Icariside II suppresses NF-κB/STAT3 signaling to prevent the progression of chronic atrophic gastritis toward gastric cancer

Regulation of Gastric Carcinogenesis by InflammatoryCytokines.

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

The aim of the study was to investigate the correlation between Helicobacter pylori (HP) infection and activation of the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway in mucosal tissues of gastric cancer and precancerous lesions. Patients with chronic atrophic gastritis (n=52) and gastric cancer (n=98) were treated in the Department of Gastroenterology at The Fifth People's Hospital of Chongqing from August 2011 to August 2016 were selected, and the biopsy tissue and serum specimens were collected. The HP infection was detected via enzyme-linked immunosorbent assay (ELISA), and the expression level of phosphorylated-Akt (p-Akt) was detected via immunohistochemistry (IHC). Moreover, in vivo experiments were performed to simulate HP infection in gastric cancer cells (MGC-803 and AGS), and the p-Akt protein level, PI3K activity and cell proliferative activity were detected. Finally, the changes in Akt protein level were detected by co-culture of gastric cancer cells via LY294002, a PI3K inhibitor, and HP. The positive rate of HP infection in patients with chronic atrophic gastritis was 84.6% (44/52), which was significantly higher than that in patients with gastric cancer [73.5% (72/98)] (p<0.05). The positive rate of HP infection in patients with early gastric cancer (86.4%) was significantly higher than that in patients with moderate-advanced gastric cancer (69.7%) (p<0.05). Results of IHC and western blot analysis revealed that the p-Akt expression level in HP-positive tissues was obviously higher than that in HP-negative tissues (p<0.05). In vitro cell experiments revealed that the PI3K activity was enhanced and the PI3K/Akt pathway was significantly activated after HP infection in tumor cells, thus promoting the proliferation of tumor cells (p<0.05) in a time-dependent manner. After LY294002 inhibited PI3K activity, Akt was not significantly activated by HP infection. Thus, HP activates the PI3K/Akt pathway in gastric cancer cells, thereby promoting tumor cell proliferation.

Helicobacter pylori infection has been considered to play significant role in gastric carcinogenesis, but only a minority of people who harbor this organism will develop gastric cancer. H. pylori infection first causes chronic non atrophic gastritis. Chronic non atrophic gastritis may evolve to atrophic gastritis and intestinal metaplasia and finally to dysplasia and adenocarcinoma. To estimate the prevalence of H. pylori infection and the precancerous gastric lesions and their relationship, in patients with dyspeptic symptoms who underwent upper gastrointestinal endoscopy at a reference center in the central region of Rio Grande do Sul state, Brazil. We analyzed gastric biopsies taken from corpus and antrum of patients who underwent upper gastrointestinal endoscopy for H. pylori detection, between 1994 and 2003. According to Sydney system, chronic non atrophic gastritis, atrophic gastritis and intestinal metaplasia were diagnosed by histological examination (H-E stain). The histological diagnoses were related to H. pylori infection status. Biopsies from 2,019 patients were included in the study. Patients mean age was 52 (+/-15) and 59% were female. Seventy six percent had H. pylori infection. Normal mucosa, chronic non atrophic gastritis, atrophic gastritis and intestinal metaplasia were diagnosed in 5%, 77%, 3% and 15%, respectively. The OR for any degree of gastric mucosa lesion in infected patients was 10 (CI95% 6.50 - 17%). The OR for infected patients had chronic non atrophic gastritis was 3 (CI95% 2,2 - 3,4). The OR for infected patients had atrophic gastritis or intestinal metaplasia was less than 1. The prevalence of H. pylori infection in this population was high (76%) and infected individuals had the probability 10 folds greater than non infected individuals to have any lesion of gastric mucosa. The prevalence of precancerous lesions was 77% for non atrophic chronic gastritis, 3% for atrophic gastritis and 15% for intestinal metaplasia. Infected patients had risk 3 folds greater than non-infected for the occurrence of non atrophic chronic gastritis. H. pylori infection did not show risk for occurrence of atrophic gastritis and intestinal metaplasia, suggesting that other risk factors should be involved in the carcinogenesis process.

