Annual/Termination Reports:

[03/13/2009] [06/08/2010] [06/08/2011] [08/17/2012] [06/27/2013]

Report Information

Participants

" Bray, Tammy- Oregon State University
" Ho, Emily - Oregon State University
" Thomson, Cynthia - University of Arizona
" Winzerling, Joy - University of Arizona
" Weaver, Connie - Purdue University
" Stoecker, Barbara - Oklahoma State University
" Lucas, Ed - Oklahoma State University
" Shane, Barry - University of California Berkeley
" Zempleni, Janos - University of Nebraska
" Bruno, Richard - University of Connecticut
" Clifford, Andy - University of California, Davis
" Hord, Norman - Michigan State University
" Chapman-Novakofski, Karen - University of Illinois
" de Mejia, Elvira - University of Illinois
" Medieros, Denis - Kansas State University

Brief Summary of Minutes

Copy of Minutes attached

Accomplishments

Short Term Outcomes & Activities:<br /> This research group has had a highly productive year. First and foremost we were able to compete and secure funding as the W2002 Bioactive research group. This effort included a re-analysis of goals, objectives and strategic partnerships as well as the integration of several new members to enhance the group dynamics and capacity. <br /> <br /> The University of Arizona (Thomson) was awarded a USDA Bioactive Food Components grant to complete as controlled feeding trial to test the dose-response of vegetable intake in modulating oxidative stress and inflammatory response in overweight post-menopausal women. This study will identify not only changes in biomarkers of vegetable exposure but also assess the association of change in these biomarkers and change in oxidative stress and inflammation. The study is testing doses of 2, 5 and 10 servings of vegetables daily. Discussions with W2002 UConn researchers led to identification of optimal biomarkers to assess oxidative stress and inflammatory response for this research. AZ has also had the opportunity to collaborate with OSU researchers to support efforts to assess dietary exposure estimates to BAFC in cruciferous vegetables for two on-going studies. In addition the Thomson Clinical research group has published several manuscripts to support research in BAFC relevant to the W2002 group. In addition, an abstract presenting the a green tea and weight loss intervention trial among breast cancer survivors was presented at FASEB in 2008 and submitted January 2009 for peer-review.<br /> <br /> Collaborations are strong between Oregon State University and AZ as well as several other sites where Dr. Ho is advancing our understanding of the role of BAFC in cruciferous vegetables to reduce cancer risk in at-risk people. The classic view of cancer etiology is that genetic alterations damage DNA structure and induce mutations resulting in non-functional proteins that lead to disease progression. More recently, the role of EPIGENETIC alterations during cancer has gained increasing attention. These epigenetic alterations affect gene expression without directly changing DNA sequences, but rather turn on or off gene expression by post-translational modifications. Interestingly, many of these epigenetic modifications can also be modified by dietary factors. For example, pharmacological histone deacetylase (HDAC) inhibitors are currently being tested in human clinical trials and are proposed to have potent anti-cancer activity. The researchers have found that sulforaphane, a chemical found cruciferous vegetables is also an HDAC inhibitor, increases acetylated histone levels and has anti-cancer properties in the prostate. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables such as broccoli. This anticarcinogen was first identified as a potent inducer of Phase 2 enzymes, but evidence is mounting that SFN acts through other cancer chemopreventive mechanisms. The group recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells and prostate epithelial cells, namely the inhibition of histone deacetylase (HDAC). In human subjects, a single dose of 68 g BroccoSprouts® inhibited HDAC activity significantly in peripheral mononuclear cells, 3 and 6 h following consumption. HPLC-mass spec methods have been developed for identifying SFN and its metabolites in plasma and urine. A significant increase in urinary and plasma SFN and metabolites can be found following broccoli sprout consumption 3-6 hours following consumption. We have also found that SFN specifically targets prostate cancer cells. Administration of sulforaphane selectively induces cell death in cancer cells, but not normal prostate epithelial cells. This work suggests that phytochemical may have the ability to alter epigenetic events that lead to disease prevention.<br /> <br /> Dr. Rich Bruno of U Conn has common research interest with several W2002 investigators related to the role of oxidative stress in chronic disease risk. Specifically he is investigating the role of oxidative stress and excess hepatic lipid accumulation which are strongly implicated in obesity-triggered nonalcoholic fatty liver disease (NAFLD). His research group has evaluated the protective bioactivities of green tea extract (GTE) in mitigating these NAFLD implicated events in genetically obese (ob/ob) mice. 6-Wk dietary supplementation of GTE at 1% (w/w), but not 0.5% reduced (p<0.05) hepatic triglyceride and total lipid whereas both doses reduced the mRNA levels of fatty acid synthase and stearoyl-CoA desaturase suggesting that GTE inhibits de novo lipogenesis. Concurrently, they observed GTE-mediated decreases in serum alanine aminotransferase, hepatic TNF-± and hepatic malondialdehyde. In addition, GTE increased the activities of the CuZn- and Mn-superoxide dismutase, catalase and glutathione peroxidase suggesting that GTE attenuated hepatic injury in association with improved oxidative stress and inflammation. Thiese works have resulted in four publications this year. These publications support the role for tocotrienols and dietary GTE in protecting against NAFLD by regulating hepatic de novo lipogenesis and attenuating inflammatory and oxidative stress responses that contribute to NAFLD. The results provide common research ground for Drs. Bruno and Thomson re: oxidative stress and disease risk as well as the evaluation of the efficacy and mechanisms of green tea in modulating obesity.<br /> <br /> Dr. Barbara J. Stoecker, Ph.D  Oklahoma as two lines of scientific investigation relevant to the W2002 efforts. The first is related to dietary components and cadmium-induced bone loss in ovariectomized rats Cadmium (Cd) has detrimental effects on bone; however, some dietary components may affect Cd toxicity. Er research group has examined the effects of dietary supplementation of potassium phosphate and/or dried plum (DP) on Cd-induced bone damage. Fifty, 90 day-old ovariectomized Sprague-Dawley rats were assigned to five treatments (n=10): 1) control (3gP/kg diet), 2) 50mg Cd and 3gP/kg, 3) 50mg Cd and 12gP/kg, 4) 200mg Cd and 3gP/kg, and 5) 200 mg Cd and 12gP/kg diet. After 45 days, half the rats in each treatment had 15% DP added to diets for 3 more months. Femoral cortical bone and microarchitecture of L4 vertebra trabecular bone was assessed with microcomputed tomography (µCT). Bone strength was evaluated using finite element analysis. Cortical thickness was decreased by Cd and by high P (p < 0.0001) but increased by DP (p<0.003). L4 bone volume fraction, trabecular separation and connectivity density were impaired synergistically by Cd and high P. With higher dietary Ca/P ratios, DP frequently maintained microarchitecture in Cd-50 rats but not in Cd-200 rats. Force to compress L4 trabecular bone was consistent in showing significant detrimental effects of Cd and high P and beneficial effects of DP in the Cd-0 and Cd-50 groups when high P was not fed. The other area of research interest of the Stroecker laboratory is in regards to the role of green tea polyphenols and bone turnover in rats. The effects of green tea polyphenols (GTP) on bone microarchitecture in middle-aged female rats without (sham, SH) and with ovariectomy (OVX) were evaluated to evaluate GTPs antioxidant capacity. A 16-week study was performed based on a 2 (SH vs. OVX) × 3 (no GTP, 0.1% GTP, and 0.5% GTP in drinking water) factorial design using 14-month-old female rats (n=10/group). An additional 10 rats were euthanized at the beginning of the study to provide baseline parameters. Analysis using dual-energy X-ray absorptiometry, histomorphometric, and micro-computed tomography [microCT in OSUs laboratory] showed that GTP supplementation resulted in (a) increased trabecular volume, thickness, number, and bone formation of proximal tibia, periosteal bone formation rate of tibia shaft, and cortical thickness and area of femur, and (b) decreased trabecular separation and bone erosion of proximal tibia, and endocortical bone eroded surface of tibia shaft. These results suggest that drinking water supplemented with GTP mitigated deterioration of bone microarchitecture in both intact and ovariectomized middle-aged female rats by suppressing bone erosion , enhancing bone formation, and modulating endocortical and cancellous bone compartments, resulting in a larger net bone volume. This line of research supports collaboration with Dr. Bruno (UConn), Dr. Thomson (UAz) and Dr. Weaver (Purdue). In addition, Dr. Stoeker has an active line of research related to nutrient adequacy during pregnancy and childhood in developing countries affording an opportunity for collaborative international research.<br /> <br /> Obesity is associated with an increased risk of colon cancer and this has been a focus of the research of Dr. Norman Hord. A dearth of nontumorigenic colon epithelial cell model systems are available to address reductionist hypotheses concerning the interaction of endocrine products of adipose tissue and cancer risk. We have used conditionally immortal murine colon epithelial cells with distinct adenomatous polyposis coli (Apc) genotypes (IMCE (Apc Min/+) and YAMC (Apc+/+) to address the roles of leptin, adiponectin and interleukin 6 (IL-6) on cell number homeostasis and to characterize interactions with secreted products of macrophages. We demonstrated that leptin, an adipose-derived hormone, induces cell proliferation in IMCE, but not YAMC, cells by inducing autocrine IL-6 production and trans-IL-6 signaling. Microarray analysis revealed that leptin-induced changes in genes regulating the Wnt/beta-catenin-mediated pathway including Mdm2, Pik3r1, and Rb1. Leptin induced IGF-mediated pathway gene expression changes and their protein products in IMCE cells. In the IMCE cells IGFBP-6, IGF-1, and Crim1 expression was upregulated, while IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and Nov expression was downregulated by leptin treatment. While leptin promoted the proliferation of IMCE cells, we have also shown that it induces the production of chemokines which may activate macrophages and promote macrophage cell chemotaxis. As such, these data provide evidence for leptin-induced cross-talk between IMCE cells and macrophages that model a potential promotional mechanism. Low serum adiponectin, a major secretory product of white adipose tissue, is associated with colon, prostate and breast cancer; serum adiponectin levels decrease as body mass index (and leptin) increase. Under serum-free conditions, adiponectin (1 µg/ml) inhibited leptin-induced autocrine IL-6 production, soluble IL-6 receptor shedding, trans-IL-6 signaling and subsequent STAT3 phosphorylation in IMCE cells. Adiponectin inhibited leptin-induced cell proliferation in the IMCE cells and this inhibition was associated with I kappa B-alpha phosphorylation, I kappa B-alpha degradation and decreased NF-kappaB p65 DNA activation and binding. These data indicate that adiponectin acts on preneoplastic colon epithelial cells to regulate cell growth via 2 distinct pathways inhibiting leptin-induced NF-kappaB-dependent autocrine IL-6 production and trans-IL-6 signaling. <br /> <br /> Edralin A. Lucas (Oklahoma) I studying Momordica charantia and the modulation of glucose and lipid parameters in mice fed high fat diet. A high fat diet contributes significantly in the development of obesity and diabetes, two major public health concerns in the US and worldwide. Momordica charantia (MC), also known as bitter melon, is a widely consumed vegetable in Asia and reported to have hypoglycemic properties. This study compared the effects of freeze-dried MC with the PPARg agonist- rosiglitazone (rosi), and the known PPARa agonist- fenofibrate (feno), on body weight and clinical parameters using a mouse model of diet-induced obesity. Eight wk old male C57BL/6 mice were randomized to 8 dietary treatment groups (n=20/group): control diet (ad lib), control diet (pair fed), high fat (HF) diet, HF + 1% MC (w/w), HF + 10% MC (w/w), HF+1% MC seeds (w/w), HF + rosi (50mg/kg diet), and HF + feno (500mg/kg diet) for 8 wks. Significant differences in body weights were observed within one week of beginning the experimental diet. The final body weights of mice receiving the 10% MC were similar to the mice receiving the control diet (ad lib). Rosiglitazone and 1% MC were not able to reduce body weight; however, fenofibrate and MC seeds mildly reduced body weight. HF fed mice exhibited the highest percent body fat. Interestingly, 10% MC prevented the increase in adiposity due to high fat diet. A high fat diet containing 10% MC, similar to rosiglitazone, normalized blood glucose after a glucose tolerance test. Triglycerides, total cholesterol, and glucose were all elevated due to high fat diet. The higher dose of MC modulated these clinical parameters similar to fenofibrate and rosiglitazone. Fenofibrate caused an enlargement of liver which was not observed in other treatment groups. The mechanism by which MC modulates glucose and body weight warrants further investigation. <br /> <br /> Dr. Janos Zempleni (University of Nebraska at Lincoln) has a focused research program in the area of repression of transposable elements by histone biotinylation and its role in cancer prevention. Transposable elements such as long terminal repeats (LTR) constitute about 45% of the human genome; transposition events impair genome stability. Fifty-four promoter-active retrotransposons have been identified in humans. Epigenetic mechanisms are important for transcriptional repression of retrotransposons, preventing transposition events and abnormal regulation of genes. Here, we demonstrate that the covalent binding of the vitamin biotin to lysine-12 in histone H4 (H4K12bio) and lysine-9 in histone H2A (H2AK9bio), mediated by holocarboxylase synthetase (HCS), is an epigenetic mechanism to repress retrotransposon transcription in human and mouse cell lines and in primary cells from a human supplementation study. Abundance of H4K12bio and H2AK9bio at intact retrotransposons and a solitary LTR depended on biotin supply and HCS activity, and was inversely linked with the abundance of LTR transcripts. Knockdown of HCS in Drosophila enhances retrotransposition in the germline. Importantly, his research group has demonstrated that depletion of H4K12bio and H2AK9bio in biotin-deficient cells correlates with increased production of viral particles, transposition events, and ultimately decreases chromosomal stability. Collectively, this study reveals a novel diet-dependent epigenetic mechanism that could affect cancer risk. This work has and will continue to afford opportunities for collaboration with several other W2002 investigators working in cancer prevention research.<br /> <br /> Dr. Andy Clifford (UCDavis)as completed compelling research in the area of age-related macular degeneration (AMD), the most common cause of irreversible blindness in elderly Americans. There is now evidence that the carotenoids, lutein and zeaxanthin are key to protecting against AMD, by filtering out blue light at a pre-receptoral level, or by quenching free radicals. Lutein and zeaxanthin are dietary xanthophyll carotenoids, that are delivered to the retina via plasma lipoproteins. Mechanisms governing the selective retinal capture and accumulation of lutein and zeaxanthin, over other carotenoids, are unknown except that lipoproteins/apolipoproteins play a key role. Xanthophyll-binding proteins in the retina capture the xanthophyll carotenoids, the Pi isoform of GSTP1 is specific for zeaxanthin but the binding protein for retinal uptake of lutein remains elusive. To explore the beneficial effects of lutein and zeaxanthin for humans one must understand how they are absorbed from the intestine, transported in serum, and taken up by the retina, use of 14C accelerator mass spectrometry (AMS) and kinetic models of datasets to facilitate this task. Dr. Cliffords work has focused on improving high throughput biological/biomedical applications AMS to quantify minute amounts of 14C. The process involves oxidation of carbon (in sample of interest) to CO2 and then reduction of CO2 to graphite-like substances that coat a -400-mesh spherical iron powder (-400MSIP) catalyst. Prior AMS methods often failed to produce robust ion currents that are required for reliable, accurate, precise, and high-throughput AMS for biological/biomedical applications. Therefore, we described our optimized method for reduction of CO2 to high-quality uniform AMS targets (1) and characterized their physical (hardness/color), morphological (Scanning Electron Micrographs), and structural (Fourier Transformed-Infra Red, FTIR; Raman; and X-Ray Defraction, XRD spectra) characteristics that guarantee accurate, precise, and high-throughput AMS measurement (2). In addition the technology was used to determine how ingested 14C-all-trans [10,10',11,11'-14C]-b-carotene is absorbed from the intestine, transported in serum, and metabolized in vivo in humans. The group has demonstrated excentral cleavage of b-carotene in humans for the first time (3). Finally, we discovered that the apparent digestibility of the 14C dose was 50 % (4). The metabolic fecal elimination and AUC0- were 0.05 and 41 %, respectively. The portion of 14C dose eliminated in urine varied 8.2 %. Plasma 14C-b-carotene and 14C- REs accounted for most of the absorbed 14C. Feces was the major excretory path. These data suggested the variable elimination of 14C via urine accounted for the variable plasma/serum responses to ingested b-carotene reported in prior studies. Our data also suggested that plasma levels of ROH plus REs should be considered in estimating vitamin A equivalency of ingested b-carotene. These methodologies have strong potential for application to numerous BAFC and thus offer opportunities to several of the W2002 investigators for collaboration.<br /> <br /> Barry Shane University of California, Berkeley has continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. One carbon metabolic fluxes and DNA and histone methylation has been evaluated in these animals and in embryonic fibroblasts. We have investigated the influence of folate and vitamin B12 status in our experimental animals using cDNA array technology and have identified a number of inflammatory response genes that are responsive to vitamin status. We continue to evaluate genetic risk factors for neural tube defects. We are continuing to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains, and are evaluating the interaction between iron and folate status. We have measured myelination rates in the B12-deficient mouse and have shown that remyelination is impaired. Mathematical models are being developed to better understand regulatory aspects of one carbon metabolism. The impact of this work is significant in that neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. The studies may indicate whether this risk can be modified by dietary changes and may shed some insight into the etiology of vitamin B12 deficiency symptoms and interactions between folate and iron.<br /> <br /> Dr. de Mejia from the University of Illinois joined the W2002 investigative team this year as her research focuses on the molecular mechanisms of chemoprevention of bioactive food components, mainly proteins/petides and flavonoids, and their safety. Thus, opportunities for collaborations with several investigators will be abundant. Her research focuses on the study of food components with health benefits; analysis, characterization and mechanism of action of antimutagenic and anticarcinogenic compounds in foods (legumes, oilseeds, and vegetables). Currently the group is working with bioactive proteins in different legumes and investigates the role of processing on the presence, concentration and physicochemical characteristics of proteins/peptides with biological potential against chronic diseases as well as their safety such as allergenic potential. Similar to Bruno (UConn) and Thomson (UAZ) this research group is also studying the health benefits of tea, in particular the molecular mechanisms underlying the biological effects of ethnic teas used in folk medicine to combat several disorders including cancer. This scientific study will introduce new materials to improve human health. In 2007-2008 this research group published over 15 manuscripts indicating involvement of Dr. de Mejia is likely to result in even greater productivity for the W2002 group.<br /> <br /> Dr. Weaver at Purdue has accomplished instrumental work during this period evaluating bone mass in adolescents. She has found that about 25% of peak bone mass is acquired during the peak rate of bone acquisition in puberty, but factors which influence skeletal calcium accretion are not well understood. We evaluated the role of vitamin D status in calcium absorption and retention in adolescent white and black girls. Her research also evaluated predictors of calcium retention in adolescent boys. Data from controlled feeding studies on a range of calcium intakes were evaluated for factors which are thought to predict calcium utilization in 55 white and 55 black girls and 31 boys. In girls, calcium intake explained about as much of the variation in calcium retention as did race (12.3 vs. 13.7%, respectively). In boys, calcium intake and IGF-1 explained 21.7 and 11.5% of the variation in calcium retention. This shows lifestyle choices can be as important for skeletal growth as genetic determinants. This kind of analysis can only be derived from controlled feeding studies. This work has resulted in the publication of numerous peer-reviewed manuscripts (see publication list). <br /> <br /> The research of Dr. Winzerlings lab (UAz) is unusual in regards to the W2002 in that they work in mosquitoes as models for iron metabolism. They recently analyzed transferrin 2 from mosquitoes to determine whether this protein is likely to be involved in iron metabolism in this animal. Tf2 showed greatest identity to melanotransferrin from humans. However, like mammalian melanotransferrin, Tf2 in mosquitoes is unresponsive to exposure to iron in a blood meal as well as to iron administrated to mosquito CCL-125 cells in culture. Life stage analysis suggests that Tf2 is most likely involved in development. Ferritin is crucial to iron metabolism in mosquitoes and man. In mosquitoes it is a primary iron transport protein. We evaluated the ability of several chemical inhibitors to block ferritin secretion in mosquito cells. CI-976 a phospholipase inhibitor blocked secretion, whereas Brefeldin A did not, suggesting that ferritin is secreted from mosquito cells by budding of vesicles from the ER membrane. However, when fed to mosquitoes as part of a blood meal, CI-976 (in ethanol) failed to reduce egg numbers or increase mortality. Thus, we are using RNAi to evaluate the effects preventing iron transport from the blood meal to the ovaries and eggs. We also have initiated studies evaluating the ovarian and egg proteome expressed following an artificial blood meal with and without hemoglobin to female mosquitoes. In addition to our mosquito work, we collaborated with a team of scientists in the Czech Republic in work on iron metabolism in ticks that transmit disease. This work determined that Tf2 is not likely involved in iron metabolism. Although CI-976 inhibits ferritin secretion from cells; feeding the compound to animals failed to reduce egg numbers or increase mortality of mosquitoes. Dietary iron is highly mitogenic in mosquitoes and stimulates synthesis of several ovarian and egg proteins. <br /> <br /> The Medeiros lab is involved in two micronutrient studies. The first one focuses on copper deficiency and cardiac hypertrophy with emphasis on mitochondria and the second on the role of iron in bone. Copper and heart disease studies: During the last year, the group published a paper on the gene program that is up-regulated in mitochondrial biogenesis in hearts from copper deficient rats. We have demonstrated that PGC1-± transcripts and protein are robustly up-regulated in hearts from copper deficient rats. This protein is thought to be the master regulator of mitochondrial biogenesis. Previously we have demonstrated that other proteins and transcription factors involved in mitochondrial biogenesis are up-regulated. However, many of these markers depend on PGC1-±. These results in tandem with other papers we have published prove that all of the markers of mitochondrial biogenesis are upregulated in hearts from copper-deficient rats. This occurs despite the fact that there does not appear to be a shift in substrate utilization. In heart disease, the heart will often shift from fatty acids to glucose as a fuel substrate source to maintain ATP levels. Here we measured rate limiting enzymes in glycolysis and found that medium chain acyl dehydrogenase (rate limiting for beta oxidation of fatty acids), phosphofructose kinase (rate limiting for glycolysis), and Phosphoenolpyruvate carboxykinase (gluconeogenesis enzyme) did not differ by copper status. This suggests that the increase in mitochondria is able to keep up with energy demands of the heart as an adaptive process. Using proteinomics, we were able to determine changes in several proteins, all of which were secondary to heart damage found in the copper deficient heart. Future studies have now focused upon chaperone proteins of cardiac cells as a function of copper deficiency. Iron restriction and bone integrity: The second area deals with iron deficiency and bone integrity. We have published previously that animals fed iron restricted diets, as well as calcium restricted diets either singly or in combination with one another, have reduced bone strength as measured by Instron breakage. Using mico-CT analysis we have been able to demonstrate increased porosity of trabecular of bone from rats fed either calcium or iron restricted diets. These studies were done in collaboration with Dr. Stoecker of Oklahoma State University. A salient additional finding from several of our studies on this topic is an apparent decrease in mineralization of bones from iron restricted animals and also with an in vitro bone cell system using an iron chelator to generate an iron deficiency. The next logical step in this study is to collaborate with others on the multi-state project to assess calcium kinetics as affected by iron restriction, looking at both bone accretion and turnover. A second line of work needed is to determine if the condition is reversible with iron repletion. Finally, human epidemiological studies are needed to confirm the feasibility of iron as a factor in human bone health. Collaborations related to iron and bone health are underway and involve Drs. Medieros, Weaver and Winzerling.<br /> <br /> Important to all this research is the role of translational research that brings research findings to the consumer. To support the translation of science at this level we have engaged the expertise and experience of Dr. Karen Chapman-Novakofski a well-recognized expert in behavior research and epidemiological study. Various mediating variables influence behavior and identifying those variables continues to be a research interest in epidemiological studies. In addition, we know that knowledge alone is not effective in changing behavior. Grounding in a behavioral theory is required for effective interventions targeting diet and lifestyle change. In addition, in-person education is becoming costly in terms of time and effort for both the educator and learner. In this regards, online interactive education may prove to be an effective alternative to group education settings, or at least augment such efforts. Her research has resulted in several publications during the report period and offers an opportunity for several W2002 investigators to expand collaborations to include epidemiological and/or outcomes-based research. <br /> <br /> <br /> Outputs:<br /> As a whole the research group within W2002 has published over 50 peer-reviewed manuscripts in 2007-2008 impacting healthcare, research technology and methodology, consumer knowledge and the food supply. We have met our objectives to expand knowledge of bioavailability of nutrients as well as to assess specific bioactivity of select BAFC in the human diet with a particular emphasis on bioactivity biomarkers/indicators of bone health, cancer risk, cardiovascular disease risk and inflammatory disorders such as obesity. In addition we have explored the role of epigenetics in health and have bridged opportunities between epidemiologists and basic scientists in regard to testing hypotheses across the spectrum of nutrition science research. We have shared methodologies, technologies, expertise and research findings in a meaningful, collaborative and interactive way thus supporting the advancement of scientific knowledge regarding the role of BAFC and nutrients in optimizing human health.<br /> <br /> Milestones:<br /> Successful renewal of the W2002 Multistate project was accomplished. For 2009 we plan to continue to build productive collaborative research projects and joint peer-reviewed manuscripts. In addition we are planning a translational research symposium for the 2010 FASEB meeting. To this end we have engaged 5 different Research Interest groups within FASEB and have submitted our proposal titled, From field to consumer-the science & translation of bioactive food component research. The symposium would be co-directed by Norman Hord and Richard Bruno members of W2002 and all speakers are within our research group.<br />

Publications

Abebe Y, Hambidge KM, Teshome A, Stoecker B, Krebs, N, Gibson R. Inadequate feeding practices and impaired growth among children from subsistence farming households in Sidama, Southern Ethiopia. Maternal and Child Nutrition, In Press, 2009. <br /> <br /> Abebe Y, Bogale A, Hambidge KM, Stoecker BJ, Arbide I, Teshome A, Krebs NF, Westcott JE, Bailey KB, Gibson RS. Inadequate intakes of dietary zinc among pregnant women from subsistence households in Sidama, Southern Ethiopia. Public Health Nutr 11:379-386, 2007.<br /> <br /> Alwerdt JL, Seigler DS, Gonzalez de Mejia E, Yousef GG, Lila MA. The Influence of Alternative Liquid Chromatography Techniques on Chemical Complexity and Bioactivity of Proanthocyanidin Mixtures. J. Agric. Food Chem. 65 (6): 1896-1906, 2008. <br /> <br /> Aparicio-Fernández X, Reynoso-Camacho R, Castaño-Tostado E, García-Gasca T, González de Mejia E, Guzmán-Maldonado H, Elizondo-Azuela G, Lila MA, Loarca-Pina G. Antiradical capacity and induction of apoptosis in HeLa cells by a <br /> Phaseolus vulgaris extract. Plant Foods Human Nutr., 63(1):35-40, 2008. <br /> <br /> Ariefdjohan M, Martin B, Lachcik P, Weaver CM. Acute and chronic effects of honey and its carbohydrate constituents on calcium absorption in rats. J. Ag. Food Chem. 56:2649-2654, 2008.<br /> <br /> Bruno RS, Dugan CE, Smyth JA, DiNatale DA, Koo SI. Green tea extract protects leptin-deficient, spontaneously obese mice from hepatic steatosis and injury. J Nutr. 138(2):323-31, 2008. <br /> <br /> Bu SY, Lerner M, Stoecker BJ, Boldrin E, Brackett DJ, Lucas EA, Smith BJ. Dried plum polyphenols inhibit osteoclastogenesis by downregulating NFATc1 and inflammatory mediators. Calcif Tissue Int. 82(6):475-88, 2008.<br /> <br /> Bu SY, Lerner M, Stoecker BJ, Boldrin E, Brackett DJ, Lucas EA, Smith, BJ. Dried plum polyphenols inhibit osteoclastogenesis by downregulating NFATc1 and inflammatory mediators. Calcified Tissue International 82:475-488, 2008. <br /> <br /> Charoenkiatkul S, Kriengsinyos W, Tutipopipat S, Suthutvoravut U, Weaver CM. Calcium absorption from commonly consumed vegetables in healthy Thai women. J. Food Sci. 73(9):H218-21, 2008.<br /> <br /> Clarke, JD, Dashwood, RH and Ho E. Multi-targeted prevention of cancer by sulforaphane. Cancer Letters, 269(2):291-304, 2008.<br /> <br /> Dashwood RH, Ho E. Dietary agents as histone deacetylase inhibitors: sulforaphane and structurally-related isothiocyanates. Nutr Rev, 66 Suppl 1:S36-8, 2008.<br /> <br /> Devareddy L, Hooshmand S, Collins JK, Lucas EA, Chai SC. Blueberry prevents bone loss in ovariectomized rat model of postmenopausal osteoporosis. J Nutr Biochem. 19(10):694-9, 2008. <br /> <br /> Dia PV, Torres S, De Lumen BO, Erdman J, Gonzalez de Mejia E. Presence of lunasin in plasma of men after soy protein consumption. Journal of Agricultural and Food Chemistry, In Press 2008.<br /> <br /> Dia VP, Berhow MA, Gonzalez de Mejia E. Bowman-Birk Inhibitor and genistein among soy compounds that synergistically inhibit nitric oxide and prostaglandin E2 pathways in lipopolysaccharide-induced macrophages. J. Agric. Food Chem., 56 (24), 1170711717, 2008. <br /> <br /> Dia PV, Wang W, Oh VL, de Lumen BO, Gonzalez de Mejia E. Isolation, purification and characterization of lunasin from defatted soybean flour and in vitro evaluation of its anti-inflammatory activity. Food Chemistry, 113 (5), 2009. doi: 10.1016/j.foodchem.2008.09.023.<br /> <br /> Droke EA, Hager KA, Lerner MR, Lightfoot SA, Stoecker BJ, Brackett DJ, Smith BJ. Soy isoflavones avert chronic inflammation-induced bone loss and vascular disease. J Inflammation (Lond) 4:17-28, 2007. <br /> <br /> Fenton JI, Nuñez NP, Yakar S, Susan N, Perkins SN, Hord NG, Hursting SD. Dietary modulation of energy balance alters the serum profile of inflammation in C57BL/6N mice. Diabetes, Obesity and Metabolism. 11(4): 343-354, 2009.<br /> <br /> Fenton, JI, Birmingham, J, Hursting, SD and Hord, NG Adiponectin blocks leptin induced NFº-B DNA binding, interleukin-6 trans- signaling and cell proliferation in ApcMin colon epithelial cells. International Journal of Cancer. 122(11): 2437-45, 2008.<br /> <br /> Fenton, JI, Lavigne JA, Perkins, SN, Liu H, Chandramouli, GVR, Shih, JH, Hord, NG, Hursting, SD Microarray analysis reveals that leptin induces autocrine/paracrine cascades to promote survival and proliferation of colon epithelial cells in an Apc genotype dependent fashion. Mol Carcinog. 2008 Jan;47(1):9-21.<br /> <br /> Frias J. Song Y S, Martínez-Villaluenga C, González de Mejia E, Vidal-Valverde C. Immunoreactivity and Amino Acid Content of Fermented Soybean Products. J. Agric. Food Chem., 56 (1), 99105, 2008.<br /> <br /> Geiser DL, Shen M-C, Mayo JJ, Winzerling, JJ. Iron Loaded Ferritin Secretion and Inhibition by in Aedes aegypti larval cells. Comparative Biochemistry and Molecular Biology. 2009 Jan 8. [Epub ahead of print], 2009.<br /> <br /> Geiser DL, Mayo JJ, