Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli1638N/+ mice

Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)(1638N/+) mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc(1638N/+) mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 +/- 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc(1638N/+) mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.     

Colonic cell proliferation and aberrant crypt foci formation are inhibited by dairy glycosphingolipids in 1, 2-dimethylhydrazine-treated CF1 mice

Dietary sphingomyelin (SM) inhibits early stages of colon cancer (appearance of aberrant crypt foci, ACF) and decreases the proportion of adenocarcinomas vs. adenomas in 1,2-dimethylhydrazine (DMH)-treated CF1 mice. To elucidate the structural specificity of this inhibition, the effects of the other major sphingolipids in milk (glycosphingolipids) were determined. Glucosylceramide (GluCer), lactosylceramide (LacCer) and ganglioside G(D3) were fed individually to DMH-treated (six doses of 30 mg/kg body weight) female CF1 mice at 0.025 or 0.1 g/100 g of the diet for 4 wk. All reduced the number of ACF by > 40% (P < 0.001), which is comparable to the reduction by SM in earlier studies. Immunohistochemical analysis of the colons revealed that sphingolipid feeding also reduced proliferation, with the most profound effect (up to 80%; P < 0.001) in the upper half of the crypts. Since the bioactive backbones of the glycosphingolipids (i.e., ceramide and other metabolites) are the likely mediators of these effects, the susceptibility of these complex sphingolipids to digestion in the colon was examined by incubating 500 microgram of each sphingolipid with colonic segments from mice and analysis of substrate disappearance and product formation by tandem mass spectrometry. All of the sphingolipids (including SM) disappeared over time with a substantial portion appearing as ceramide. Partially hydrolyzed intermediates (such as GluCer from LacCer or G(D3)) were not detected, which suggests that the cleavage involves colonic (or microflora) endoglycosidases. In summary, consumption of dairy SM and glycosphingolipids suppresses colonic cell proliferation and ACF formation in DMH-treated mice; hence, many categories of sphingolipids affect these key events in colon carcinogenesis.     

Inhibitory effects of calcium against intestinal cancer in human colon cancer cells and ApcMin/+ mice

The aim of the study was to investigate the inhibitory effects of calcium against intestinal cancer in vitro and in vivo. We first investigated the effects of calcium treatment in HCT116 and HT29 human colon cancer cells. At the concentration range of 0.8-2.4 mM, calcium significantly inhibited cell growth (by 9-29%), attachment (by 12-26%), invasion (by 15-31%), and migration (by 19-61%). An immunofluorescence microscope analysis showed that the treatment with calcium (1.6 mM) for 24 h increased plasma membrane β-catenin but decreased nuclear β-catenin levels in HT29 cells. We then investigated the effect of dietary calcium on intestinal tumorigenesis in Apc^Min/+ mice. Mice received dietary treatment starting at 6 weeks of age for the consecutive 8 weeks. The basal control diet contained high-fat (20% mixed lipids by weight) and low-calcium (1.4 mg/g diet) to mimic the average Western diet, while the treatment diet contained an enriched level of calcium (5.2 mg calcium/g diet). The dietary calcium treatment decreased the total number of small intestinal tumors (by 31.4%; P < 0.05). The largest decrease was in tumors which were ≥ 2 mm in diameter, showing a 75.6% inhibition in the small intestinal tumor multiplicity (P < 0.001). Immunohistochemical analysis showed significantly reduced nuclear staining of β-catenin (expressed as nuclear positivity), but increased plasma membrane staining of β-catenin, in the adenomas from the calcium-treated groups in comparison to those from the control group (P < 0.001). These results demonstrate intestinal cancer inhibitory effects of calcium both in human colon cancer cells and Apc^Min/+ mice. The decreased β-catenin nuclear localization caused by the calcium treatment may contribute to the inhibitory action.     

熊脱氧胆酸对小鼠结肠癌抑制作用及机制

目的 探讨熊脱氧胆酸(UDCA)对1,2-二甲肼(DMH)所致小鼠结肠癌抑制作用及可能机制.方法 ICR小鼠喂养1周后,按体重随机分为3组,其中2组腹腔注射DMH,剂量30mg/(kg.bw),每周1次,连续6周诱导结肠癌模型,另一组为空白对照组.从第7周开始在一组(UDCA组)饲料中添加UDCA,剂量3g/kg;另一组(DMH组)饮食不做处理.所有各组均喂食标准AIN-93饲料,28周后处死小鼠,取结肠粘膜进行小鼠碱性鞘磷脂酶(alk-SMase)的活性表达分析.结果 与DMH组相比,给予UDCA组小鼠结肠肿瘤数目明显减少(t=2.77,P<0.05),病理检查肿瘤恶性程度也显著低于DMH组;alk-SMase活性检测中,UDCA组结肠粘膜及内容物alk-SMase活性分别为22.56%和28.97%,其中结肠内容物活性UDCA组比DMH组提高了近14倍;蛋白免疫印迹试验时,UDCA组alk-SMase蛋白表达明显强于DMH组.结论 UDCA对DMH所致小鼠结肠癌有抑制作用,其可能的机制是通过上调小鼠结肠粘膜alk-SMase活性及表达.     

High dietary niacin may increase prostaglandin formation but does not increase tumor formation in ApcMin/+ mice

High doses of niacin (nicotinic acid) used to treat dyslipidemias cause flushing, due to high levels of prostaglandin D(2) (PGD(2)). GPR109A, a G-protein coupled receptor, triggers the flushing in the skin. In addition to boosting PGD(2), niacin binding to GPR109A activates the entire prostanoid cascade. We found that GPR109A occurs throughout the gastrointestinal tract. Mice that alternated between a 1% niacin diet and a control diet had higher urinary prostaglandin E(2) (PGE(2)) metabolite levels when on niacin (2.8-fold increase; 95% confidence interval, 1.8-3.9). PGE(2) promotes tumors in the intestines, whereas PGD(2) may have an opposite effect, on the basis of our report showing that transgenic hematopoietic prostaglandin D synthase suppresses intestinal adenomas in Apc(Min/+) mice. To determine if either tumor growth or tumor suppression prevails, we fed Apc(Min/+) mice a 1% niacin diet and assessed tumor development. A 1% niacin diet did not affect the number of tumors scored histologically in Apc(Min/+) mice at 14 wk (33 mice on niacin, 33 controls). Although niacin stimulates production of various prostaglandins, our results support an interpretation that very high intakes of niacin are safe in relation to intestinal tumors in this model.     

Dietary soy protein isolate ameliorates atherosclerotic lesions in apolipoprotein E-deficient mice potentially by inhibiting monocyte chemoattractant protein-1 expression

Soy-based diets reportedly protect against the development of atherosclerosis; however, the underlying mechanism(s) for this protection remains unknown. In this report, the mechanism(s) contributing to the atheroprotective effects of a soy-based diet was addressed using the apolipoprotein E knockout (apoE-/-) mice fed soy protein isolate (SPI) associated with or without phytochemicals (SPI+ and SPI-, respectively) or casein (CAS). Reduced atherosclerotic lesions were observed in aortic sinus and enface analyses of the descending aorta in SPI+- or SPI(-)-fed apoE-/- mice compared with CAS-fed mice. SPI+-fed mice showed 20% fewer lesions compared with SPI(-)-fed mice. Plasma lipid profiles did not differ among the 3 groups, suggesting alternative mechanism(s) could have contributed to the atheroprotective effect of soy-based diets. Real-time quantitative PCR analyses of proximal aorta showed reduced expression of monocyte chemoattractant protein-1 (MCP-1), a monocyte chemokine, in mice fed both soy-based diets compared with the CAS-fed mice. These findings paralleled the reduced number of macrophages observed in the lesion site in the aorta of SPI+- or SPI(-)-fed mice compared with CAS-fed mice. In an in vitro LPS-induced inflammation model, soy isoflavones (genistein, daidzein, and equol alone or in combination) dose dependently inhibited LPS-induced MCP-1 secretion by macrophages, suggesting a role for soy isoflavones for the protective in vivo effects. Collectively, these findings suggest that the reduction in atherosclerotic lesions observed in mice fed the soy-based diet is mediated in part by inhibition of MCP-1 that could result in reduced monocyte migration, an early event during atherogenesis.     

Chemopreventive effects of orange peel extract (OPE). I: OPE inhibits intestinal tumor growth in ApcMin/+ mice

Orange peel is a rich source of flavonoids with polymethoxyflavones as major constituents, compounds associated with potential antioxidant, anti-inflammatory, and antitumor activities. We studied the effect of an orange peel extract (OPE) on intestinal tumor growth in Apc(Min/+) mice, a mouse model for human familial adenomatous polyposis (FAP). The OPE contained 30% polymethoxyflavones, a mixture that included tangeretin (19.0%), heptamethoxyflavone (15.24%), tetramethoxyflavone (13.6%), nobiletin (12.49%), hexamethoxyflavone (11.06%), and sinensitin (9.16%). Apc(Min/+) mice were fed one of four diets: (1) AIN-76A control diet; (2) a new Western-style diet (NWD), i.e., AIN-76A diet modified with decreased calcium, vitamin D, and methyl-donor nutrients and increased lipid content); (3) NWD with 0.25% OPE; and (4) NWD with 0.5% OPE, with all additives premixed in the diet. After 9 weeks of feeding NWD to the Apc(Min/+) mice, tumors increased mainly in the colon, with tumor multiplicity increasing 5.3-fold and tumor volume increasing 6.7-fold. After feeding 0.5% OPE in NWD, the development of tumors markedly decreased, with multiplicity decreasing 49% in the small intestine and 38% in the colon. NWD also led to increased apoptosis in intestinal tumors, and 0.5% OPE in NWD further increased apoptosis in tumors of the small and large intestine. Findings indicated that OPE inhibited tumorigenesis in this preclinical mouse model of FAP, and increased apoptosis may have contributed to this effect.     

Dietary supplementation of resveratrol suppresses colonic tumour incidence in 1,2-dimethylhydrazine-treated rats by modulating biotransforming enzymes and aberrant crypt foci development

Diet-induced changes in the activities of bacterial enzymes are known to play a role in colon cancer development. Resveratrol has been implicated as a protective agent in carcinogenesis. In the present study, the effect of resveratrol on the activities of faecal and colonic biotransforming enzymes such as beta-glucuronidase, beta-glucosidase, beta-galactosidase, mucinase, nitroreductase and faecal sulfatase activity was assessed. The total number of aberrant crypt foci and their distribution in the proximal, medial and distal colon were observed in 1,2-dimethylhydrazine (DMH)-induced rats (group 3) and other treatment groups (groups 4-6). DMH (0.02 g/kg body weight) was given subcutaneously once a week for 15 consecutive weeks, and the experiment was terminated at 30 weeks. DMH-treated rats showed elevated levels of cancer-associated bacterial enzyme activities, whereas on resveratrol supplementation in three different regimens, rats showed lowered activities. Resveratrol supplementation throughout the experimental period (group 6) exerted a more pronounced effect (P < 0.01) by modulating the development of aberrant crypt foci and the activities of bacterial enzymes than did the other treatment regimens (groups 4 and 5). Thus, the present results demonstrate the inhibitory effect of resveratrol on DMH-induced colon carcinogenesis in rats.     

Dietary sphingomyelin and other sphingolipids in health and disease

Sphingolipids are found in all eukaryotic and some prokaryotic cells and therefore most foods contain varying amounts. They are digested in the intestinal tract, and the bioactive metabolites (i.e. ceramide, sphingosine) are released. In mouse models, the supplementation of the diet with complex sphingolipids significantly reduced early stages in colon carcinogenesis and tumour formation, providing an insight into the association between diet and cancer.     

Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis in APOE*3Leiden mice

BACKGROUND: The prevalence of dyslipidemia and obesity resulting from excess energy intake and physical inactivity is increasing. The liver plays a pivotal role in systemic lipid homeostasis. Effective, natural dietary interventions that lower plasma lipids and promote liver health are needed. OBJECTIVE: Our goal was to determine the effect of dietary sphingolipids on plasma lipids and liver steatosis. DESIGN: APOE*3Leiden mice were fed a Western-type diet supplemented with different sphingolipids. Body cholesterol and triacylglycerol metabolism as well as hepatic lipid concentrations and lipid-related gene expression were determined. RESULTS: Dietary sphingolipids dose-dependently lowered both plasma cholesterol and triacylglycerol in APOE*3Leiden mice; 1% phytosphingosine (PS) reduced plasma cholesterol and triacylglycerol by 57% and 58%, respectively. PS decreased the absorption of dietary cholesterol and free fatty acids by 50% and 40%, respectively, whereas intestinal triacylglycerol lipolysis was not affected. PS increased hepatic VLDL-triacylglycerol production by 20%, whereas plasma lipolysis was not affected. PS increased the hepatic uptake of VLDL remnants by 60%. Hepatic messenger RNA concentrations indicated enhanced hepatic lipid synthesis and VLDL and LDL uptake. The net result of these changes was a strong decrease in plasma cholesterol and triacylglycerol. The livers of 1% PS-fed mice were less pale, 22% lighter, and contained 61% less cholesteryl ester and 56% less triacylglycerol than livers of control mice. Furthermore, markers of liver inflammation (serum amyloid A) and liver damage (alanine aminotransferase) decreased by 74% and 79%, respectively, in PS-fed mice. CONCLUSION: Sphingolipids lower plasma cholesterol and triacylglycerol and protect the liver from fat- and cholesterol-induced steatosis.     

Dietary soy beta-conglycinin (7S globulin) inhibits atherosclerosis in mice

Although beta-conglycinin (7S globulin), a major soy storage protein, stimulates the expression of LDL receptors and the degradation of LDL by hepatocytes in vitro, the in vivo effects of dietary beta-conglycinin on the cardiovascular system are unknown. We assessed the effects of dietary beta-conglycinin and other soy peptide fractions on the development of atherosclerosis in atherosclerosis-susceptible mice. At 6 wk of age, male and ovariectomized female apolipoprotein (apo) E-null mice and LDL receptor-null, apoB transgenic mice were assigned randomly to treatment groups that differed only in the source of dietary protein: 1) casein/lactalbumin, 2) isoflavone-containing soy protein isolate, 3) beta-conglycinin, 4) glycinin (11S globulin, another major soy storage protein), 5) beta-conglycinin-devoid soy protein, and 6) W008 (a peptide fraction produced by hydrolysis and precipitation of soy protein isolate). After 4 mo, aortic atherosclerosis (cholesteryl ester content) and plasma lipoprotein cholesterol concentrations were quantified using GLC. Relative to mice fed casein/lactalbumin-based diets, the extent of atherosclerosis was reduced in ovariectomized female mice fed all soy protein-containing diets. Relative to mice fed isoflavone-containing soy protein isolate, atherosclerosis was reduced only in mice fed the beta-conglycinin-containing diet. Mean reductions were 39 and 67% (all P <0.05) in male and ovariectomized female apoE null mice and 66% (P < 0.05) in male LDL receptor null mice. These effects were unrelated to variation in isoflavone content of the protein source and only minimally related to plasma lipoprotein cholesterol concentrations. We conclude that a diet rich in beta-conglycinin has atheroprotective effects that greatly exceed those of isoflavone-containing soy protein isolate and do not depend on LDL receptors or influences on plasma lipoproteins.     

Fructooligosaccharide and soy isoflavone suppress colonic aberrant crypt foci and cyclooxygenase-2 expression in dimethylhydrazine-treated rats

This study investigated the inhibitory effects of soy isoflavones and fructooligosaccharide (FOS) on colon carcinogenesis. Sprague-Dawley male rats were injected with 1,2-dimethylhydrazine (DMH) and given experimental diets that contained 0%, 3%, 6%, or 9% FOS with or without soy isoflavones (1,000 mg/kg of diet). After 12 weeks, colonic aberrant crypt foci (ACF) formation, cyclooxygenase-2 (COX-2) expression, and fecal bile acid profiles were determined. The numbers of ACF, the numbers of ACF containing four or more crypts per focus of colonic mucosa, and the levels of COX-2 protein in the colonic epithelial tissues were significantly decreased in a dose-dependent manner in the FOS-fed, DMH-treated rats (P < .001), as compared to the DMH-treated control rats. Soy isoflavones significantly decreased the number of ACF with four or more aberrant crypts per focus (P < .001) and the amount of COX-2 protein (P < .01), independently of the effect of the oligosaccharide. The highest suppression of ACF formation was obtained with soy isoflavones combined with >or=6% FOS. No significant relationship was found between the dosage of FOS or soy isoflavones and the concentration of fecal secondary bile acid. We conclude that the combination of FOS and soy isoflavones inhibits colonic ACF formation and reduces COX-2 expression in DMH-treated rats.     

Dietary mustard seeds (Sinapis alba Linn) suppress 1,2-dimethylhydrazine-induced immuno-imbalance and colonic carcinogenesis in rats

In a Wistar rat model, prolonged supplementation of mustard seed (MS) to the diet significantly ameliorates the induction of colorectal carcinomas by 1,2-dimethylhydrazine (DMH). The expression of the splenocyte major histocompatibility complex class I (MHCI) was found significantly enhanced, whereas that of the major histocompatibility complex class II (MHCII) was significantly decreased. Compared to that of control animals, the proportion of spleenic B- and dendritic cells (DC) was amplified in the MS group. The expressions of MHCI, as well as that of MHCII, were increased in DC cells; whereas in B cells, MHCI expression was augmented but that of MHCII moderately decreased. The percentages of CD8+CD28+ and CD4+CD28+ cells were increased in the MS group, while the CD4+CD25+Foxp3+ subset was depressed. Plasma analysis showed that DMH-exposure induced amplified amounts of interleukin (IL)-4, IL-5, IL-10, and transforming growth factor-beta, whereas MS feeding counteracted this effect but enhanced IL-2, IL12p70, IL21, TNF-alpha, and interferon-gamma. In the SW480 colon adenocarcinoma cell-line, the cytotoxicity of spleenic T-cells from MS-fed animals was significantly increased. In the DMH-exposed rats, the expression of perforin in the spleenic T-cells was dramatically decreased, whereas MS abolished this depression. In summary, dietary MS suppresses DMH-induced immuno-imbalance as well as colon carcinogenesis in rats.     

Dietary resveratrol does not affect intestinal tumorigenesis in Apc(Min/+) mice

To determine its effect on intestinal tumorigenesis and the protumorigenic COX pathway in Apc(Min/+) mice, resveratrol was administered as a powdered admixture in the diet at 0, 4, 20, or 90 mg/kg body weight for 7 wk. In two separate experiments, resveratrol did not affect intestinal tumor load. It was stable in the diet under experimental conditions, circulated in the plasma as the glucuronide-conjugated form and reached the tumors as evidenced by significant decreases in PGE2 levels. However, immunohistochemical staining of intestinal tumors revealed no changes in COX-2 expression. This study demonstrates that resveratrol consumed ad libitum in the diet, does not modify tumorigenesis in Apc(Min/+) mice.     

Dietary supplementation with high-selenium soy protein reduces pulmonary metastasis of melanoma cells in mice

The effect of high-selenium (Se) soy protein on pulmonary metastasis of murine B16BL6 melanoma cells was investigated in male C57BL6 mice. Isolated soy proteins (ISP) from soybeans grown with and without Se foliar application during seed development were compared. Five diets were studied, a basal AIN-93G diet or a basal diet containing 10% low-Se ISP, 5% low-Se + 5% high-Se ISP, 10% high-Se ISP, or 10% low-Se ISP supplemented with Se equivalent to that of the 10% high-Se ISP diet. The Se concentrations of the 5 diets were 0.13, 0.13, 1.9, 3.6, and 3.0 microg/g, respectively. Mice were fed the diet for 2 wk before and 2 wk after an i.v. injection of 5 x 10(4) viable cells. At necropsy, the number and size of tumors that had developed in the lungs were determined. In the control group, 13/18 mice exhibited > or = 50 tumors. The numbers of mice with > or = 50 tumors were 8/18, 7/18, 3/18, and 6/17 in the ISP-fed groups, respectively. The differences between the 10% high-Se ISP group, the Se-supplemented 10% low-Se group, and the control were significant (P < 0.05). Dietary supplementation with 10% low-Se ISP significantly decreased the mean number of tumors per group and the tumor size compared with the control. A greater reduction in these variables occurred in mice fed the 10% high-Se ISP diet. The inhibition by the Se-supplemented 10% low-Se ISP diet was similar to that by the 10% high-Se ISP diet. The whole-blood Se concentration was inversely related to the tumor number (R = -0.87, P = 0.052), tumor cross-sectional area (R = -0.91, P < 0.05), and tumor volume (R = -0.93, P < 0.05). These findings suggest that Se is responsible for the greater antimetastatic effect of the high-Se ISP. We conclude that the high-Se soy protein has a greater inhibitory effect than the low-Se soy protein on pulmonary metastasis of melanoma cells in mice.     

Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type mice from carcinogen-induced colon cancer

Consumption of soy foods has been weakly associated with reduced colon cancer risk. Colon cancer risk is influenced by estrogen exposure, although the mechanism through which this occurs is not defined. Conversion of estradiol (E2) to estrone (E1) may be protective in the colon. We hypothesized that dietary phytoestrogens, or E1, would reduce colon tumorigenesis via an estrogen receptor (ER)-dependent mechanism. Ovariectomized ERalphaKO or wild-type (WT) female mice were fed diets containing casein (Casein), soy protein without isoflavones (Soy-IF), soy protein + genistein (Soy+Gen), soy protein + NovaSoy (Soy+NSoy) or soy protein + estrone (Soy+E1) from weaning. Colon tumors were induced with azoxymethane. Tumor incidence was affected by diet but not genotype. Colon tumor incidence was lower in ERalphaKO and WT mice fed the Soy+E1 diet compared with those fed the casein or Soy-IF diets. Mice fed Soy+NSoy had a lower tumor incidence than mice fed casein, but not Soy-IF. Genistein did not affect tumor incidence. Soy protein, independently of phytoestrogens or E1, significantly reduced relative colon weight, tumor burden and multiplicity. Relative colon weight was lower (P=0.008) in mice fed Soy+E1 than in the other soy-fed groups. Tumor incidence in this group was lower than in the casein and soy-IF-fed groups and tended to be lower than in the others (P=0.020). Hence, soy protein and NSoy protect mice from colon cancer, and E1 further reduces colon tumorigenesis in mice, independently of ERalpha.     

Dietary fish oil and curcumin combine to modulate colonic cytokinetics and gene expression in dextran sodium sulphate-treated mice

Both fish oil (FO) and curcumin have potential as anti-tumour and anti-inflammatory agents. To further explore their combined effects on dextran sodium sulphate (DSS)-induced colitis, C57BL/6 mice were randomised to four diets (2 × 2 design) differing in fatty acid content with or without curcumin supplementation (FO, FO+2 % curcumin, maize oil (control, MO) or MO+2 % curcumin). Mice were exposed to one or two cycles of DSS in the drinking-water to induce either acute or chronic intestinal inflammation, respectively. FO-fed mice exposed to the single-cycle DSS treatment exhibited the highest mortality (40 %, seventeen of forty-three) compared with MO with the lowest mortality (3 %, one of twenty-nine) (P = 0·0008). Addition of curcumin to MO increased (P = 0·003) mortality to 37 % compared with the control. Consistent with animal survival data, following the one- or two-cycle DSS treatment, both dietary FO and curcumin promoted mucosal injury/ulceration compared with MO. In contrast, compared with other diets, combined FO and curcumin feeding enhanced the resolution of chronic inflammation and suppressed (P < 0·05) a key inflammatory mediator, NF-κB, in the colon mucosa. Mucosal microarray analysis revealed that dietary FO, curcumin and FO plus curcumin combination differentially modulated the expression of genes induced by DSS treatment. These results suggest that dietary lipids and curcumin interact to regulate mucosal homeostasis and the resolution of chronic inflammation in the colon.     

Three Nordic berries inhibit intestinal tumorigenesis in multiple intestinal neoplasia/+ mice by modulating beta-catenin signaling in the tumor and transcription in the mucosa

Berries contain a number of compounds that are proposed to have anticarcinogenic properties. We studied the effects and molecular mechanisms of wild berries with different phenolic profiles on intestinal tumorigenesis in multiple intestinal neoplasia/+ mice. The mice were fed a high-fat AIN93-G diet (Con) or AIN93-G diets containing 10% (w:w) freeze-dried bilberry, lingonberry (LB), or cloudberry (CB) for 10 wk. All 3 berries significantly inhibited the formation of intestinal adenomas as indicated by a 15-30% reduction in tumor number (P < 0.05). CB and LB also reduced tumor burden by over 60% (P < 0.05). Compared to Con, CB and LB resulted in a larger (P < 0.05) proportion of small adenomas (43, 69, and 64%, respectively) and a smaller proportion of large adenomas (56, 29, and 33%, respectively). Beta-catenin and cyclin D1 in the small and large adenomas and in the normal-appearing mucosa were measured by Western blotting and immunohistochemistry. CB resulted in decreased levels of nuclear beta-catenin and cyclin D1 and LB in the level of cyclin D1 in the large adenomas (P < 0.05). Early changes in gene expression in the normal-appearing mucosa were analyzed by Affymetrix microarrays, which revealed changes in genes implicated in colon carcinogenesis, including the decreased expression of the adenosine deaminase, ecto-5'-nucleotidase, and prostaglandin E2 receptor subtype EP4. Our results indicate that berries are potentially a rich source of chemopreventive components.     

Dietary conjugated linoleic acid (CLA) induces apoptosis of colonic mucosa in 1,2-dimethylhydrazine-treated rats: a possible mechanism of the anticarcinogenic effect by CLA.

One of the objectives of the present study was to investigate whether 1 % conjugated linoleic acid (CLA) in the diet reduced tumour incidence in the colon of 1,2-dimethylhydrazine (DMH)-treated rats. Colon cancer was induced by injecting 6-week-old, male, Sprague-Dawley rats with 15 mg/kg DMH twice per week for 6 weeks. They were fed either 1 % CLA or a control diet ad libitum for 30 weeks. Dietary CLA significantly decreased colon tumour incidence (P<0.05). Our second objective was to investigate whether apoptosis in the colon mucosa of DMH-treated rats was affected by the amount of dietary CLA and whether the changes in apoptosis were related to those in fatty acid-responsive biomarkers. For this purpose, rats were killed after being fed a diet containing 0 %, 0.5 %, 1 % or 1.5 % CLA for 14 weeks. CLA was undetected in the mucosa of rats fed the 0 % CLA diet and increased to 5.9 mg/g phospholipid in rats fed the 0.5 % diet. The apoptotic index estimated by the terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling technique was increased by 251 % and the 1,2-diacylglycerol content was decreased by 57 % in rats fed 0.5 % CLA. No further changes in these variables were observed when CLA in the diet was raised to 1.0 % or 1.5 %. However, dietary CLA decreased mucosal levels of prostaglandin E2, thromboxane B2 and arachidonic acid in a dose-dependent manner. The present data indicate that dietary CLA can inhibit DMH-induced colon carcinogenesis by mechanisms probably involving increased apoptosis.     

Dietary soy and soy isoflavones have gender-specific effects on plasma lipids and isoflavones in golden Syrian f(1)b hybrid hamsters

The specific components of soy responsible for its beneficial effects on plasma lipids are unknown. Golden Syrian F(1)B Hybrid hamsters (75 male, 74 female) were evaluated for the effect of dietary soy and soy isoflavones on plasma lipids. They were fed the following diets for 16 wk: casein/lactalbumin (C/L), soy protein with isoflavones [Soy(+)], soy protein with isoflavones removed [Soy(-)], Soy(-) plus isoflavone extract (IF), and C/L + IF. At necropsy, plasma total cholesterol, HDL cholesterol (HDLC), LDL + VLDL cholesterol (LDL + VLDLC), isoflavones, and uterine and accessory gland weights were measured. Male hamsters fed the three soy-containing diets had lower LDL + VLDLC concentrations than those fed the two C/L diets (P < 0.01), and those fed Soy(-) + IF did not differ from those fed Soy(+). In females, diet did not affect plasma LDL + VLDLC concentration. Females fed Soy(+) or Soy(-) had higher HDLC (P < 0.05) than those fed C/L. HDLC was not affected by diet in males. Due to higher equol production (P < 0.01), males had greater plasma isoflavone concentrations (P < 0.01) than females. There was a positive association between plasma total isoflavones and LDL + VLDLC (r = 0.65, P < 0.05) in females. These data suggest gender differences in plasma lipid and isoflavone responses to soy- based diets in Syrian F(1)B Hybrid hamsters, which offer an opportunity to explore effects of sex hormones on isoflavone metabolism and the effects of isoflavones on lipid metabolism.