Abnormal Savda Munziq, an Herbal Preparation of Traditional Uighur Medicine, May Prevent 1,2-dimethylhydrazine-Induced Rat Colon Carcinogenesis.

The study tried to assess the chemoprotective effect of abnormal Savda Munziq (ASMq) on 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Male F344 rats were randomized into eight groups: Group 1 was served as control, no DMH injection was given and treated daily with normal saline. Rats in Groups 2-8 were given a single intraperitoneal injection of DMH (20 mg/kg body weight) at the beginning of the study. Group 2 was served as negative control, administered with normal saline until the end of the experiment after the single DMH injection. Groups 3-5 were served as pretreatment group, administered with ASMq ethanol extract at 400, 800 and 1600 mg/kg body weight, respectively, until the 45th day, continued by normal saline administration for another 45 days. Groups 6-8 were served as the treatment group, administered with normal saline for the first 45 days from the day of DMH injection, ASMq ethanol extract at three different doses to be administered until the end of the second 45th day. All rats were sacrificed at 91st day and the colons were analyzed for aberrant crypt foci (ACF) formation and crypt multiplicity. Results showed that ASMq ethanol extract reduced the number of ACF, AC and crypt multiplicity significantly (P < .05). It suggested that ASMq ethanol extract had chemoprotective effects on DMH-induced colon carcinogenesis, by suppressing the development of preneoplastic lesions, and probably exerted protection against the initiation and promotion steps of colon carcinogenesis.

Synergic effect of vitamin A and high-fat diet in adipose tissue development and nuclear receptor expression in young rats.

In order to study the effects of dietary lipids and vitamin A on the development of adipose tissues, young rats were submitted for 8 d to a control or to two cafeteria diets with normal (Caf) or higher (Caf + ) vitamin A levels. Retinoid (retinoic acid receptor (RAR) a, RARg, retinoid X receptor(RXR) alpha) and fatty acid (PPARgamma) receptor mRNA was measured in the subcutaneous white adipose tissue (Swat) and in isolated mature adipocytes by RT-PCR. The stroma vascular fraction was cultured in vitro to test the capacities of the adipocyte precursors to proliferate and differentiate.The Caf diet enriched in vitamin A resulted in an increased adiposity, due to increased adipocyte hypertrophy. This was concomitant with a lower expression of RARa and RARg mRNA (234.6 and 238.6 %) and a higher expression of PPARgamma (+59 %) in the Swat and, to a less extent,in isolated adipocytes. Positive correlations were obtained between PPARgamma mRNA and Swat weights and between PPARgamma and RXRalpha mRNA. By contrast, RARgamma mRNA and Swat masses were negatively correlated. The adipocyte precursors from Caf + Swat proliferated more,in vitro, at the beginning of the culture. This difference progressively disappeared and was totally absent after 8 d of culture, but with a higher percentage of differentiated preadipocytes (+80.3 %) in the Caf + group. In conclusion, lipids and vitamin A act synergistically on the normal growth of the adipose tissue in young rats, concomitant with an imbalance in the pattern of the nuclear receptors. These changes influence the early normal development of the endogenous adipocyte precursors.

The effect of body weight on altered expression of nuclear receptors and cyclooxygenase-2 in human colorectal cancers.

BACKGROUND: Epidemiological studies on risk factors for colorectal cancer (CRC) have mainly focused on diet, and being overweight is now recognized to contribute significantly to CRC risk. Overweight and obesity are defined as an excess of adipose tissue mass and are associated with disorders in lipid metabolism. Peroxisome proliferator-activated receptors (PPARs) and retinoid-activated receptors (RARs and RXRs) are important modulators of lipid metabolism and cellular homeostasis. Alterations in expression and activity of these ligand-activated transcription factors might be involved in obesity-associated diseases, which include CRC. Cyclooxygenase-2 (COX-2) also plays a critical role in lipid metabolism and alterations in COX-2 expression have already been associated with unfavourable clinical outcomes in epithelial tumors. The objective of this study is to examine the hypothesis questioning the relationship between alterations in the expression of nuclear receptors and COX-2 and the weight status among male subjects with CRC. METHOD: The mRNA expression of the different nuclear receptor subtypes and of COX-2 was measured in 20 resected samples of CRC and paired non-tumor tissues. The association between expression patterns and weight status defined as a body mass index (BMI) was statistically analyzed. RESULTS: No changes were observed in PPAR gamma mRNA expression while the expression of PPAR delta, retinoid-activated receptors and COX-2 were significantly increased in cancer tissues compared to normal colon mucosa (P or= 25) compared to subjects with healthy BMI (P = 0.002). CONCLUSION: Our findings show that alterations in the pattern of nuclear receptor expression observed in CRC do not appear to be correlated with patient weight status. However, the analysis of COX-2 expression in normal colon mucosa from subjects with a high BMI suggests that COX-2 deregulation might be driven by excess weight during the colon carcinogenesis process.

A high-fat diet generates alterations in nuclear receptor expression: prevention by vitamin A and links with cyclooxygenase-2 and beta-catenin.

Epidemiologic studies suggest that intake of high energy from fat, inducing overweight, increases the risk of cancer development and promotes colon carcinogenesis. It is therefore important to understand which parameters are affected early on by a high-fat diet in order to devise and improve protective nutritional strategies. We investigated the effect of high energy/fat intake on colon mucosa of male Wistar rats induced by a single 1,2-dimethylhydrazine (DMH) injection. Aberrant crypt foci (ACF) were numbered and modifications in cyclooxygenase-2 (COX-2) and beta-catenin levels assessed. Peroxisome proliferator- and retinoic acid-activated receptors (PPAR and RAR, RXR) are key transcription factors regulating gene expression in response to nutrient-activated signals. A short-term study was designed to evaluate whether alterations in mRNA expression of nuclear receptors can be detected at the beginning of the weight gain phase induced by an appetizing hyperlipidic diet (HLD). HLD consumption induced early downregulation of PPARgamma (-33.1%) and RARbeta (-53.1%) mRNA expression concomitant with an increase in levels of COX-2 (+45.5%) and beta-catenin (+84.56%) and in the number of ACF (191.56 +/- 88.60 vs. 21.14 +/- 11.64, p < 0.05). These findings suggest that HLD increases ACF occurrence, possibly through alterations in the mRNA expression profile of nuclear receptors. Moreover, the use HLD rich in retinyl esters or supplemented with all-trans retinoic acid led to a reduction in the number of ACF. Vitamin A also prevented HLD-induced alterations and the increase in levels of COX-2 and beta-catenin. The present observations show a protective role for vitamin A against disturbances associated with HLD exposure in induced colon carcinogenesis.

Vitamin A prevents high fat diet-induced ACF development and modifies the pattern of expression of peroxisome proliferator and retinoic acid receptor m-RNA.

Some dietary compounds, among them fats, are modulators of colon cancer risk. This study reports the modulating effects of n-6, with or without vitamin A, on promotion of colon preneoplasic lesions induced by 1,2-dimethylhydrazine (DMH) and on the expression of nuclear receptors (PPARgamma, RXRalpha, and RARbeta). One group of male Fisher rats was fed a basic diet (5% safflower oil) and two groups were fed a high-fat diet (HFD, 25% safflower oil). Of these, one was supplemented with 200 IU vitamin A for 5 mo. The safflower oil contained polyunsaturated fatty acids, mainly linoleic acid (73%). The data showed an increasing effect of safflower oil-enriched diet on aberrant crypt foci occurrence and multiplicity. This effect was impaired by vitamin A supplementation. In addition, an HFD-related up-regulation of PPARgamma and a concomitant down-regulation of RARbeta mRNA expression were observed with or without chemical initiation and were prevented by vitamin A. Moreover, when treated with DMH, HFD rats exhibited a dramatically decreased expression of RXRalpha mRNA (-49%). It was hypothesized that HFD, leading to hyperexpression of PPARgamma, would produce an alteration of retinoic acid signaling and, in this way, create a background modulating colon cancer risk.

Effects of dairy products on heterocyclic aromatic amine-induced rat colon carcinogenesis.

Heterocyclic aromatic amines (HAA) are initiating agents of colon carcinogenesis in animals and are suspected in the aetiology of human colon cancer. In the context of prevention, it seems interesting to test possible protective compounds, such as fermented milk, against HAA food carcinogens. Male F344 rats were used in a model of HAA-induced colon carcinogenesis. The HAA, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (ratio 1:1:1) were administered in food for a 7 week induction period, with a cumulative dose of 250 mg of the HAA, per kg body weight. Four different diets were given to four rat groups: supplemented with 20% water, 30% non-fermented milk, 30% Bifidobacterium animalis DN-173 010 fermented milk and 30% Streptococcus thermophilus DN-001 158 fermented milk. Fecal mutagenicity was quantified during the induction period. At the end of the treatment, DNA lesion levels were determined in the liver and colon using the number of 8-oxo-7,8-dihydro-2'desoxyguanosine (8-oxodGuo) oxidized bases, "3D Test" and comet assay. The metabolic activity of hepatic and colon cytochrome P450 (CYP450) 1A1 and 1A2 was also evaluated. Aberrant colon crypts were scored, 8 weeks after the last HAA treatment. The results showed that dairy products decreased the incidence of aberrant crypts in rats: 66% inhibition with the milk-supplemented diet, 96% inhibition with the B.animalis fermented milk-supplemented diet and 93% inhibition with the S.thermophilus fermented milk-supplemented diet. Intermediate biomarkers showed that there was a decrease in HAA metabolism, fecal mutagenicity and colon DNA lesions. These results demonstrate the early protective effect of milk in the carcinogenesis process. This effect being more pronounced in the case of milk fermented by lactic acid bacteria.