The present study was designed to investigate the modulatory role of dietary curcumin on (i) azoxymethane (AOM)-induced ornithine decarboxylase (ODC), tyrosine protein kinase (TPK) and arachidonic acid metabolism in liver and colonic mucosa of male F344 rats, (ii) in vitro arachidonic acid metabolism in the liver and colonic mucosa and (iii) AOM-induced aberrant crypt foci (ACF) formation in the colon of F344 rats. At 5 weeks of age groups of animals were fed one of the experimental diets containing 0 or 2000 p.p.m. curcumin. Two weeks later all the animals except the vehicle-treated groups were given s.c. injections of AOM, 15 mg/kg body wt, once weekly for 2 weeks. The animals intended for biochemical study were killed 5 days later and the colonic mucosa and liver were analyzed for ODC, TPK, lipoxygenase and cyclo-oxygenase metabolites. The animals intended for ACF study were killed 9 weeks later and analyzed for ACF in the colon. The results indicated that in saline-treated animals dietary curcumin significantly inhibited the ODC (P < 0.001) and TPK (P < 0.05) activities in the liver and colonic mucosa. Dietary curcumin significantly decreased the levels of AOM-induced ODC activity in the liver and colon (P < 0.0001) and TPK activity in the liver and colon (P < 0.01-0.0001) and the formation of 5(S)-, 8(S)-, 12(S)- and 15(S)-hydroxyeicosatetraenoic acids (HETEs) in the liver and colon (P < 0.0001). Also, curcumin suppressed AOM-induced prostaglandin (PG) and thromboxane (Tx) formation in the liver (PGE2, PGF2 alpha, PGD2, 6-keto-PGF1 alpha and TxB2 to 40, 59, 55, 53 and 39% respectively) and in the colon (PGE2 and PGF2 alpha to 39 and 41% respectively). Further, dietary curcumin reduced the in vitro formation of HETEs, PGs and Tx in a dose-dependent manner. AOM-induced colonic ACF were significantly (P < 0.001) inhibited in the animals fed the curcumin diet. The results of the present study indicate that curcumin, present in turmeric, inhibits AOM-induced colonic preneoplastic lesions and other cellular events relevant to colon carcinogenesis.
Purpose: Epidemiologic studies have linked the consumption of fruits and vegetables to reduced risk of several types of cancer. Laboratory animal model studies have provided evidence that stilbenes, phenolic compounds present in grapes and blueberries, play a role in inhibiting the risk of certain cancers. Pterostilbene, a naturally occurring stilbene from blueberries, was tested for its preventive activity against colon carcinogenesis. Experimental Design: Experiments were designed to study the inhibitory effect of pterostilbene against the formation of azoxymethane-induced colonic aberrant crypt foci (ACF) preneoplastic lesions in male F344 rats. Beginning at 7 weeks of age, rats were treated with azoxymethane (15 mg/kg body weight s.c., once weekly for 2 weeks). One day after the second azoxymethane treatment, rats were fed experimental diets containing 0 or 40 ppm of pterostilbene. At 8 weeks after the second azoxymethane treatment, all rats were sacrificed, and colons were evaluated for ACF formation and for inhibition of inducible nitric oxide synthase (iNOS) and proliferating cell nuclear antigen. Effects on mucin MUC2 were also determined. Results: Administration of pterostilbene for 8 weeks significantly suppressed azoxymethaneinduced formation of ACF (57% inhibition, P < 0.001) and multiple clusters of aberrant crypts (29% inhibition, P < 0.01). Importantly, dietary pterostilbene also suppressed azoxymethaneinduced colonic cell proliferation and iNOS expression. Inhibition of iNOS expression by pterostilbene was confirmed in cultured human colon cancer cells. Conclusions:The results of the present study suggest that pterostilbene, a compound present in blueberries, is of great interest for the prevention of colon cancer.Stilbenes, such as resveratrol and pterostilbene, are a subset of naturally occurring phenolic compounds known to have diverse pharmacologic activities including cancer chemopreventive activity (1 -4). Stilbenes have been found in some berries (e.g., blueberries, cranberries, sparkleberries, lingonberries, and grapes; ref. 5), thus, consumption of these small fruits may help improve health. It is interesting that dietary black raspberries significantly suppressed N-nitrosomethylbenzylamine -induced rat esophageal carcinogenesis (6). The discovery of resveratrol as a cancer-preventive agent has fostered interest in testing the cancer-preventive activity of other naturally occurring stilbenes in many laboratories. Notably, pterostilbene, a dimethylether analogue of resveratrol, was found to be as effective as resveratrol in preventing carcinogeninduced preneoplastic lesions in a mouse mammary organ culture model (2). Additionally, i.v. administration of pterostilbene to mice inhibited metastatic growth of B16M-F10 melanoma cells in the liver, a common site for metastasis development (7).Pterostilbene and resveratrol have very similar pharmacologic properties (2,8). In addition to the aforementioned activity in the mouse mammary organ culture model, both compounds are strong antio...
Stilbenes are phytochemicals present in grapes, berries, peanuts and red wine. A widely studied stilbene, resveratrol (trans-3,5,4'-trihydroxystilbene), has been shown to exert antioxidant, anti-inflammatory, chemopreventive and antiaging effects in a number of biological systems. We reported earlier that pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene), a structurally related stilbene found in blueberries, was effective in reducing the incidence and multiplicity of aberrant crypt foci formation in the colon of rats injected with azoxymethane (AOM). Our present study was to identify the chemopreventive potential of pterostilbene with colonic tumor formation as an end point and further to evaluate the mechanistic action of pterostilbene during colon carcinogenesis. F344 rats were given two AOM injections subcutaneously when they were 7 and 8 weeks old and continuously fed the control or 40 p.p.m. pterostilbene diet for 45 weeks. Overall analyses indicated that pterostilbene reduced colon tumor multiplicity of non-invasive adenocarcinomas, lowered proliferating cell nuclear antigen and downregulated the expression of beta-catenin and cyclin D1. Pterostilbene decreased mucosal levels of the proinflammatory cytokines, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-4. Colon tumors from pterostilbene-fed animals showed reduced expression of inflammatory markers as well as nuclear staining for phospho-p65, a key molecule in the nuclear factor-kappaB pathway. In HT-29 cells, pterostilbene reduced the protein levels of beta-catenin, cyclin D1 and c-MYC, altered the cellular localization of beta-catenin and inhibited the phosphorylation of p65. Our data with pterostilbene in suppressing colon tumorigenesis, cell proliferation as well as key inflammatory markers in vivo and in vitro suggest the potential use of pterostilbene for colon cancer prevention.
This study was conducted to obtain additional information about the adaptations after 12 wk of high-fat diet (HFD) per se or HFD combined with endurance training in the rat using a two [diet: carbohydrate (CHO) or HFD] by two (training: sedentary or trained) by two (condition at death: rested or exercised) factorial design. Adaptation to prolonged HFD increases maximal O2 uptake (VO2max; 13%, P less than 0.05) and submaximal running endurance (+64%, P less than 0.05). This enhancement in exercise capacity could be attributed to 1) an increase in skeletal muscle aerobic enzyme activities (3-hydroxyacyl-CoA dehydrogenase and citrate synthase in soleus and red quadriceps) or 2) a decrease in liver glycogen breakdown in response to 1 h exercise at 80% VO2max. When training is superimposed to HFD, the most prominent finding provided by this study is that the diet-induced effects are cumulative with the well-known training effect on VO2max, exercise endurance, oxidative capacity of red muscle, and metabolic responses to exercise, with a further reduction in liver glycogen breakdown.
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