methylnitronitrosoguanidine and Intestinal-Diseases

Doublecortin and calcium/calmodulin-dependent protein kinase-like-1 (DCAMKL1) is a candidate marker for progenitor cells in the gastrointestinal mucosa. Lineage cells in the gastric mucosa are derived from progenitor cells, but this process can be altered after injury. Therefore, we explored DCAMKL1 expression under pathological conditions.. An immunohistochemical analysis was performed in rat stomach with acute superficial injury, chronic ulcer, intestinal metaplasia and dysplasia.. DCAMKL1 was exclusively expressed in immature quiescent cells in the isthmus of normal fundic glands, where putative progenitor cells are thought to reside. DCAMKL1-positive cells and proliferating cells shed into the lumen after superficial injury and re-appeared during the regenerative process, mainly in the superficial mucosa. In the marginal mucosa around the active ulcer, parietal and chief cells diminished, foveolar hyperplasia was evident, and trefoil factor family 2 (TFF2)/spasmolytic polypeptide-expressing metaplasia (SPEM) emerged at the gland base. DCAMKL1 cells re-emerged in the deep mucosa juxtaposed with SPEM and proliferating cells. In the healing ulcer, the TFF2 cell population expanded and seemed to redifferentiate to chief cells, while proliferating cells and DCAMKL1 cells appeared above and below the TFF2 cells to promote healing. SPEM appeared and PCNA cells increased in the intestinalized mucosa, and DCAMKL1 was expressed in the proximity of the PCNA cells in the deep mucosa. DCAMKL1, PCNA and TFF2 were expressed in different dysplastic cells lining dilated glands near SPEM.. The ultrastructural appearance of DCAMKL1-positive cells and the expression patterns of DCAMKL1 in normal and pathological states indicate that the cells belong to a progenitor cell population. DCAMKL1 expression is closely associated with TFF2/SPEM cells after injury. DCAMKL1 cells repopulate close to proliferating, hyperplastic, metaplastic and dysplastic cells, and the progenitor zone shifts according to the pathological circumstances.

Topics: Acetic Acid; Animals; Biomarkers; Cell Proliferation; Disease Models, Animal; Doublecortin Protein; Doublecortin-Like Kinases; Gastric Mucosa; Intestinal Diseases; Male; Metaplasia; Methylnitronitrosoguanidine; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Regeneration; Stem Cells; Stomach; Stomach Diseases; Stomach Ulcer; Trefoil Factor-2

The effects of chronic progesterone treatment on gastric tumorigenesis were examined in 6-week-old male SD rats. The rats were castrated, progesterone or testosterone pellets were implanted, and, starting one week after the operation, 100 mg/liter of N-methyl-N'-nitro- N-nitrosoguanidine (MNNG) was administered in the drinking water for 16 weeks. Every 2 months the pellets were changed. Group 1 animals received castration plus MNNG while Groups 2 and 3 also received progesterone and testosterone, respectively. In the Group 4 case, progesterone and testosterone were administered alternately for 2-month periods and in Group 5 MNNG was given to intact animals. All survivors were killed one year after the start of MNNG treatment. In Group 1 the incidence of gastric tumors was significantly decreased as compared with the Group 5 value. The Group 2 incidence, in contrast, was similar to that in Group 5, and the size of the observed gastric tumors was massively increased. The area of the pyloric gland mucosa was also greater than in other groups. Testosterone treatment was associated with a less pronounced increase in tumor size and a recovery in incidence. The results indicate that progesterone may exert a promoting influence on gastric tumor development.

Topics: Animals; Body Weight; Drug Synergism; Intestinal Diseases; Male; Methylnitronitrosoguanidine; Orchiectomy; Precancerous Conditions; Progesterone; Rats; Rats, Sprague-Dawley; Stomach Neoplasms; Testosterone

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was given to 3 groups of male Wistar rats in different doses of 25 micrograms/ml, 50 micrograms/ml and 100 micrograms/ml with their drinking water for 32 weeks. After 50 weeks the antrum region of the stomach was investigated by serial sections. All animals showed tubules with metaplastic intestinal epithelium. The different values of metaplastic glands in the antrum region of the stomach were 187 (25 micrograms MNNG), 76 (50 micrograms MNNG) and 51 (100 micrograms MNNG). They indicate an inverse relationship of the frequency of intestinal metaplasia and the MNNG dose. As opposed to this dose-response pattern, cytotoxic alterations, regenerative hyperplastic lesions and tumours of the stomach are more frequent after medium of high MNNG doses. It is therefore suggested that the induction of intestinal metaplasia is a specific effect of the carcinogen mainly in the low dose range.

Topics: Animals; Dose-Response Relationship, Drug; Intestinal Diseases; Intestine, Small; Male; Metaplasia; Methylnitronitrosoguanidine; Pyloric Antrum; Rats; Rats, Inbred Strains; Stomach Diseases

The effects of the C-terminal tetrapeptide of gastrin, tetragastrin, on the colonic mucosa on Days 15 and 25 during intrarectal administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and its effects on the incidences of colonic tumors in experimental Wk 20 and 35 were investigated in Wistar rats. Administration of tetragastrin in depot form during instillation of MNNG resulted in significant decreases in the incidences of mucosal erosions, ulcerations, and atypical regenerative glandular hyperplasias in the colonic mucosa, most of these lesions being greater in the distal half of the colon. Administration of tetragastrin also significantly decreased the incidences and/or numbers of colonic tumors in Wk 20 and 35. The distribution of colonic tumors induced in Wk 20 and 35 corresponded well to those of erosions, ulcerations, and atypical regenerative glandular hyperplasias induced during the administration of MNNG. These findings suggest that the effect of tetragastrin in decreasing the incidences of erosions, ulcerations, and atypical regenerative glandular hyperplasias in the colonic mucosa during instillation of MNNG is related to its effect in reducing the development of colonic tumors.

Topics: Animals; Colonic Neoplasms; Drug Administration Schedule; Gastrins; Intestinal Diseases; Intestinal Mucosa; Methylnitronitrosoguanidine; Rats; Tetragastrin; Time Factors