte-colony stimulating factor (G-CSF), were significantly increased in indomethacin-treated groups compared with the sham groups. The development of intestinal lesions by indomethacin was inhibited in IL-17A(-/-) mice compared with wild-type mice, together with significant suppression of the increased levels of MPO activities and KC, MCP-1, and G-CSF levels. CONCLUSION: These findings demonstrate that IL-17A contributes to the development of indomethacin-induced small intestinal injury through upregulation of G-CSF, KC, and MCP-1. IL-17A might be a promising new therapeutic target to treat NSAID-induced enteritis.

Multiple gene status in Helicobacter pylori strains and risk of gastric cancer development.

BACKGROUND/AIM: The identification of the vacA intermediate region has provided new insights into the role of vacA heterogeneity in relation to gastro-duodenal pathogenesis. The aim of this study was to assess vacA polymorphism in Iranian Helicobacter pylori strains and its association with cagA as a major virulence determinant, gastric histopathology and disease. METHODS: vacA polymorphism and serum antibody responses were studied in 207 H. pylori-infected (139 NUD, 34 PUD, and 34 GC) patients and correlated with gastric histopathology. RESULTS: Multivariate logistic regression analysis found intermediate region typing superior to signal or mid region typing for screening high risk patients. vacA i1 allele was identified as an independent predictor of dysplasia (OR = 9.044; 95% CI: 1.11-73.33). Possession of s1/i1/cagA(+) strains was also identified as a predictor of intestinal metaplasia (OR = 3; 95% CI: 1.13-7.95), dysplasia (OR = 9.9; 95% CI: 1.23-80.86) and risk of GC (OR = 6.9; 95% CI: 2.5-18.66) as well as induction of anti-VacA sero-positivity (OR = 5.04; 95% CI: 1.8-13.6). Anti-VacA serology correctly detected 83.8% of s1/i1/cagA(+) strains carried by high-risk patients. CONCLUSIONS: The current study emphasizes the implication of vacA polymorphic structure, especially the s1/i1/cagA(+) genotype, in increasing the risk of GC by revealing their association with gastric pre-neoplastic changes and their reflection in VacA sero-positivity which encourages the application of noninvasive procedures in population screening.

Gastroduodenal mucosal defense.

PURPOSE OF REVIEW: The gastroduodenum has multiple means by which it resists injury from intrinsic and extrinsic factors, including gastric acid, nonsteroidal anti-inflammatory drugs, and Helicobacter pylori. We review recent insights into the mechanisms by which the gastroduodenum resists injury and discuss factors contributing to defensive failure. RECENT FINDINGS: Duodenal bicarbonate secretion, a primary defensive mechanism, is mediated by the downregulated in adenoma anion exchanger and is stimulated by estrogens. Nonsteroidal anti-inflammatory drug gastric damage is dependent on toll-like receptor signaling. Portal hypertensive gastropathy impairs extracellular signal-regulated kinase 1/2 phosphorylation, increasing oxidative stress. H. pylori-induced peptic ulcer disease is associated with inadequate regulatory T cell responses. SUMMARY: Enhanced understanding of the mechanisms of gastroduodenal defense and injury provides new insight into potential therapeutic targets, which contributes towards the development of more well tolerated and more effective therapies.