These results suggest that ADM exerts cytostatic effects on neoplastic and normal undifferentiated cells through the inhibition of DNA synthesis by DNA intercalation, and cytotoxic effects on neoplastic cells through the accumulation of reactive oxygen species resulting from low scavenger enzyme activities. The cytotoxic effects on normal differentiated cells may be related to the high levels of production of reactive oxygen species due to high mitochondrial NADH-cytochrome c reductase activity.
In enamel fluorosis model rats treated with sodium fluoride, secretory ameloblasts of incisor tooth germs exhibited disruption of intracellular trafficking. We examined whether heterotrimeric G proteins participated in the disruption of vesicular trafficking of the secretory ameloblast exposed to fluoride, using immunoblotting and pertussis toxin (IAP)-induced adenosyl diphosphate (ADP)-ribosylation for membrane fractions of the cell. Immunoblotting of crude membranes, post supernatants of the ameloblast, with anti-G(alpha i3/alpha o) and anti-G(alpha s) antibodies showed that Gi3 or Go proteins existed in the secretory ameloblast, but Gs protein did not. Immunoblotting of the subcellular membrane fractions indicated that the Gi3 or Go proteins were located in the Golgi membrane, but were not in the rough endoplasmic reticulum (rER) membrane. Autoradiograph of IAP-induced ADP-ribosylation, however, showed the existence of IAP-sensitive G proteins both in rER and Golgi membranes. Fluoride treatment decreased the G proteins bound to both membranes. These findings indicate that different G proteins, both of which are IAP-sensitive, are present in the rER and Golgi apparatus, and suggest that these G proteins participate in the disturbance of intracellular transport of the secretory ameloblast exposed to fluoride.
Fluoride, which is an environmental toxicant, is a potent inducer of mottled enamel in humans and rats. To define the influence of fluoride on the secretory pathway in enamel fluorosis, mottled enamel was induced in the incisor tooth germs of rats by subcutaneous injections of sodium fluoride for 4 days, and then morphological and cytochemical changes of the secretory ameloblast were examined in the tooth germs with HRP-labeled lectin (Con A, GS-I, SBA and PNA) and En3 antibody labeling amelogenins. The accumulation of small vesicles on the route of the secretory pathway between the rER and the Golgi apparatus, disorder of Golgi stacks, and formation of abnormal large granules in distal cytoplasm were seen in the secretory ameloblast. Lectin staining patterns of the secretory ameloblast indicated the disturbance of the vesicular transport between the rER and the Golgi apparatus, and disorganization of the Golgi stack. Immunolabeling of the cell showed disruption of the sorting and fusion process on the secretory pathway. These results suggest that the fluoride disturbs the intracellular transport in the synthesis-secretory pathway of the ameloblast, and that this effect of fluoride on the synthesis-secretory pathway participates in the formation of enamel fluorosis.
To examine the effect of food restriction on immune functions in the tumor-bearing state, mice were divided into a control group (fed 5.0 g diet/d; 71 kJ/d) and a 60% food-restricted group (fed 3.0 g diet/d; 43 kJ/d) at 8-wk of age, and 4 wk later, L1210 tumor cells were inoculated intradermally. In the food-restricted mice, tumor growth was significantly suppressed, and mean survival time after the tumor inoculation was prolonged (P < 0.05). The plasma concentrations of two antitumor cytokines, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), were greater in the food-restricted group before tumor inoculation (P < 0. 05). Furthermore, the food-restricted mice had significantly higher plasma levels of IFN-gamma and TNF-alpha after tumor inoculation, although the treatment significantly increased these cytokine levels in both groups. Splenic natural killer cell cytotoxicity was also higher in the tumor-bearing food-restricted mice than in controls (P < 0.05). Food-restricted mice have strong antitumor immunity, and as a result, tumor growth is suppressed and survival time is prolonged in these mice.
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