Modulation of methotrexate-induced intestinal mucosal injury by dietary factors.

Methotrexate (MTX)-induced intestinal mucosal injury in animals has been studied to understand how MTX can cause gastrointestinal disorders, but the pathogenesis of gastrointestinal disorders is still uncertain. We have attempted to reveal how dietary factors influence intestinal toxicity due to MTX. Mice were fed normal chow (NC) or a high-fat high-sucrose diet (HFHSD) before oral administration of MTX. While MTX significantly decreased the survival rates of mice fed HFHSD, the intestinal epithelial injury was detected. MTX excretion in the feces of mice fed HFHSD was reduced. Change of diets between NC and HFHSD influences the survival. The survival rates of the mice fed a high-sucrose diet or control diet were higher than those fed HFHSD. Higher survival rates were observed in mice fed a high-fat high-sucrose diet modified (HFHSD-M) in which casein was replaced by soybean-derived proteins. The survival rates of mice treated with vancomycin were lower than those administered neomycin. Microbiome and metabolome analyses on feces suggest a similarity of the intestinal environments of mice fed NC and HFHSD-M. HFHSD may modify MTX-induced toxicity in intestinal epithelia on account of an altered MTX distribution as a result of change in the intestinal environment.

Effects of nicotine on cultured cells suggest that it can influence the formation and resorption of bone.

The acute effects of nicotine [1-methyl-2-(3-pyridyl)pyrrolidine] on the formation and resorption of bone were examined in cultures of clonal rat calvarial osteogenic cells (ROB-C26) and clonal mouse calvarial preosteoblastic cells (MC3T3-E1), as well as in osteoclast-like cells formed during coculture of mouse bone marrow cells and clonal stromal cells from mouse bone marrow, ST2 cells, at concentrations that occur in the saliva of smokeless tobacco users. Nicotine stimulated the rate of deposition of Ca(2+) by ROB-C26 cells, as well as the alkaline phosphatase activity of these cells, in a dose-dependent manner. However, both activities decreased in MC3T3-E1 cells that had been exposed to nicotine. These results indicate that nicotine affected osteoblastic differentiation in osteoblast-like cells. By contrast, nicotine reduced, in a dose-dependent manner, the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) and the formation of pits on slices of dentine, both of which are typical characteristics of osteoclasts. Our results suggest that nicotine might have critical effects on bone metabolism.