methylnitronitrosoguanidine and Gastritis--Atrophic

Topics: Animals; Carcinogens; Epithelium; Gastric Acid; Gastric Mucosa; Gastritis, Atrophic; Humans; Methylnitronitrosoguanidine; Mucus; Rats; Regional Blood Flow; Risk Factors; Stomach Neoplasms; Sulfhydryl Compounds

CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The HE and ELISA methods were applied to detect the treatment effects. WB, qRT-PCR, immunohistochemistry, TUNEL, and GES-1 cell flow cytometry approaches were employed to probe the mechanisms. The CAG model was successfully established. The ELISA and HE staining data showed that the RUT treatment effects on CAG rats were reflected by the amelioration of histological damage. The qRT-PCR and WB analyses indicated that the protective effect of RUT is related to the upregulation of the SHH pathway and downregulation of the downstream of apoptosis to improve gastric cellular survival. Our data suggest that RUT induces a gastroprotective effect by upregulating the SHH signaling pathway and stimulating anti-apoptosis downstream.

Topics: Animals; Gastritis, Atrophic; Hedgehog Proteins; Methylnitronitrosoguanidine; Mice; Nitrosoguanidines; Quinazolines; Rats; Signal Transduction

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

We examined the development of gastric cancer risk screening, from rat pepsinogen studies in an experimental rat gastric carcinogenesis model induced with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and human pepsinogen studies in the 1970s and 1980s to the recent "ABC method" for human gastric cancer risk screening. First, decreased expression or absence of a major pepsinogen isozyme, PG1, was observed in the rat gastric mucosa from the early stages of gastric carcinogenesis to adenocarcinomas following treatment with MNNG. In the 1980s, decreases in PGI in the human gastric mucosa and serum were identified as markers of atrophic gastritis. In the 1990s, other researchers revealed that chronic infection with Helicobacter pylori (Hp) causes atrophic gastritis and later gastric cancer. In the 2000s, a gastric cancer risk screening method combining assays to detect serum anti-Hp IgG antibody and serum PGI and PGII levels, the "ABC method", was established. Eradication of Hp and endoscopic follow-up examination after the ABC method are recommended to prevent gastric cancer.

Topics: Animals; Carcinogenesis; Early Detection of Cancer; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Methylnitronitrosoguanidine; Pepsinogen A; Persistent Infection; Rats; Stomach Neoplasms

Zuojin Pill (ZJP) is a classic prescription composed of Coptis chinensis and Tetradium ruticarpum (A.Juss.) T.G.Hartley, which is often used in the treatment of digestive system diseases.. The purpose of this study was to explore the therapeutic effect and potential mechanism of ZJP on chronic atrophic gastritis (CAG) induced by MNNG.. The GES-1 and rat model of CAG was established by MNNG. Detection of cell viability, morphological changes and proliferation of GES-1 by CCK-8 and high content screening (HCS) assay. G-17, IL-8 and TNF-α in rat serum were detected by ELISA kit. The expression of related mRNA and protein on TGF-β1/PI3K/Akt signal axis were detected by RT-PCR and Western blot.. The results showed that ZJP could significantly improve the GES-1 damage induced by MNNG and improve the gastric histomorphology of CAG rats. The intervention of ZJP could significantly reduce the content of G-17 and inflammatory factors IL-8, TNF- α, IL-6 and IL-1β, inhibit the expression of TGF-β1, PI3K and their downstream signals p-Akt, p-mTOR, P70S6K, and promote the expression level of PTEN, LC3-II and Beclin-1.. ZJP has a good therapeutic effect on CAG induced by MNNG, which may be closely related to the inhibition of TGF-β1/PI3K/Akt signal pathway.