Since the discovery of Helicobacter pylori (H. pylori) infection as the major cause of gastroduodenal disorders including acute and chronic gastritis, gastroduodenal ulcer, chronic atrophic gastritis, and gastric cancer almost three decades ago, the possibility of preventing these clinical diseases through eradicating H. pylori has been the focus of active research, but soon debate in the scientific community, though eradication opens the feasibility of cancer prevention and the removal of bacteria significantly prevents development or recurrence of peptic ulcer diseases and some clinical diseases, was proposed due to uncertainty in either achievement of complete eradication or inefficacy in cancer prevention with eradication alone. Still its linkage to gastric cancer is incontestable. Since the multiple combination of bacterial factors, environmental insults, and the host immune response that drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward gastric cancer is intervened, simple eradication deemed the feasibility of cancer prevention. Therefore, our group open strong hypothesis that non-microbial, dietary approach might be the alternate, for which several interventions of nutritional components can highlight rejuvenation of chronic atrophic gastritis as well as amelioration of H. pylori-associated procarcinogenic inflammation. In this review article, the experience and outcome regarding nutritional application to rejuvenate gastric atrophy will be introduced, using Korean red ginseng, garlic extracts, cancer preventive Korea kimchi, n-3 polyunsaturated fatty acids (PUFA), special form of licorice, and probiotics. The detailed influence of dietary intervention and bacterial eradication therapy on disease progression and reversibility of premalignant lesions are discussed.

Chronic (atrophic) gastritis is a progressive disease which in a small proportion of patients leads to severe (total) atrophy (severe grade of chronic gastritis) of the antral or body mucosa or both. Chronic gastritis is a premalignant condition which favours the development of gastric cancer. Chronic gastritis precedes gastric cancer and shows a severalfold increase in the risk of gastric cancer compared to subjects with histologically normal stomach. Several tentative modifications to the estimate of the risks may be presented: (i) a severe risk of developing gastric cancer is restricted to subjects with a severe grade of chronic gastritis (ii) the risk of gastric cancer is increased in subjects who have either severe antral or body chronic gastritis, the risk being approximately three to five times higher in the antral chronic gastritis (B-type of gastritis) than in the body chronic gastritis (A type of gastritis); (iii) the antral and body chronic gastritis are independent risk factors for gastric cancer, the joint risks being multiplicands of the marginal risks i.e., the estimated risk is highest in those subjects who show severe chronic gastritis in both the antrum and the body (AB type of gastritis); (iiii) the chronic gastritis mediated gastric cancer risk is limited to gastric cancers of the intestinal type, and thus covers only a proportion of all cases of gastric cancer. In the highest risk groups it may be estimated that the probability of a subject developing gastric cancer in subsequent decades is up to 30% if the subject is a young man who has severe chronic gastritis in his antrum, or who has it coexistently in the antrum and body.

It has been well documented that Helicobacter pylori (H.pylori) infection is a risk factor for aggravating gastric mucosal atrophy. However, the exact molecular mechanism mediating this process is not fully elucidated. The purpose of this study was to identify biomarkers, which may predict the risk for progression of chronic atrophic gastritis (CAG) with H.pylori. GSE27411 was downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) between H.pylori-infected samples without CAG and H.pylori-infected CAG samples were analyzed. Gene Ontology and pathway enrichment analyses were performed, followed by protein-protein interaction network construction. We used immunohistochemistry analysis to identify DEGs in 20 chronic gastritis, 20 CAG, and 22 gastric cancer (GC) specimens. A total of 303 upregulated and 26 downregulated DEGs were identified. The pathways enriched by upregulated DEGs were mainly related to fat digestion and absorption, peroxisome proliferator-activated receptor signaling pathway, and chemical carcinogenesis. Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) had the highest degrees in protein-protein interaction network. Moreover, the positive rates of CYP3A4 protein expression in chronic gastritis, CAG, and GC were 10% (2/20), 55% (11/20), and 77.3% (17/22), respectively (P<0.001). The Kaplan-Meier analysis revealed that elevated expression of CYP3A4 was significantly associated with worse overall survival and first progression, respectively (P<0.0001). According to the findings of this study, the expression of CYP3A4 might be related to the potential carcinogenic transformation of CAG to GC. Therefore, CYP3A4 may be biomarkers to predict progression of CAG and poor prognosis of gastric cancer.

