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Biomedical subjects

Nancy D Turner

Publications and source records attributed to Nancy D Turner.

At least 19 recordsLinked to original sources
PubMed2005

Suppression of colon carcinogenesis by bioactive compounds in grapefruit.

This study evaluated the hypothesis that untreated and irradiated grapefruit as well as the isolated citrus compounds naringin and limonin would protect against azoxymethane (AOM)-induced aberrant crypt foci (ACF) by suppressing proliferation and elevating apoptosis through anti-inflammatory activities. Male Sprague-Dawley rats (n = 100) were provided one of five diets: control (without added grapefruit components), untreated or irradiated (300 Gy, 137Cs) grapefruit pulp powder (13.7 g/kg), naringin (200 mg/kg) or limonin (200 mg/kg). Rats were injected with saline or AOM (15 mg/kg) during the third and fourth week and colons were resected (6 weeks post second injection) for evaluation of ACF, proliferation, apoptosis, and cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) protein levels. Experimental diets had no effect on the variables measured in saline-injected rats. However, in AOM-injected rats, the experimental diets suppressed (P < or = 0.02) aberrant crypt and high multiplicity ACF (HMACF; P < or = 0.01) formation and the proliferative index (P < or = 0.02) compared with the control diet. Only untreated grapefruit and limonin suppressed (P < or = 0.04) HMACF/cm and expansion (P < or = 0.008) of the proliferative zone that occurred in the AOM-injected rats consuming the control diet. All diets elevated (P < or = 0.05) the apoptotic index in AOM-injected rats, compared with the control diet; however, the greatest enhancement was seen with untreated grapefruit and limonin. Untreated grapefruit and limonin diets suppressed elevation of both iNOS (P < or = 0.003) and COX-2 (P < or = 0.032) levels observed in AOM-injected rats consuming the control diet. Although irradiated grapefruit and naringin suppressed iNOS levels in AOM-injected rats, no effect was observed with respect to COX-2 levels. Thus, lower levels of iNOS and COX-2 are associated with suppression of proliferation and upregulation of apoptosis, which may have contributed to a decrease in the number of HMACF in rats provided with untreated grapefruit and limonin. These results suggest that consumption of grapefruit or limonin may help to suppress colon cancer development.

Animals↗
PubMed2005

A two-stage normalization method for partially degraded mRNA microarray data.

MOTIVATION: The goal of the study is to obtain genetic information from exfoliated colonocytes in the fecal stream rather than directly from mucosa cells within the colon. The latter is obtained through invasive procedures. The difficulties encountered by this procedure are that certain probe information may be compromised due to partially degraded mRNA. Proper normalization is essential to obtaining useful information from these fecal array data. RESULTS: We propose a new two-stage semiparametric normalization method motivated by the features observed in fecal microarray data. A location-scale transformation and a robust inclusion step were used to roughly align arrays within the same treatment. A non-parametric estimated non-linear transformation was then used to remove the potential intensity-based biases. We compared the performance of the new method in analyzing a fecal microarray dataset with those achieved by two existing normalization approaches: global median transformation and quantile normalization. The new method favorably compared with the global median and quantile normalization methods. AVAILABILITY: The R codes implementing the two-stage method may be obtained from the corresponding author.

Algorithms↗
PubMed2005

Bioactive compounds of grapefruit (Citrus paradisi Cv. Rio Red) respond differently to postharvest irradiation, storage, and freeze drying.

In the present study, the effect of irradiation, storage, and freeze drying on grapefruit bioactive compounds was investigated. Grapefruits were exposed to one of two irradiation doses: 0 (control) or 300 Gy (137Cs, a proposed treatment against fruit flies) and then stored for up to 6 days. At the last storage time point (6 days after harvest), grapefruit pulp from control and irradiated fruits was freeze-dried. Bioactive compounds were extracted from Rio Red grapefruit pulp and analyzed with reverse phase liquid chromatography while volatile compounds were analyzed using gas chromatography. Freeze-dried pulp from irradiated fruits had a higher (P < or = 0.05) flavonoid content (naringin and narirutin) as compared to the freeze-dried pulp from the control fruits. Freeze-drying treatment reduced (P < or = 0.05) the lycopene content, but the reduction (P < or = 0.05) in beta-carotene content occurred only in the control fruit. Reduction in d-limonene and myrcene was observed in the irradiated fruits at 6 days after harvest and in the freeze-dried samples. These results warrant testing of the effect of postharvest treatments and processing on bioactive compounds in functional systems as they have varied effects on different bioactive compounds of grapefruit.