Topics: Animals; Beclin-1; Cell Line; Cell Proliferation; Cell Survival; Chronic Disease; Disease Models, Animal; Drugs, Chinese Herbal; Epithelial Cells; Gastritis, Atrophic; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Methylnitronitrosoguanidine; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Dehydroevodiamine (DHE) is a quinazoline alkaloid isolated from a Chinese herbal medicine, named Euodiae Fructus (Wu-Zhu-Yu in Chinese). This study aimed to investigate the therapeutic effects and potential mechanism of DHE on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chronic atrophic gastritis (CAG) based on integrated approaches.. Therapeutic effects of DHE on serum biochemical indices and histopathology of gastric tissue in MNNG-induced CAG rats were analyzed. MNNG-induced GES-1 human gastric epithelial cell injury model was established. Cell viability and proliferation was quantified by a cell counting kit-8 assay. Cell morphology and mitochondrial membrane potential (MMP) were detected by a high content screening (HCS) assay. Cell migration and invasion were detected by a Transwell chamber. Moreover, UHPLC-Q-TOF/MS was performed to investigate the potential metabolites and signaling pathway affecting the protective effects of DHE on MNNG-induced cell migration and invasion of GES-1. Furthermore, in view of the key role of angiogenesis in the transformation of inflammation and cancer, this study explored relative mRNA and protein expression levels of HIF-1α-mediated VEGF pathway in vivo and in vitro by RT-PCR and Western Blotting, respectively.. The results showed that the therapeutic effects of DHE on CAG rats were presented in down-regulation serum biochemical indices and alleviating histological damage of gastric tissue. Besides, DHE has an effect on increasing cell proliferation of GES-1 cells, ameliorating MNNG-induced gastric epithelial cell damage and mitochondrial dysfunction. In addition, DHE could inhibit MNNG induced migration and invasion of GES-1 cells. Cell metabolomics analyses showed that the protective effect of DHE on GES-1 cells is mainly associated with the regulation of inflammation metabolites and energy metabolism related pathways. It was found that DHE has a regulating effect on tumor angiogenesis and can inhibit the relative gene and protein expression of HIF-1α-mediated VEGF signaling pathway.. The present work highlighted the role of DHE ameliorated gastric injury in MNNG-induced CAG rats in vivo and GES-1 cell migration in vitro by inhibiting HIF-1α/VEGF angiogenesis pathway. These results suggest that DHE may be the effective components of Euodiae Fructus, which provides a new agent for the treatment of CAG.

Topics: Alkaloids; Animals; Cell Proliferation; Cells, Cultured; Epithelial Cells; Gastritis, Atrophic; Humans; Methylnitronitrosoguanidine; Rats

This study investigated the effect and mechanism of Astragalus polysaccharides (APS) on chronic atrophic gastritis (CAG) induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in rats. Histomorphological, hormone-level, and immunohistochemistry experiments were used to investigate the gastric mucosal injury. Pathological changes were readily found in CAG rats. Compared to the control rats, the CAG rats showed significantly decreased plasma levels of gastrin and somatostatin while their motilin levels increased. Moreover, PGE2 in gastric tissue increased and serum sIgA decreased significantly, while the GSH/GSSG ratio showed no change. Immunohistochemical detection showed that the expression of EGFR, COX-2, and MMP-2 was higher in the gastric tissue of CAG rats. After APS treatment, the gastric morphology of CAG rats improved. APS increased plasma gastrin and somatostatin levels significantly but had no significant effect on the motilin level. APS also decreased tissue PGE2 and increased serum sIgA in CAG rats without affecting the GSH/GSSH ratio. This study suggested that APS had a beneficial effect on CAG rats by deregulating EGFR at its downstream effectors COX-2 and MMP-2.

Topics: Animals; Astragalus Plant; Chronic Disease; Female; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Glutathione; Male; Methylnitronitrosoguanidine; Polysaccharides; Rats; Rats, Sprague-Dawley; Somatostatin

The experiments presented here were done to evaluate whether the levels of CO2 in respiratory air during the 13C-bicarbonate breath test (13C-BBT) may be used as a marker of non-invasive diagnosis of the levels of atrophic gastritis. Twenty-eight patients with chronic gastritis and five healthy volunteers were enrolled in the study. Moreover, experimental gastritis was induced in rats by N-methy-N-nitro-N-nitrosoguanidine. In human, the levels of atrophic gastritis were evaluated from the vascular pattern of the gastric fornix. Total delta 13CO2 calculated from the 13C-BBT and the mucosal thickness ratio (MTR) were measured in rats with experimental gastritis. The levels of 13CO2 were significantly higher from patients with a vascular pattern at the fornix than in those without a vascular pattern (p<0.01). There was a good correlation between MTR and the levels of 13CO2, in rats with experimental gastritis (p<0.01). These findings indicate that the levels of 13CO2 during 13C-BBT reflect the levels of atrophic gastritis and show its clinical significance for non-invasive evaluation of atrophic gastritis. This has important clinical implications in selecting Helicobacter pylori-positive cases for therapy and follow-up.