Objectives: To assess the diagnostic value of endoscopical findings compared to histopathological diagnosis, to delineate the relative frequency and pattern of different types of gastritis and their association with H. pylori and intestinal metaplasia in our locality, and to compare the results of this study with those of others. Methods: In a cross sectional study 150 selected patients with different upper gastrointestinal symptoms have been examined at endoscopy units in Ibn-Sina teaching hospital and Al-Jamhori teaching hospital in Mosul city, from the first of June 2013 to the first of March 2014, all were assessed endoscopically and biopsies from both antral and body mucosa were taken for histopathological examination. Results: This study has revealed gastritis histopathologically in 96.6% of cases, and the agreement between endoscopical and histophathological diagnosis was 88%. The chronic superficial gastritis represented the highest relative frequency in this histopathologically diagnosed gastritis, where it was seen in 61.3% of the cases and it’s relative frequency decreased with advance age, while chronic atrophic gastritis was diagnosed in 30% of the cases and it’s relative frequency increased with advanced age, while gastric atrophy wasn’t detected in any case. Acute gastritis was detected in only 5.3% of the cases. Helicobacter pylori was detected in 67% of cases. A significant association was detected between chronic gastritis and Helicobacter pylori infection, and its frequency decreased with increased severity of glandular atrophy. Follicular gastritis was diagnosed in 51% of chronic atrophic gastritis and 91.3% of them were Helicobacter pylori positive cases. By the use of the special stain AB/PAS pH (2.5), intestinal metaplasia has been diagnosed in 23% of cases and it’s relative frequency increased with advanced age. Conclusion: There is a high rate of concordance (88%) between endoscopical findings and histopathological diagnosis of gastritis. Among gastritis chronic variety was the commonest. H. pylori had a significant association with chronic gastritis (chronic superficial gastritis and chronic atrophic gastritis). Intestinal metaplasia has been detected mainly in chronic atrophic gastritis and its frequency increased with advanced age.

Diagnostic value of combined detection of three gastric functions and Helicobacter pylori typing in chronic gastritis and gastric cancer

How to Manage a Patient With Gastric Intestinal Metaplasia: An International Perspective

This Month in Gastroenterology

Background: Histone deacetylase 6 (HDAC6) plays a role in the progression of many tumors. However, the relationship between the level of HDAC6 expression and gastric tumorigenesis is still unclear. Here, we illustrate the potential correlation between Helicobacter pylori (HP) infection and the variation of HDAC6 expression in different gastric lesions, as well as the clinical significance of HDAC6 expression in gastric cancer (GC) patients. Materials and Methods: Between 2011 and 2016, 364 patients with different types of gastric lesions were enrolled in Baotou City Central Hospital. Immunostaining of HDAC6 expression and HP infection were performed in the following cohort including 21 normal tissues (Normal); 40 samples with chronic superficial gastritis (CSG); 106 with chronic atrophic gastritis (CAG); 94 with intestinal metaplasia (IM); 64 with dysplasia (DYS) and 39 with gastric cancer (GC). Survival analysis was performed in another 80 GC patients using the Kaplan-Meier method and multivariate Cox regression analyses. The level of HDAC6 expression was determined by Real-time PCR, Western blotting and IHC staining in gastric cell lines and tissues. Furthermore, the correlation between HDAC6 expression and clinicopathological features and prognosis was analyzed in the GC cohort. HP strains were lavaged into Kunming mice to investigate the effects of HP infection on the expression of different HDAC members in this mouse model. Results: Higher levels of HDAC6 expression were detected in normal and premalignant lesions than in the GC tissues (p<0.01), and decreased HDAC6 expression was associated with HP infection and TNM stage (p<0.01 and p=0.048, respectively). Multivariate analysis revealed that HDAC6 expression was an independent predictor of the outcome of GC patients (p=0.04). HP mediated HDAC6 expression in the cell lines and KM mice. HP infection could promote HDAC1 and HDAC4 expression as determined by Western blotting. Conclusions: HDAC6 is a promising biomarker for early diagnosis and prognosis during the oncogenic transformation of gastric cancer.