Ascorbic Acid↗
PubMed2005

Comparing automatic and manual image processing in FLARE assay analysis for colon carcinogenesis.

Measurement of the amount of oxidative damage to DNA is one tool that can be used to estimate the beneficial effect of diet on the prevention of colon carcinogenesis. The FLARE assay is a modification of the single-cell gel electrophoresis (Comet) assay, and provides a measure of the 8OHdG adduct in the cells. In this paper, we present two innovations to the existing methods of analysis. The first one is related to the FLARE assay itself. We describe automated image analysis techniques that can be expected to measure oxidative damage faster, reproducibly, with less noise, and hence achieve greater statistical power. The proposed technique is compared to an existing technique, which was more manual and thus slower. The second innovation is our statistical analysis: we exploit the shape of FLARE intensity histograms, and show statistically significant diet effects in the duodenum. Previous analyses of this data concentrated on simple summary statistics, and found only marginally statistically significant diet effects. With the new imaging method and measure of oxidative damage, we show cells in the duodenum exposed to fish oil as having more oxidative damage than cells exposed to corn oil.

Journal Article↗
PubMed2005

Tissue-specific attenuation of endogenous DNA I-compounds in rats by carcinogen azoxymethane: possible role of dietary fish oil in colon cancer prevention.

I-compounds are bulky covalent DNA modifications that are derived from metabolic intermediates of nutrients. Some I-compounds may play protective roles against cancer, aging, and degenerative diseases. Many carcinogens and tumor promoters significantly reduce I-compound levels gradually during carcinogenesis. Colon cancer is the second leading cause of cancer death in the United States, whereas cancer of the small intestine is relatively rare. Here we have studied levels of I-compounds in DNA of colon and duodenum of male Sprague-Dawley rats treated with azoxymethane. The effects of dietary lipids (fish oil or corn oil) on colon and duodenal DNA I-compounds were also investigated. Rats fed a diet containing fish oil or corn oil were treated with 15 mg/kg azoxymethane. Animals were terminated 0, 6, 9, 12, or 24 hours after injection. I-compound levels were analyzed by the nuclease P1-enhanced (32)P-postlabeling assay. Rats treated with azoxymethane displayed lower levels of I-compounds in colon DNA compared with control groups (0 hour). However, I-compound levels in duodenal DNA were not diminished after azoxymethane treatment. Animals fed a fish oil diet showed higher levels of I-compounds in colonic DNA compared with corn oil groups (mean adduct levels for fish and corn oil groups were 13.35 and 10.69 in 10(9) nucleotides, respectively, P = 0.034). Taken together, these results support claims that fish oil, which contains a high level of omega-3 polyunsaturated fatty acids, may have potent chemopreventive effects on carcinogen-induced colon cancer. The fact that duodenal I-compounds were not diminished by azoxymethane treatment may have been due to the existence of tissue-specific factors protecting against carcinogenesis. In conclusion, our observations show that endogenous DNA adducts may serve not only as sensitive biomarkers in carcinogenesis and cancer prevention studies, but are also helpful to further our understanding of the chemopreventive properties of omega-3 fatty acids and mechanisms of carcinogenesis.

Analysis of Variance↗
PubMed2005

Differential response to DNA damage may explain different cancer susceptibility between small and large intestine.

Although large intestine (LI) cancer is the second-leading cause of cancer-related deaths in the United States, small intestine (SI) cancer is relatively rare. Because oxidative DNA damage is one possible initiator of tumorigenesis, we investigated if the SI is protected against cancer because of a more appropriate response to oxidative DNA damage compared with the LI. Sixty rats were allocated to three treatment groups: 3% dextran sodium sulfate (DSS, a DNA-oxidizing agent) for 48 hrs, withdrawal (DSS for 48 hrs + DSS withdrawal for 48 hrs), or control (no DSS). The SI, compared with the LI, showed greater oxidative DNA damage (P < 0.001) as determined using a quantitative immunohistochemical analysis of 8-oxodeoxyguanosine (8-oxodG). The response to the DNA adducts in the SI was greater than in the LI. The increase of TdT-mediated dUTP-biotin nick end labeling (TUNEL)-positive apoptosis after DSS treatment was greater in the SI compared with the LI (P < 0.001), and there was a positive correlation (P = 0.031) between DNA damage and apoptosis in the SI. Morphologically, DSS caused an extensive loss of crypt structure shown in lower crypt height (P = 0.006) and the number of intact crypts (P = 0.0001) in the LI, but not in the SI. These data suggest that the SI may be more protected against cancer by having a more dynamic response to oxidative damage that maintains crypt morphology, whereas the response of the LI makes it more susceptible to loss of crypt architecture. These differential responses to oxidative DNA damage may contribute to the difference in cancer susceptibility between these two anatomic sites of the intestine.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Fish oil decreases oxidative DNA damage by enhancing apoptosis in rat colon.