Topics: Age Factors; Animals; Body Height; Body Weight; Breath Tests; Buffers; Carbon Dioxide; Carbon Isotopes; Disease Models, Animal; Gastric Mucosa; Gastritis, Atrophic; Humans; Male; Methylnitronitrosoguanidine; Rats; Rats, Wistar; Sex Factors; Sodium Bicarbonate

It has been demonstrated that mucosal cell proliferation in atrophic gastritis is significantly accelerated, although the dynamics of the cell proliferation and differentiation have not been well characterized. We sequentially analyzed the markers of proliferation and differentiation of rat atrophic gastritis induced by MNNG. Immunohistochemical staining by anti-BrdU, anti-PCNA, and anti-PDGF-BB antibodies demonstrated that cell proliferation in atrophic gastritis was accelerated not only in the parenchymal tissue but also in the mesenchymal tissue. Expression of a gap junction protein (connexin 32), which is a marker for differentiation of epithelial cells, was reduced during the progression of atrophy. Some apoptotic cells were observed in the lower to middle third of the atrophic mucosa, whereas apoptotic cells were rarely seen in normal mucosa, which suggests that apoptosis in these parts of the mucosa may be related to the occurrence of mucosal atrophy.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Division; Connexins; Gap Junction beta-1 Protein; Gastric Mucosa; Gastritis, Atrophic; Male; Methylnitronitrosoguanidine; Rats; Rats, Wistar

This study was conducted to examine the possible relationship among connexin 32 (Cx32) expression, cell proliferation and differentiation in the normal stomach, N-methyl-N'-nitro-nitrosoguanidine (MNNG)-induced atrophic gastritis, and carcinoma in rats. Atrophic gastritis and adenocarcinoma were induced by the administration of MNNG for 8 and 30 weeks, respectively. Cell proliferation was detected by staining with 5-bromo-2'-deoxyuridine (BrdU). The proliferative zone (BrdU-positive zone), located in the lower third of the gastric gland in controls, was elongated in atrophic gastritis. In adenocarcinoma, BrdU-positive cells were distributed diffusely. Cx32 expression was investigated by an indirect immunofluorescence method. In both control and atrophic gastritis specimens, Cx32 fluorescence was abundant in the surface epithelium, but was rarely detected in the glandular portion or the proliferative zone. The length of the Cx32-positive mucosa was significantly less than the control value in atrophic gastritis and no such positive mucosa was visible in adenocarcinoma. The results of this study indicate that the loss of cell-cell communication through the gap junction, associated with elongation of the proliferative cell zone, may be manifested much earlier than carcinoma. We regard this model as useful for investigating the development of atrophic gastritis into gastric carcinoma.

Topics: Adenocarcinoma; Animals; Carcinogens; Cell Communication; Cell Differentiation; Cell Division; Connexins; Female; Fluorescent Antibody Technique, Indirect; Gap Junction beta-1 Protein; Gastric Mucosa; Gastritis, Atrophic; Methylnitronitrosoguanidine; Rats; Rats, Wistar; Stomach Neoplasms

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

The relationship between operative procedures and the incidence of remnant stomach carcinoma was investigated in male Wistar rats orally treated with N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine]. A total of 178 rats was divided into 5 groups: After gastrectomy in which half of the glandular stomach was removed, group 1 received Billroth II reconstruction; group 2 was given short Roux-en-Y reconstruction; group 3 had long Roux-en-Y reconstruction; group 4 received gastrotomy alone; and group 5 consisted of nonoperated control rats. The incidence of gastric adenocarcinoma in MNNG-treated rats was significantly higher in group 1 (38.9%) as compared with that in group 3 (7.1%) and that in group 5 (9.5%). All tumors developed in the gastroenteric anastomotic area. Histologic examination of the gastric mucosa revealed atrophic gastritis and erosion in the gastroenteric anastomotic area, especially in rats with carcinoma. These findings seem to implicate the duodenogastric reflux, especially the reflux of bile acids, in the development of remnant stomach carcinoma in rats.

Topics: Animals; Carcinoma; Duodenogastric Reflux; Gastrectomy; Gastric Mucosa; Gastritis, Atrophic; Gastrostomy; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms; Time Factors