methylnitronitrosoguanidine and Inflammation

Chi006Eese herbal medicine Weifuchun Tablets (WFC) approved by the State Food and Drug Administration in 1982 has been widely used in treating a variety of chronic stomach disorders including Chronic atrophic gastritis (CAG) and Gastric precancerous lesions in China clinically. This study aimed to investigate the efficacy and potential mechanism of WFC in treating Gastric intestinal metaplasia (GIM) and Gastric dysplasia (GDys).. Rat GIM and GDys established by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) combined with hot paste, ethanol injury, and intermittent fasting were intervened by WFC. Body weight, histopathology, pH of gastric acid, pepsin activity, intestinal metaplasia index and inflammation were detected. Rat bone marrow derived macrophages (BMDMs) pretreated with WFC were stimulated by LPS. Inflammatory factors and the nuclear factor-kappa B (NF-κB) pathway were assessed. GES-1 cells pretreated by WFC were stimulated by MNNG and TNF-α, intestinal metaplasia index, the NF-κB pathway and interaction between P65 and CDX2 were detected.. WFC improved rat body weight, histopathology, pH value of gastric acid, activity of gastric pepsin, intestinal metaplasia (CDX2), inflammation (IL-1β, IL-6 and TNF-α), macrophage aggregation (CD68) in gastric mucosa in rat GIM and GDys. WFC inhibited inflammation (IL-1β and TNF-α) by inactivating the NF-κB pathway. WFC reduced the expression of CDX2 by inhibiting the binding of CDX2 promoter TSS upstream region with p65.. WFC blocked GIM and GDys associated with inflammation by regulating the NF-κB pathway.

Topics: Animals; Gastric Mucosa; Hyperplasia; Inflammation; Metaplasia; Methylnitronitrosoguanidine; NF-kappa B; Pepsin A; Precancerous Conditions; Rats; Stomach Neoplasms; Tumor Necrosis Factor-alpha

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a common alkylating agent, which can be experimentally used as a chemical mutagen and carcinogen, extensively existing in the environment. Folic acid (FA), part of the B group of vitamins, plays an important role in defending against inflammation and reducing the risk of cancers. Nevertheless, there is little research on the protective effects of FA against MNNG-induced esophageal inflammation, and its underlying mechanism still remains elusive. Hence, in the present study, we exposed MNNG to SD rats and esophageal cells to establish the esophageal inflammation models. Our research aims to explore the protective roles of FA against esophageal inflammation induced by MNNG via NF-κB pathway by CCK-8, EdU, RT-qPCR, ELISA, H&E, Western blot. Our results revealed that MNNG decreased the viability of esophageal cells, which was restored under FA intervention. Besides, FA relieved the elevation of IL-6, IL-8 and TNF-α in MNNG-induced esophageal inflammation. Moreover, histopathological analysis showed that epithelial spinous cells proliferated in mucous layer, and inflammatory cells were locally infiltrated in the submucosa after MNNG exposure, while the pathological damage of esophageal tissues was gradually alleviated along with increasing FA doses. And Western blot results demonstrated that FA could relieve the rise of phosphorylated IκBα (p-IκBα) and phosphorylated p65 (p-p65) proteins induced by MNNG. Therefore, it is reasonable to believe that FA has a crucial role in preventing MNNG-induced esophageal inflammation through inhibiting the NF-κB pathway, thereby down-regulating the expressions of IL-6, IL-8 and TNF-α.

Topics: Animals; Folic Acid; Inflammation; Interleukin-6; Interleukin-8; Methylnitronitrosoguanidine; NF-kappa B; NF-KappaB Inhibitor alpha; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Protective effect of Tagetes erecta flowers essential oils was investigated on oxidative stress, immune response, inflammation, and apoptosis against N-methyl-N'nitro-N-nitroguanidine (MNNG) induced gastric cancer in rats. Essential oil were extracted from Tagetes erecta flowers and analyzed using gas chromatography-mass spectrometry (GC-MS). For observing a protective effect against MNNG induced gastric cancer, we divided rats into 4 groups (group A to D) having 10 rats in each group. Performed various experiments and measured a different parameters to investigate antioxidant activity, immune response, anti-inflammatory and anti-apoptotic activity. The levels of malondialdehyde were markedly increased in the presence of N-methyl-N'nitro-N-nitroguanidine, whereas, the antioxidant activities of superoxide dismutase, and catalase were lowered in the treated rats in contrast with the control. Intervention with TEEO to gastric cancer-induced rats upregulated the redox status and the activity of the immune system to decrease cancer risk. The proinflammatory cytokines (IL-6 and TNF-α) secretions that were induced by MNNG were markedly inhibited by TEEO. Administration of TEEO also significantly reduced terminal deoxynucleotidyl transferase dUTP nick end labeling positive gastric cancer cells, expression of mRNA of caspase-3, and Bax. Whereas, the expression of Bcl-2 was increased. Additionally, downregulation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and IκBα degradation and the nuclear factor-κB (NF-κB) p65 expression in tissues of the stomach of MNNG-induced-rats were markedly elevated due to TEEO. This suggested possession of TEEO with a protective shield against MNNG induced gastric cancer by the exertion of antioxidative stress, anti-apoptotic response, the anti-inflammatory response through Nrf2/HO-1, and NF-κB signaling pathways.

Topics: Animals; Antioxidants; Apoptosis; Catalase; Cell Line, Tumor; Flowers; Gas Chromatography-Mass Spectrometry; Guanidines; Heme Oxygenase (Decyclizing); Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Inflammation; Male; Methylnitronitrosoguanidine; Mice; Neoplasm Proteins; NF-E2-Related Factor 2; NF-KappaB Inhibitor alpha; Nucleocytoplasmic Transport Proteins; Oils, Volatile; Oxidative Stress; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Signal Transduction; Stomach Neoplasms; Tagetes

Both Helicobacter pylori (Hp) and bile acids are gastric carcinogens. An experimental model of duodenogastric reflux in Mongolian gerbils was developed and was used to study the effects of Hp infection and duodenogastric reflux on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced glandular stomach tumorigenesis independently and synergistically. Male Mongolian gerbils underwent both inoculation with Hp, and had duodenogastric reflux (DR) induced, or neither, followed by MNNG administration. Animals were sacrificed at week 40, and histopathological examination of their excised stomachs and serological investigation were performed. Glandular stomach adenocarcinomas were observed in animals that underwent Hp inoculation and/or induction of DR after MNNG administration, and glandular stomach adenomas were found in animals inoculated with Hp after MNNG administration. The incidence of glandular stomach tumors was significantly higher in animals inoculated with Hp after MNNG administration and in animals undergoing combined Hp inoculation, DR induction and MNNG administration than in animals only administered MNNG. These findings indicate that Hp infection has a stronger tumorigenic effect than the exposure to duodenal contents, and duodenal contents may attenuate the effect of Hp on glandular stomach tumorigenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Deoxyguanosine; Duodenogastric Reflux; Gastrointestinal Contents; Gerbillinae; Helicobacter Infections; Inflammation; Male; Methylnitronitrosoguanidine; Mongolia; Neoplasms, Glandular and Epithelial; Stomach Neoplasms