methylnitronitrosoguanidine and Gastritis

Animal models are being used to study the mechanisms by which Helicobacter spp. induce gastric disease. To assess the effects of a natural gastric pathogen, Helicobacter mustelae, in the development of chronic gastritis, premalignancy and cancer, the ferret model was studied under natural and experimental conditions.. H. mustelae-infected ferrets were used to study the metabolism of nitrates/nitrites, which are dietary and endogenously formed substances that have been linked to gastric cancer. The ferret was also manipulated by performing gastric reconstructive surgery to study the processing of nitrite and nitrate and to assess the effect of surgery on gastric pathology. In addition, the ferret was tested for its suitability as an animal model for the induction of gastric cancer by oral dosing with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The influence of these variables on gastric pathology and/or metabolic outcomes was examined, and the results in ferrets were compared to findings in humans.. The ferret appears to be an ideal model for studying various gastric parameters and how these factors influence the development of H. mustelae-associated gastric disease. Gastric reconstructive surgery did not effect nitrite processing or overall severity of gastritis in ferrets. However, a single dose of MNNG (50 mg/kg) produced an unprecedented 90% gastric carcinoma in H. mustelae-infected ferrets. This implies that chronic inflammation induced by the bacterium is a cofactor in gastric carcinogenesis.

Topics: Adenocarcinoma; Animals; Disease Models, Animal; Ferrets; Gastric Mucosa; Gastritis; Helicobacter; Helicobacter Infections; Methylnitronitrosoguanidine; Nitrosamines; Proliferating Cell Nuclear Antigen; Stomach; Stomach Neoplasms

Chronic atrophic gastritis (CAG) is an important stage in the transformation of the normal gastric mucosa into gastric cancer. Granule Dendrobii (GD), a proprietary Chinese medicine, has proven clinical efficacy in treating CAG. GD might promote the reversal of precancerous lesions by improving them in CAG patients. However, the mechanism of GD in CAG treatment is relatively less understood. Here, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced CAG rats were treated with GD and its efficacy was evaluated by observing the changes in the rats' weight and the pathology of gastric tissues. The potential effect of GD on the bacteria was predicted and verified in the large and small intestines and stomachs of CAG rats using amplicon sequencing and RT-qPCR. The results showed that GD could ameliorate the symptoms of body weight loss in CAG rats. Hematoxylin-Eosin (HE) and Alcian Blue (AB) staining showed that GD significantly improved the pathological state of the gastric mucosa in CAG rats. The relative abundance (RA) of Lactobacillus and Turicibacter significantly decreased after GD intervention compared with that of the model group (P < 0.05), indicating that GD might improve CAG by regulating the RA of Lactobacillus and Turicibacter. These findings revealed that Lactobacillus and Turicibacter as bacteria agents associated with gastritis, have the potential to inhibit gastric cancer, especially Turicibacter maybe another pathogen of CAG besides Helicobacter pylori (HP), which is worthy of further study. Meanwhile, the findings provided new ideas and materials for the research and development of new CAG drugs.

Topics: Animals; Gastritis; Gastritis, Atrophic; Lactobacillus; Methylnitronitrosoguanidine; Rats; Stomach Neoplasms

Although many studies have examined changes in gut microbiota composition in gastric carcinogenesis to clarify the mechanism of action of anticancer drugs, it is unclear whether animal models of gastric carcinogenesis adequately reflect the disease in humans.. To address this issue, the present study investigated changes in the gut microbiome profile of a rat model of gastric carcinogenesis established using a combination of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium salicylate, irregular fasting, and ranitidine. The rats were divided into control (Normal), chronic non-atrophic gastritis (CNAG), chronic atrophic gastritis (CAG), precancerous lesion of gastric cancer (PLGC), and gastric cancer (GC) groups according to histopathological features. Gut microbiome in gastric carcinogenesis profiling was performed by 16S rRNA gene sequencing of rat feces samples.. We found that gut bacterial species richness increased whereas species diversity decreased during gastric carcinogenesis, with the most significant changes detected in the PLGC group. Gut microbiota community composition differed across groups, with the greatest similarities observed between CNAG and CAG groups and between PLGC and GC groups. There were significant differences in taxonomic representation at the phylum level: the PLGC group had the highest ratio of Firmicutes/Bacteroidetes whereas the GC group had the highest abundance of Proteobacteria and Actinobacteria.. These results indicate that changes in the gut microbiome in a rat model of MNNG-induced gastric carcinogenesis are similar to those observed in humans, thus providing a useful tool for evaluating the efficacy and mechanism of action of novel monotherapies or drug combinations for the treatment of gastric carcinogenesis.

Topics: Animals; Bacteria; Carcinogenesis; Dysbiosis; Feces; Food Deprivation; Gastritis; Gastrointestinal Microbiome; Male; Methylnitronitrosoguanidine; Ranitidine; Rats; RNA, Bacterial; RNA, Ribosomal, 16S; Sodium Salicylate; Stomach Neoplasms

Mesenchymal stem cells (MSCs) are a critical component of the tumor microenvironment. Upon distinct pathological stimulus, MSCs show phenotypic and functional changes. Gastric cancer is one of the leading causes of cancer‑related deaths worldwide. The roles and mechanisms of MSCs in gastric cancer have not been well characterized. In the present study, we investigated the roles of MSCs in the malignant transformation from gastritis to gastric cancer using an N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer model. We isolated MSCs from the gastric tissues of normal (RGN-MSCs) and MNNG-exposed rats (RGI-MSCs), and compared the biological properties of RGI-MSCs with RGN-MSCs. We found that RGI-MSCs had increased proliferative and migratory capabilities than these capacities noted in the RGN-MSCs. In addition, RGI-MSCs produced higher levels of IL-6, CXCL10 and MCP-1 than RGN-MSCs. Moreover, RGI-MSCs promoted the migration of normal gastric mucosa epithelial cells by inducing epithelial-mesenchymal transition (EMT). The upregulation of miR-374 in RGI-MSCs was partially responsible for their increased proliferative and migratory capabilities. Collectively, our findings provide new evidence for the roles of MSCs in gastric carcinogenesis, suggesting that targeting gastric cancer-associated MSCs may represent a novel avenue for gastric cancer therapy.

Topics: Animals; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Chemokine CXCL10; Epithelial-Mesenchymal Transition; Gastritis; Humans; Interleukin-6; Mesenchymal Stem Cells; Methylnitronitrosoguanidine; MicroRNAs; Neoplastic Stem Cells; Rats; Stomach Neoplasms; Tumor Microenvironment

Gastric cancer results from a combination of Helicobacter pylori (H pylori) infection, exposure to dietary carcinogens, and predisposing genetic make-up. Because the role of these factors in gastric carcinogenesis cannot be determined readily in human beings, the present study examined the role of an oral carcinogen and H pylori infection in rhesus monkeys.. Gastroscopies were performed in 23 monkeys assigned to 4 groups: controls; nitrosating carcinogen ethyl-nitro-nitrosoguanidine administration alone; inoculation of a virulent H pylori strain alone (H); and ethyl-nitro-nitrosoguanidine in combination with H pylori (EH). Follow-up gastroscopies and biopsies were performed at 3-month intervals for 5 years for pathologic and molecular studies.. Postinoculation, H and EH groups showed persistent infection and antral gastritis. Starting at 2 and 5 years, respectively, gastric intestinal metaplasia and intraepithelial neoplasia developed in 3 EH monkeys but in no other groups. Transcriptional analysis of biopsy specimens at 5 years revealed group-specific expression profiles, with striking changes in EH monkeys, plus a neoplasia-specific expression profile characterized by changes in multiple cancer-associated genes. Importantly, this neoplastic profile was evident in nonneoplastic mucosa, suggesting that the identified genes may represent markers preceding cancer.. Gastric intraglandular neoplasia is induced in primates when H pylori infection is associated with consumption of a carcinogen similar to the nitrosamines found in pickled vegetables, suggesting that H pylori and the carcinogen synergistically induce gastric neoplasia in primates.

Topics: Animals; Biopsy; Carcinogens; Carcinoma in Situ; Cell Transformation, Neoplastic; Cluster Analysis; Diet; Disease Models, Animal; Disease Progression; DNA Repair; Female; Gastritis; Gastroscopy; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Macaca mulatta; Male; Metaplasia; Methylnitronitrosoguanidine; Oligonucleotide Array Sequence Analysis; Precancerous Conditions; Stomach Neoplasms; Time Factors

To investigate the effect of Ginkgo biloba extract on gastric precancerous lesions in rats.. 80 4-week-old Wistar rats were randomly divided into four groups: a control group, a model group, a low and a high dose Ginkgo biloba extract intervention group; 20 in each group. Gastric precancerous lesions were induced by giving them 100 mg/L N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) solution to drink ad libitum for 20 weeks. In addition to the MNNG, the intervention groups were lavaged with Ginkgo biloba extract (0.5 mg/kg/d in the low dose group, 1.5 mg/kg/d in the high dose group) for 20 weeks. Starting from week 21 all the rats were fed with normal rat chow and tap water. At the end of week 30 the rats were killed. The histopathological changes of their gastric mucosa, ISA, NGI, the serum and gastric mucosal SOD/MDA and the expressions of oncogenes were studied.. The incidence of mild to severe intestinal metaplasia and dysplasia were significantly lower in the intervention groups than those in the model group (P < 0.01). The ISA and NGI in the intervention groups were significantly lower than those in the model group (P < 0.01). In the intervention groups the activity of SOD was increased and the concentration of MDA was decreased (P < 0.01). Expressions of Bcl-2, c-myc and FasL decreased in the intervention groups, whereas the expression of Fas increased. When compared with the model group, the differences were statistically significant (P < 0.01, P < 0.05, respectively).. Ginkgo biloba extract can increase anti-oxidative activity and inhibit the progression of gastric precancerous lesions via the regulation of cell proliferation and apoptosis.

Topics: Animals; Antioxidants; Apoptosis; Body Weight; Cell Division; Disease Progression; Dose-Response Relationship, Drug; Fas Ligand Protein; fas Receptor; Gastric Mucosa; Gastritis; Gene Expression; Ginkgo biloba; Malondialdehyde; Methylnitronitrosoguanidine; Plant Extracts; Precancerous Conditions; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Rats; Rats, Wistar; Serum Albumin; Stomach Neoplasms; Superoxide Dismutase

The effect of prolonged administration of the cytokine interleukin (IL)-1beta on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was examined in Wistar rats. In addition, we examined the effects on the proliferating cell nuclear antigen (PCNA) labeling index and the hepatocyte growth factor (HGF) immunoreactivity of the gastric mucosa. The rats received intraperitoneal injections of 0.1 or 0.3 microg/kg body weight of IL-1beta every other day after oral treatment with MNNG for 25 weeks. Long-term administration of IL-1beta at high dose, but not at low dose, significantly increased the incidence of gastric cancer in week 52. Administration of IL-1beta at high dose also significantly increased the labeling index and the HGF immunoreactivity of the gastric antral mucosa, and induced inflammatory cell infiltration and glandular atrophy of the gastric mucosa. Because IL-1beta production in the gastric mucosa is increased in patients with Helicobacter pylori-associated gastritis and eradiation of the organism significantly decreases the IL-1beta production, these findings suggest that Helicobacter pylori-associated gastric carcinogenesis may be in part mediated through IL-1beta.

Topics: Adenocarcinoma; Animals; Cell Division; Drug Synergism; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Interleukin-1; Male; Methylnitronitrosoguanidine; Neoplasm Invasiveness; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Stomach; Stomach Neoplasms

Helicobacter pylori (Hp) is thought to be a stomach carcinogen from epidemiological findings. To determine the effects of infection with the bacteria on experimental carcinogenesis, a study of the glandular stomach of Mongolian gerbils (MGs) was performed. Male MGs were treated with N-methyl-N'-nitro-N-nitrosoguanidine followed by inoculation with Hp or infected with Hp followed by N-methyl-N'-nitro-N-nitrosoguanidine administration. Animals were killed at week 50, and their excised stomachs underwent microbiological and histopathological examinations. In addition, a serological investigation was performed. The incidences of adenocarcinomas were significantly higher in animals treated with 60 or 300 p.p.m. N-methyl-N'-nitro-N-nitrosoguanidine for 10 weeks followed by Hp inoculation or Hp followed by 20 p.p.m. N-methyl-N'-nitro-N-nitrosoguanidine for 30 weeks than in the respective controls. Moreover, tumour-bearing animals had higher titres of anti-Hp antibodies than tumour-free animals. Of interest was the finding that a dose of 100 p.p.m. N-methyl-N'-nitro-N-nitrosoguanidine given to infected gerbils eradicated the Hp in about half the animals, with a concomitant reduction in the promoting effect. No tumours were found in animals infected with Hp without N-methyl-N'-nitro-N-nitrosoguanidine or non-treated gerbils. Hp infection enhances glandular stomach carcinogenesis in MGs treated with N-methyl-N'-nitro-N-nitrosoguanidine. Animals with high titres of anti-Hp antibodies are at greatest risk of developing neoplasms.