To search the role of Helicobacter pylori (H. pylori) in the progression of gastric carcinogenesis. A cohort study was conducted by cluster randomized sampling in Linqu County, a rural area in Shandong Province in northeast China, where the mortality of gastric cancer (GC) is among the highest in the world. In 1989-1990, a gastroscopic examination and serum test was launched among subjects aged 35-64 from 14 randomized villages. Histological diagnosis of gastric mucosa and enzyme-linked immunosorbent assay was used to detect gastric lesions and anti-H. pylori of all participants. A repeated gastroscopic screening was offered to all cohort members in 1994 and 1999 respectively, and all the GC cases, regardless of natural ones or ones by gastroscopy, were registered in the follow-up periods. Fifty-eight cases of GC were identified in 2469 subjects during the 10-year follow-up, 44 were observed in 1603 H. pylori-positive persons (2.74%) and 14 in 866 H. pylori-negative persons (1.62%). The incidence rate of GC in H. pylori-positive is significantly higher than in H. pylori-negative (OR = 1.871, 95% CI: 1.012 - 3.459). There was no significant difference in the progression of gastric carcinogenesis between H. pylori-positive and H. pylori-negative (P > 0.05) among subjects with normal or superficial gastritis (SG) at baseline. In contrast, the significant difference was found in baseline chronic gastritis (CAG) group (P < 0.01), and the GC incidence rate in H. pylori-positive (7/615) is higher than in H. pylori-negative (0/470, P = 0.019). The difference of gastric lesions between H. pylori-positive and H. pylori-negative in subjects with intestinal metaplasia (IM) and dysplasia (DYS) at baseline was statistically significant after a 10-year follow-up (P < 0.05, P < 0.01, respectively), but the GC incidence rate in H. pylori-positive is similar to the rate in H. pylori-negative at the two groups (17/573 and 7/224 in IM group, P = 0.907; 19/368 and 7/122 in DYS group, P = 0.806). H. pylori is a key risk factor that prompts the transition from chronic atrophic gastritis to advanced precancerous lesions and influences the whole progression of precancerous gastric lesions. H. pylori, perhaps can not cause GC directly, increases the risk of GC in company with other carcinogens. H. pylori seemingly has no important effect on the development of GC when gastric mucosa is normal or superficial gastritis, but this conclusion is required to be further confirmed.

When the body is infected with the bacterium Helicobacter pylori, a cytokine cascade is launched, which plays a key role in the progression of chronic inflammatory and destructive processes in the gastric mucosa. Thus, the secretion of a number of cytokines is stimulated, which in turn contribute to the attraction of immunocompetent cells and the development of inflammatory changes. However, hyperproduction of cytokines can lead to atrophic changes in the gastric mucosa and, as a result, degeneration into gastric cancer. Thus, the role of cytokines in precancerous conditions is ambiguous. On the one hand, they activate the immune response aimed at eliminating the pathogen. On the other hand, they themselves contribute to the progression of the disease.The complex clinical and laboratory study included patients: 60 with chronic gastritis (CG), 55 with chronic atrophic gastritis (CAG), 50 with gastric cancer (GC, stage I-II, morphological variant – adenocarcinoma) and 60 – control group. The diagnoses were verified according to international and Russian recommendations and confirmed by laboratory and instrumental studies. All patients were comparable in terms of gender and age characteristics (p &gt; 0.05). All patients had specific IgG to H. pylori. The study was approved by the Local Ethics Committee of the FRC KSC SB RAS (protocol No. 11 dated November 11, 2013). All ethical requirements were observed, and the patients signed the informed consent form for participation. Patients and persons of the control group underwent a single blood sampling from the cubital vein upon admission to vacutainers with heparin.The levels of IL-2, IL-4, IL-8, TNFα, interferon-γ in the blood serum of patients and healthy individuals were determined using the enzyme immunoassay method using reagent kits manufactured by JSC “VectorBest”. Statistical data processing was carried out using the Statistica for Windows 8.0 application package.All patients with H. pylori-associated diseases (CG, CAG, GC) showed an increase in pro-inflammatory (IL-2, IL-8, IFNγ) with a significant increase in IL-8 in all patients and IFNγ in gastric cancer and antiinflammatory cytokine (IL-4) with a maximum value in gastric cancer. A combined Th1 and Th2 is found – a mediated immune response with a maximum violation of cytokine regulation in gastric cancer.

Objective To investigate the association of Helicobacter pylori(Hp) infection and human gastric precancerous lesions as well as cancer.Methods Hp infection conditions of chronic atrophic gastritis (CAG),gastric epithelial dysplasia(GED),intestinal metaplasia(IM) and gastric cancer (Ca) in 151 gastric endoscopic biopsy and subtotal gastrectomy specimens were detected by means of Hematoxylin Eosin,Warthin Starrry and HID AB(pH2.5) PAS stainings.Relationship between Hp infection and above mentional lesions were analysed statistically.Results 1)Infection rates of Hp were 66.2%(100/151) in our cases.Hp infection was frequent seen in gastric non cardic mucosa,particularly in antrac area.Infection rates were not association with sexual distinction.(2)Hp infection conditions were not interrelated with the occurrence of CAG,IM Ⅰand Ⅱtype,diffuse type gastric cancer( P 0.05),but were closely correlated with the development of IM Ⅲ type,GED(particularly GED Ⅱ?Ⅲ grade) and intestinal type gastric cancer( P 0.05).Conclusion Hp infection was an important etiologic factor that caused IM Ⅲ type,moderate and server GED as well as intestinal type gastric cancer.