To determine if dietary fish oil protects against colon cancer by decreasing oxidative DNA damage at the initiation stage of colon tumorigenesis, oxidative DNA damage, proliferation, and apoptosis were assessed by colonic crypt cell position using quantitative immunohistochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG), Ki-67, and TUNEL assay, respectively. Sixty rats were provided one of two diets (corn oil or fish oil) and dextran sodium sulfate (DSS, an inducer of oxidative DNA damage) treatments (no DSS, 3% DSS, or DSS withdrawal). Fish oil feeding resulted in lower 8-OHdG levels (P = 0.038), higher levels of apoptosis (P = 0.035), and a lower cell proliferative index (P = 0.05) compared with corn oil feeding. In the top third of the crypt, fish oil caused an incremental stimulation of apoptosis with increased DNA damage (P = 0.043), whereas there was no such relationship with corn oil. Because polyps and tumors develop from DNA damage that leads to loss of growth and death control, the significant difference in fish oil vs. corn oil on these variables may account, in part, for the observed protective effect of fish oil against oxidatively induced colon cancer.

Animals↗
PubMed2004

Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat.

The mechanisms by which n-3 polyunsaturated fatty acids (PUFAs) decrease colon tumor formation have not been fully elucidated. Examination of genes up- or down-regulated at various stages of tumor development via the monitoring of gene expression relationships will help to determine the biological processes ultimately responsible for the protective effects of n-3 PUFA. Therefore, using a 3 x 2 x 2 factorial design, we used Codelink DNA microarrays containing approximately 9000 genes to help decipher the global changes in colonocyte gene expression profiles in carcinogen-injected Sprague Dawley rats. Animals were assigned to three dietary treatments differing only in the type of fat (corn oil/n-6 PUFA, fish oil/n-3 PUFA, or olive oil/n-9 monounsaturated fatty acid), two treatments (injection with the carcinogen azoxymethane or with saline), and two time points (12 hours and 10 weeks after first injection). Only the consumption of n-3 PUFA exerted a protective effect at the initiation (DNA adduct formation) and promotional (aberrant crypt foci) stages. Importantly, microarray analysis of colonocyte gene expression profiles discerned fundamental differences among animals treated with n-3 PUFA at both the 12 hours and 10-week time points. Thus, in addition to demonstrating that dietary fat composition alters the molecular portrait of gene expression profiles in the colonic epithelium at both the initiation and promotional stages of tumor development, these findings indicate that the chemopreventive effect of fish oil is due to the direct action of n-3 PUFA and not to a reduction in the content of n-6 PUFA.

Animals↗
PubMed2004

Pro-oxidant environment of the colon compared to the small intestine may contribute to greater cancer susceptibility.

The colon and small intestine have inherent differences (e.g. redox status) that may explain the variation in cancer occurrence at these two sites. This study examined basal and induced (oxidative challenge) reactive oxygen species (ROS) generation, antioxidant enzyme activity and oxidative DNA damage. Basal ROS and antioxidant enzyme activities in the colon were greater than in the small intestine. During oxidative stress, 8-oxo-deoxyguanosine (8-oxodG) DNA adducts in the colon exceeded levels in the small intestine concomitant with increased ROS. Thus the colon responds to oxidative stress less effectively than the small intestine, possibly contributing to increased cancer incidence at this site.

Animals↗
PubMed2004

An increase in reactive oxygen species by dietary fish oil coupled with the attenuation of antioxidant defenses by dietary pectin enhances rat colonocyte apoptosis.

We showed previously that the dietary combination of fish oil, rich in (n-3) fatty acids, and the fermentable fiber pectin enhances colonocyte apoptosis in a rat model of experimentally induced colon cancer. In this study, we propose that the mechanism by which this dietary combination heightens apoptosis is via modulation of the colonocyte redox environment. Male Sprague-Dawley rats (n = 60) were fed 1 of 2 fats (corn oil or fish oil) and 1 of 2 fibers (cellulose or pectin) for 2 wk before determination of reactive oxygen species (ROS), oxidative DNA damage, antioxidant enzyme activity [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)] and apoptosis in isolated colonocytes. Fish oil enhanced ROS, whereas the combination of fish oil and pectin suppressed SOD and CAT and enhanced the SOD/CAT ratio compared with a corn oil and cellulose diet. Despite this modulation to a seemingly prooxidant environment, oxidative DNA damage was inversely related to ROS in the fish oil and pectin diet, and apoptosis was enhanced relative to other diets. Furthermore, apoptosis increased exponentially as ROS increased. These results suggest that the enhancement of apoptosis associated with fish oil and pectin feeding may be due to a modulation of the redox environment that promotes ROS-mediated apoptosis.

Animals↗
PubMed2004

Glutathione metabolism and its implications for health.

Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.

Cysteine↗
PubMed2003

Dietary fiber and coronary disease: does the evidence support an association?

Large, prospective, epidemiologic studies show a protective effect of dietary fiber against coronary heart disease (CHD) and form the basis for new recommendations from the National Academy of Science for fiber intake (38 and 25 g/d for young men and women, respectively, based on an intake of 14 g of fiber per 1000 kcal). Mechanisms by which fibers may protect against CHD include lowering blood cholesterol (soluble fibers), attenuating blood triglyceride levels (mostly soluble fibers), decreasing hypertension (all fibers), and normalizing postprandial blood glucose levels (all fibers). An important consideration in making diet recommendations to protect against CHD is that the total amount of fiber from fiber-containing foods is important, and individuals should not just be counseled to focus on soluble fiber.

Blood Glucose↗
PubMed2003

Testing for spatial correlation in nonstationary binary data, with application to aberrant crypt foci in colon carcinogenesis.

In an experiment to understand colon carcinogenesis, all animals were exposed to a carcinogen, with half the animals also being exposed to radiation. Spatially, we measured the existence of what are referred to as aberrant crypt foci (ACF), namely, morphologically changed colonic crypts that are known to be precursors of colon cancer development. The biological question of interest is whether the locations of these ACFs are spatially correlated: if so, this indicates that damage to the colon due to carcinogens and radiation is localized. Statistically, the data take the form of binary outcomes (corresponding to the existence of an ACF) on a regular grid. We develop score-type methods based upon the Matern and conditionally autoregressive (CAR) correlation models to test for the spatial correlation in such data, while allowing for nonstationarity. Because of a technical peculiarity of the score-type test, we also develop robust versions of the method. The methods are compared to a generalization of Moran's test for continuous outcomes, and are shown via simulation to have the potential for increased power. When applied to our data, the methods indicate the existence of spatial correlation, and hence indicate localization of damage.

Biometry↗
PubMed2003

Fish oil enhances targeted apoptosis during colon tumor initiation in part by downregulating Bcl-2.

We have shown that fish oil is protective against colon tumorigenesis, primarily by upregulating apoptosis. Production of prostaglandin E2 (PGE2) in colon cancer cells by cyclooxygenase (COX)-I and -II is known to inhibit apoptosis by induction of bcl-2. Because we have shown that fish oil downregulates PGE2 and COX-II, we hypothesized that this upregulation of apoptosis would be coincident with a downregulation of bcl-2. Bcl-2 was localized within the colonic crypt by quantitative immunohistochemistry (IHC), and scraped colonic mucosa was used for immunoblot analysis of bcl-2. The tissue used for bcl-2 analysis was from the rats used to determine apoptosis. Briefly, tissues were collected from rats consuming diets containing either corn oil or fish oil at 3, 6, 9, and 12 h after carcinogen injection. The correlation between bcl-2 and apoptosis was also determined. Bcl-2 expression decreased until 9 h (P < 0.05), whereas apoptosis increased until 9 h (P < 0.01). Bcl-2 expression and apoptosis were negatively correlated in both the proximal (P < 0.05) and distal colon (P < 0.005). Fish oil decreased bcl-2 expression (P < 0.05) and increased apoptosis (P < 0.05) in the top third of the crypt in the distal colon. In conclusion, one pathway by which fish oil may mediate apoptosis and thus protect against colon tumorigenesis is by downregulation of anti-apoptotic bcl-2.

Analysis of Variance↗
PubMed2002

Oncogenic ras alters sensitivity of mouse colonocytes to butyrate and fatty acid mediated growth arrest and apoptosis.

Docosahexaenoic acid (DHA) and butyrate favorably modulate colonocyte proliferation and apoptosis. In order to elucidate how oncogenic Ras modulates responses to these chemopreventive nutrients, we incubated isogenic non-transformed and Ras malignant transformed mouse colon cells with butyrate and DHA or linoleic acid (LA). Combining DHA with 1mM butyrate decreased proliferation relative to LA or no PUFA treatment in both cell lines. At a higher butyrate dose (5mM), caspase 3 activity was elevated to a greater extent in Ras transformed cells. Only non-transformed cells were sensitive to the apoptogenic effects of DHA, indicating that Ras transformation alters sensitivity to dietary chemopreventive agents.

Animals↗
PubMed2002

Dietary n-3 PUFA alter colonocyte mitochondrial membrane composition and function.

There is experimental evidence that dietary fish oil, which contains the n-3 fatty acid family, i.e., EPA and DHA, protects against colon tumor development, in part by increasing apoptosis. Since mitochondria can act as central executioners of apoptosis, we hypothesized that EPA and DHA incorporation into colonocyte mitochondrial membranes, owing to their high degree of unsaturation, would enhance susceptibility to damage by reactive oxygen species (ROS) generated via oxidative phosphorylation. This, in turn, would compromise mitochondrial function, thereby initiating apoptosis. To test this hypothesis, colonic crypts were isolated from rats fed either fish oil, purified n-3 fatty acid ethyl esters, or corn oil (control). Dietary lipid source had no effect on colonic mitochondrial phospholipid class mole percentages, although incorporation of EPA and DHA was associated with a reduction in n-6 fatty acids known to enhance colon tumor development, i.e., linoleic acid LNA) and its metabolic product, arachidonic acid (ARA). Select compositional changes in major phospholipid pools were correlated to alterations in mitochondrial function as assessed by confocal microscopy. The mol% sum of LNA plus ARA in cardiolipin was inversely correlated with ROS (P = 0.024). Ethanolamine glycerophospholipid ARA (P = 0.046) and choline glycerophospholipid LNA (P = 0.033) levels were positively correlated to mitochondrial membrane potential. In contrast, ethanolamine glycerophospholipid EPA (P = 0.042) and DHA (P = 0.024) levels were negatively correlated to mitochondrial membrane potential. Additionally, EPA and DHA levels in choline glycerophospholipids (P = 0.026) were positively correlated with caspase 3 activity. These data provide evidence in vivo indicating that dietary EPA and DHA induce compositional changes in colonic mitochondrial membrane phospholipids that facilitate apoptosis.

Animals↗
PubMed2002

Opportunities for nutritional amelioration of radiation-induced cellular damage.

The closed environment and limited evasive capabilities inherent in space flight cause astronauts to be exposed to many potential harmful agents (chemical contaminants in the environment and cosmic radiation exposure). Current power systems used to achieve space flight are prohibitively expensive for supporting the weight requirements to fully shield astronauts from cosmic radiation. Therefore, radiation poses a major, currently unresolvable risk for astronauts, especially for long-duration space flights. The major detrimental radiation effects that are of primary concern for long-duration space flights are damage to the lens of the eye, damage to the immune system, damage to the central nervous system, and cancer. In addition to the direct damage to biological molecules in cells, radiation exposure induces oxidative damage. Many natural antioxidants, whether consumed before or after radiation exposure, are able to confer some level of radioprotection. In addition to achieving beneficial effects from long-known antioxidants such as vitamins E and C and folic acid, some protection is conferred by several recently discovered antioxidant molecules, such as flavonoids, epigallocatechin, and other polyphenols. Somewhat counterintuitive is the protection provided by diets containing elevated levels of omega-3 polyunsaturated fatty acids, considering they are thought to be prone to peroxidation. Even with the information we have at our disposal, it will be difficult to predict the types of dietary modifications that can best reduce the risk of radiation exposure to astronauts, those living on Earth, or those enduring diagnostic or therapeutic radiation exposure. Much more work must be done in humans, whether on Earth or, preferably, in space, before we are able to make concrete recommendations.

Animals↗