Topics: Adenocarcinoma; Animals; Antibodies, Bacterial; Carcinogens; Cell Differentiation; Cocarcinogenesis; Drug Administration Schedule; Edema; Gastric Mucosa; Gastritis; Gastrointestinal Hemorrhage; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Hyperplasia; Male; Metaplasia; Methylnitronitrosoguanidine; Precancerous Conditions; Specific Pathogen-Free Organisms; Stomach Neoplasms; Stomach Ulcer; Time Factors

The aim of this study was to determine whether gastric epithelial proliferation due to gastric Helicobacter infection in mice represents a preneoplastic lesion.. Helicobacter heilmannii infected and uninfected mice were treated with 150 microg/ml N-methyl-N'-nitro-N-nitrosoguanidine in drinking water for either 20 or 38 weeks. Mice were killed 12 or 18 months after bacterial inoculation.. All infected mice developed lymphoplasmocytic gastritis and epithelial hyperplasia. Proliferative gastric lesions were characterised by nodular hypertrophy of the glandular mucosa, multifocal epithelial hyperplasia, and elevated BrdU labeling index. Intestinal metaplasia and true atrophy were not present but proliferative glands were poorly differentiated, lined by mucus-type epithelial cells with no parietal, chief or other specialized cell types. Neoplasms developed only in MNNG-treated mice. of the 180 treated mice the following neoplasms developed: 14 squamous cell carcinomas of mouth and forestomach; 37 hemangiosarcomas of the intestinal serosa; and 15 splenic lymphomas. No tumors were present in the glandular gastric mucosa, and infection did not affect tumor incidence. p53 overexpression occurred in 79% of hemangiosarcomas and 71% of squamous cell carcinomas but not in normal or proliferative gastric glandular mucosa.. Gastric proliferative lesions in Helicobacter-infected mice are not preneoplastic, and the combination of an alkylating agent and non-neoplastic proliferation does not result in gastric carcinogenesis in mice.

Topics: Animals; Bromodeoxyuridine; Carcinogens; Disease Models, Animal; Female; Gastric Mucosa; Gastritis; Gene Expression Regulation, Neoplastic; Genes, p53; Helicobacter; Helicobacter Infections; Methylnitronitrosoguanidine; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Stomach Neoplasms

N-Methyl-N-nitro-N'-nitrosoguanidine (MNNG) is a gastric carcinogen in several animal species and has been used in a number of systems to dissect the co-carcinogenic potential of various compounds in the induction of gastric adenocarcinoma. Recent epidemiological evidence suggests that Helicobacter pylori may play a role as a co-carcinogen in the etiology of this tumor in humans and we have been interested in developing an animal model to study this possibility. A related organism, H. mustelae, naturally colonizes the ferret stomach and causes persistent chronic gastritis. The pathology elicited by H. mustelae in ferrets has many similarities with the human disease including different stages of multifocal atrophic gastritis which underlie the gastric ulcer and gastric carcinoma syndrome. There is little evidence, however, demonstrating the susceptibility of ferrets toward chemical carcinogenesis. We have consequently undertaken a study to ascertain whether 10 6-month-old female ferrets given a single oral dose of MNNG (50-100 mg/kg) would develop adenocarcinoma of the stomach. Five age-matched unmanipulated control animals were included for comparative purposes. All 15 ferrets were infected with H. mustelae. Nine of 10 ferrets dosed with MNNG developed gastric adenocarcinoma (29-55 months after dosing), while none of the five historical control ferrets examined an average of 63 months after the initiation of the study developed gastric tumors. By comparison, we have not observed gastric adenocarcinoma, nor has it been reported, in > 10 years of observation of untreated ferrets naturally infected with H. mustelae. The H. mustelae-infected ferret, with demonstrated susceptibility to a gastric carcinogen, plus the recent availability of specific pathogen-free ferrets, should now allow longitudinal studies in vivo to probe the role of Helicobacter in the development of gastric cancer.

Topics: Adenocarcinoma; Animals; Biopsy; Cocarcinogenesis; Disease Models, Animal; Female; Ferrets; Gastritis; Helicobacter Infections; Longitudinal Studies; Methylnitronitrosoguanidine; Pyloric Antrum; Stomach; Stomach Neoplasms

Topics: Adenocarcinoma; Aflatoxins; Animals; Chronic Disease; Female; Gastritis; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms

Topics: Animals; Disease Models, Animal; Gastric Juice; Gastric Mucosa; Gastritis; Gastritis, Atrophic; Male; Methylnitronitrosoguanidine; Parietal Cells, Gastric; Rats; Taurocholic Acid

Topics: Animals; Bile; Gastritis; Hyperplasia; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach