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Biomedical subjects

Cindy D Davis

Publications and source records attributed to Cindy D Davis.

17 recordsLinked to original sources
PubMed2006

Both selenoproteins and low molecular weight selenocompounds reduce colon cancer risk in mice with genetically impaired selenoprotein expression.

Selenium has cancer protective effects in a variety of experimental systems. Currently, it is not known whether selenoproteins or low molecular weight selenocompounds are responsible for this activity. To evaluate the contribution of selenoproteins to the cancer protective effects of selenium, we used transgenic mice that carry a mutant selenocysteine transfer RNA gene, which causes reduced selenoprotein synthesis. Selenium homeostasis was characterized in liver and colon of wild-type and transgenic mice fed selenium-deficient diets supplemented with 0, 0.1, or 2.0 microg selenium (as selenite)/g diet. (75)Se-labeling, Western blot analysis, and enzymatic activities revealed that transgenic mice have reduced (P < 0.05) liver and colon glutathione peroxidase expression, but conserved thioredoxin reductase expression compared with wild-type mice, regardless of selenium status. Transgenic mice had more (P < 0.05) selenium in the nonprotein fraction of the liver and colon than wild-type mice, indicating a greater amount of low molecular weight selenocompounds. Compared with wild-type mice, transgenic mice had more (P < 0.05) azoxymethane-induced aberrant crypt formation (a preneoplastic lesion for colon cancer). Supplemental selenium decreased (P < 0.05) the number of aberrant crypts and aberrant crypt foci in both wild-type and transgenic mice. These results provide evidence that a lack of selenoprotein activity increases colon cancer susceptibility. Furthermore, low molecular weight selenocompounds reduced preneoplastic lesions independent of the selenoprotein genotype. These results are, to our knowledge, the first to provide evidence that both selenoproteins and low molecular weight selenocompounds are important for the cancer-protective effects of selenium.

Animals↗
PubMed2006

Differential effects of dietary selenium (se) and folate on methyl metabolism in liver and colon of rats.

A previous study compared the effects of folate on methyl metabolism in colon and liver of rats fed a selenium-deficient diet (< 3 microg Se/kg) to those of rats fed a diet containing supranutritional Se (2 mg selenite/kg). The purpose of this study was to investigate the effects of folate and adequate Se (0.2 mg/kg) on methyl metabolism in colon and liver. Weanling, Fischer-344 rats (n = 8/diet) were fed diets containing 0 or 0.2 mg selenium (as selenite)/kg and 0 or 2 mg folic acid/kg in a 2 x 2 design. After 70 d, plasma homocysteine was increased (p < 0.0001) by folate deficiency; this increase was markedly attenuated (p < 0.0001) in rats fed the selenium-deficient diet compared to those fed 0.2 mg Se/kg. The activity of hepatic glycine N-methyltransferase (GNMT), an enzyme involved in the regulation of tissue S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), was increased by folate deficiency (p < 0.006) and decreased by selenium deprivation (p < 0.0003). Colon and liver SAH were highest (p < 0.006) in rats fed deficient folate and adequate selenium. Although folate deficiency decreased liver SAM (p < 0.001), it had no effect on colon SAM. Global DNA methylation was decreased (p<0.04) by selenium deficiency in colon but not liver; folate had no effect. Selenium deficiency did not affect DNA methyltransferase (Dnmt) activity in liver but tended to decrease (p < 0.06) the activity of the enzyme in the colon. Dietary folate did not affect liver or colon Dnmt. These results in rats fed adequate selenium are similar to previous results found in rats fed supranutritional selenium. This suggests that selenium deficiency appears to be a more important modifier of methyl metabolism than either adequate or supplemental selenium.

Animals↗
PubMed2005

Nutritional "omics" technologies for elucidating the role(s) of bioactive food components in colon cancer prevention.

Evidence continues to implicate dietary components and genetic susceptibilities as important determinants of cancer risk and tumor behavior. Variation in cancer incidence among and within populations with similar dietary patterns suggests that an individual's response may reflect interactions with genetic factors, which may modify gene, protein, and metabolite expression patterns. Nutrigenomics, defined as the interaction between nutrition and an individual's genome, will likely provide important clues about responders and nonresponders. In this symposium, the role of bioactive food components in colon cancer susceptibility was used to exemplify the application of "omic" technologies for cancer prevention. Topics that were addressed included dietary changes and gene polymorphisms (nutrigenetics), DNA methylation (nutritional epigenomics), gene expression (nutritional transcriptomics), altered formation or bioactivation of proteins (proteomics), and characterizing how the quantity and timing of exposure influence small molecular weight cellular constituents (metabolomics). The final presentation focused on exfoliated cells as a surrogate sample for the evaluation of bioactive food components in cancer prevention. The goal of the symposium was to provide an example of each of the "omic" technologies as they relate to nutrition, cancer risk, and tumor behavior, and to help the participants understand that an integrated framework that simultaneously examines all of the "omic" technologies is needed.

Colonic Neoplasms↗
PubMed2004

Frontiers in nutrigenomics, proteomics, metabolomics and cancer prevention.

While dietary habits continue to surface as a significant factor that may influence cancer incidence and tumor behavior, there is considerable scientific uncertainty about who will benefit most. Adequate [corrected] knowledge about how the responses depend on an individual's genetic background (nutrigenetic effects), the cumulative effects of food components on genetic expression profiles (nutritional transcriptomics and nutritional epigenomics effects), the occurrence and activity of proteins (proteomic effects) and/or the dose and temporal changes in cellular small molecular weight compounds (metabolomics effects) will [corrected] assist in identifying responders and non-responders. Expanding the information about similarities and differences in the "omic" responses across tissues will not only provide clues about specificity in response to bioactive food components but assist in the identification of surrogate tissues and biomarkers that can be used for predicting a response. Deciphering the importance of each of these potential sites of regulation will be particularly challenging but does hold promise in explaining many of the inconsistencies in the literature.

Anticarcinogenic Agents↗
PubMed2004

DNA methylation, cancer susceptibility, and nutrient interactions.

DNA methylation is an important epigenetic mechanism of transcriptional control. DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of cancer. Aberrant methylation of DNA (global hypomethylation accompanied by region-specific hypermethylation) is frequently found in tumor cells. Global hypomethylation can result in chromosome instability, and hypermethylation has been associated with the inaction of tumor suppressor genes. Preclinical and clinical studies suggest that part of the cancer-protective effects associated with several bioactive food components may relate to DNA methylation patterns. Dietary factors that are involved in one-carbon metabolism provide the most compelling data for the interaction of nutrients and DNA methylation because they influence the supply of methyl groups, and therefore the biochemical pathways of methylation processes. These nutrients include folate, vitamin B(12), vitamin B(6), methionine, and choline. However, looking at individual nutrients may be too simplistic. Dietary methyl (folate, choline, and methionine) deficiency in combination causes decreased tissue S-adeno-sylmethionine, global DNA hypomethylation, hepatic steatosis, cirrhosis, and ultimately hepatic tumorigenesis in rodents in the absence of carcinogen treatment. Other dietary components such as vitamin B(12), alcohol, and selenium may modify the response to inadequate dietary folate.

Animals↗
PubMed2003

Effect of selenium-enriched broccoli diet on differential gene expression in min mouse liver(1,2).

Multiple intestinal neoplasia (Min) mice are a good model for investigating the effects of dietary alterations in a genetic model for intestinal cancer. Previous studies have shown that selenium-enriched broccoli effectively reduces colon cancer susceptibility. Although colon cancer cells mainly metastasize to the liver, little is known about the effects of selenium-enriched broccoli on gene expression in mouse liver. To better understand the protective role for selenium-enriched broccoli in tumorigenesis, a gene profile of the mouse liver was analyzed. Mice were fed either 0.11 mg selenium/kg control diet or 2.1 mg selenium/kg selenobroccoli diets for 10 weeks. Use of mouse pathway finder-1 GEArrays revealed that selenium-enriched broccoli moderately increased ikBalphakappaB, hsp86, gadd45 gene transcripts. In addition, analysis of the binding of liver nuclear proteins to (32)P-labeled probes demonstrated that selenium-enriched broccoli enhanced the binding of transcription factor p53, NFkappaB, AP-1 to their cis-acting elements. Collectively, these results suggest for the first time that selenium-enriched broccoli activates certain pro-apoptotic genes linked to p53, NFkappaB and stress signal pathways in response to "danger signals" such as tumorigenesis.

Animals↗
PubMed2003

Low dietary copper increases fecal free radical production, fecal water alkaline phosphatase activity and cytotoxicity in healthy men.

One possible dietary factor that may increase susceptibility to colon cancer is inadequate copper intake. The objective of this study was to investigate the effects of low and adequate copper intakes on copper nutriture and putative risk factors for colon cancer susceptibility in healthy men. Seventeen healthy free-living nonsmoking men aged 21-52 y completed a 13-wk controlled feeding study in a randomized crossover design. The basal diet contained 0.59 mg Cu/13.65 MJ. After a 1-wk equilibration period in which the men consumed the basal diet supplemented with 1.0 mg Cu/d, they were randomly assigned to receive either the basal diet or the basal diet supplemented with 2 mg Cu/d for 6 wk. After the first dietary period, the men immediately began to consume the other level of Cu for the last 6 wk. They collected their feces during the equilibration period and during the last 2 wk of the two dietary periods for free radical and fecal water analysis. Low dietary copper significantly (P < 0.01) increased fecal free radical production and fecal water alkaline phosphatase activity. Low dietary copper significantly (P < 0.0001) decreased fecal water copper concentrations but did not affect fecal water volume, pH, iron or zinc concentrations. In contrast to the fecal analysis, hematological indicators of copper status were not significantly affected by the dietary treatments. These results suggest that low dietary copper adversely affects fecal free radical production and fecal water alkaline phosphatase activity, which are putative risk factors for colon cancer.

Adult↗
PubMed2003

Use of exfoliated cells from target tissues to predict responses to bioactive food components.

A host of bioactive food components have been proposed to promote health and reduce the risk of disease states. It is clear that not all individuals respond identically to these essential and nonessential food components. Genetic polymorphisms may influence absorption, metabolism and accumulation of bioactive food components, thereby influencing their actions in target tissues. Unfortunately, serum concentrations of bioactive food components may not correlate with tissue concentrations and may therefore under- or overestimate the response in target tissues. Exfoliated cells may be useful to assess the actions of nutrients in specific tissues. Although not extensively examined, evidence already suggests the usefulness of these cells in predicting changes in gene expression, DNA methylation, DNA damage, protein expression and accumulation of dietary components. Although there are limitations on the collection of exfoliated cells, the inaccessibility of tissues they can represent raises intriguing possibilities for their ability to predict the outcome of nutritional intervention studies.

Biological Products↗
PubMed2003

Down-regulation of proliferating cell nuclear antigen gene expression occurs during cell cycle arrest induced by human fecal water in colonic HT-29 cells.

Cancer is a disease in which the cell cycle is altered, and the elucidation of the mechanisms by which constituents of human fecal water influence the cell cycle can lead to noninvasive measurement of colon cancer risk. The purpose of the present study was to investigate the effect of human fecal water on HT-29 cell-cycle progression with sodium selenite as a reference for comparison. Both human fecal water (2.5-5.0%) and selenite (3-4 micro mol/L) significantly inhibited cell growth. Cell-cycle analysis revealed that human fecal water decreased the proportion of S + G2 phase cells and increased that of G1 phase cells. In contrast, selenite decreased G1 phase cells and increased proportions of S and G2 phase cells. Both 5% human fecal water and 4 micro mol/L selenite greatly increased the mRNA level of the cyclin-dependent kinase inhibitor gene p21(waf1). Interestingly, the mRNA levels of cyclin A and proliferating cell nuclear antigen (PCNA) were dramatically decreased by 69 and 62%, respectively, in HT-29 cells treated with fecal water but not selenite. In contrast, the mRNA level of DNA damage-inducible transcript 1, gadd45, was significantly increased by 2.28-fold in HT-29 cells treated with selenite but not fecal water. Furthermore, a PCNA gene promoter was cloned into a luciferase reporter construct and its activity was significantly reduced in a dose-dependent manner in cells treated with fecal water but not selenite. Collectively, these results suggest that human fecal water and selenite can differentially induce growth arrest genes, and that PCNA gene expression is uniquely and highly sensitive to human fecal water.

Body Water↗
PubMed2003

Dietary manganese intake and type of lipid do not affect clinical or neuropsychological measures in healthy young women.

Because manganese (Mn) is potentially toxic, and because dietary fat type may affect Mn absorption, the objectives of the current study were to determine whether diets containing very low or very high amounts of Mn and enriched in either saturated or unsaturated fats affected measures of neuropsychological and basic metabolic function. Healthy young women were fed for 8 wk each, in a crossover design, diets that provided 0.8 or 20 mg of Mn/d. One half of the subjects received 15% of energy as cocoa butter, and one half received 15% of energy as corn oil. A meal containing (54)Mn was fed after 4 wk, and subjects underwent whole-body counting for the next 21 d. Blood draws and neuropsychological tests were administered at regular intervals during the dietary periods. When subjects consumed the diets low in Mn, compared with the high Mn diets, they absorbed a significantly higher percentage of (54)Mn, but had a significantly longer biological half-life of the absorbed (54)Mn. Manganese intake did not affect any neurological measures and only minimally affected psychologic variables. These data show that efficient mechanisms operate to maintain Mn homeostasis over the range of intakes that may be encountered in a mixed Western diet. Thus, dietary intakes of Mn from 0.8 to 20 mg for 8 wk likely do not result in Mn deficiency or toxicity signs in healthy adults.

Absorption↗
PubMed2003

Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation, global DNA methylation and one-carbon metabolism in rats.

Several observations suggest a role for DNA methylation in cancer pathogenesis. Although both selenium and folate deficiency have been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one-carbon metabolism. Thus, the purpose of this study was to investigate the interactive effects of dietary selenium and folate. Weanling, Fischer-344 rats (n = 23/diet) were fed diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg folate/kg in a 2 x 2 factorial design. After 3 and 4 wk of a 12-wk experiment, 19 rats/diet were injected intraperitoneally with dimethylhydrazine (DMH, 25 mg/kg) and 4 rats/diet were administered saline. Selenium deficiency decreased (P < 0.05) colonic DNA methylation and the activities of liver DNA methyltransferase and betaine homocysteine methyltransferase and increased plasma glutathione concentrations. Folate deficiency increased (P < 0.05) the number of aberrant crypts per aberrant crypt foci, the concentration of colonic S-adenosylhomocysteine and the activity of liver cystathionine synthase. Selenium and folate interacted (P < 0.0001) to influence one-carbon metabolism and cancer susceptibility such that the number of aberrant crypts and the concentrations of plasma homocysteine and liver S-adenosylhomocysteine were the highest and the concentrations of plasma folate and liver S-adenosylmethionine and the activity of liver methionine synthase were the lowest in rats fed folate-deficient diets and supplemental selenium. These results suggest that selenium deprivation ameliorates some of the effects of folate deficiency, probably by shunting the buildup of homocysteine (as a result of folate deficiency) to glutathione.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2002

Dietary selenite and azadeoxycytidine treatments affect dimethylhydrazine-induced aberrant crypt formation in rat colon and DNA methylation in HT-29 cells.

Several observations implicate a role for altered DNA methylation in cancer pathogenesis. The global level of DNA methylation is generally lower; however, DNA methyltransferase (Dnmt1) activity is usually higher in tumor cells than in normal cells. The purpose of this study was to investigate whether the Dnmt1 inhibitor, 5-aza-2'-deoxycytidine (aza-dC) would alter the effect of dietary selenium on the formation of aberrant crypts. Weanling rats (n = 60) were fed three concentrations of selenium (deficient, 0.1 and 2.0 mg/kg diet) in a Torula yeast-based diet. Half of the rats were injected weekly with aza-dC (1 mg/kg, subcutaneously) and half were injected with the vehicle control (PBS). After 3.5 wk of consuming the experimental diets, the rats were given two injections of dimethylhydrazine (DMH; 25 mg/kg, intraperitoneally). Rats fed the selenium-deficient diet and injected with PBS had significantly (P < 0.006) more aberrant crypts than rats fed 0.1 or 2.0 mg selenium/kg diet (244 +/- 21 vs. 165 +/- 9 and 132 +/- 14, respectively). In contrast, when rats were injected with aza-dC, there was a significant (P < 0.0001) reduction in aberrant crypt formation and dietary selenium had no effect (62 +/- 8 vs. 77 +/- 13 vs. 54 +/- 8, in rats fed 0, 0.1 and 2.0 mg selenium/kg diet, respectively). HT-29 cells cultured in the absence of selenium had significantly hypomethylated DNA but significantly more Dnmt1 protein expression than cells cultured in the presence of 1 or 2 micromol/L selenium. These results suggest that aza-dC treatment may protect selenium-deficient rats against carcinogen-induced aberrant crypt formation.

Administration, Oral↗
PubMed2002

Selenium-enriched broccoli decreases intestinal tumorigenesis in multiple intestinal neoplasia mice.

Multiple intestinal neoplasia (Min) mice are a good model for the investigation of the effects of dietary alterations in a genetic model for intestinal cancer. Previous studies have shown that selenium-enriched broccoli is protective against chemically induced colon cancer susceptibility. This study investigated whether selenium-enriched broccoli would be protective against intestinal cancer susceptibility in Min mice. Five-week-old heterozygotic male Min mice were fed an AIN-93-based diet containing either low-selenium broccoli or an equivalent amount of high-selenium broccoli for 10 wk. Mice fed the selenium-enriched broccoli had fewer (P < 0.02) small intestinal (46.4 +/- 3.7 vs. 65.6 +/- 6.1) and large intestinal (0.43 +/- 0.17 vs. 1.93 +/- 0.27) tumors than those fed an equivalent amount of unenriched broccoli. Min mice fed the selenium-enriched broccoli had small but significant (P < 0.0001) increases in plasma and liver selenium concentrations and red blood cell glutathione peroxidase activity. These results extend previous observations that selenium-enriched broccoli is protective against chemically induced mammary and colon cancer in rats.

Animals↗
PubMed2002

Dietary copper affects azoxymethane-induced intestinal tumor formation and protein kinase C isozyme protein and mRNA expression in colon of rats.

Previous studies have show that changes in protein kinase C (PKC) isoform expression may be related to increased susceptibility of copper-deficient rats to aberrant crypt formation. The purpose of this study was to determine whether dietary copper would affect azoxymethane-induced intestinal tumor formation and PKC isozyme expression in normal colonic mucosa and tumor samples. Eighty weanling Fischer-344 rats were randomly assigned to diets that contained either 0.8 or 5.3 microg Cu/g diet. After 24 and 31 d of diet consumption, 30 rats/diet were administered azoxymethane (15 mg/kg i.p.) and 10 rats/diet were administered saline. Rats continued to consume their respective diets for an additional 38 wk. Rats injected with azoxymethane and fed the low copper diet had a significantly (P < 0.0001) greater small intestinal and total tumor incidence compared with rats fed adequate dietary copper. However, dietary copper did not affect colon tumor incidence. Low dietary copper significantly (P < 0.004) decreased PKC alpha protein expression in normal but not in tumor tissue. In contrast, low dietary copper did not affect PKC delta or zeta protein expression in either the normal or tumor tissue. PKC alpha and delta protein and mRNA expression were lower in tumor tissue than in normal tissue. These results along with previous observations suggest that dietary copper-mediated changes in PKC alpha, delta and zeta protein expression are not as important for colon tumor promotion/progression as they are for tumor initiation.

Animals↗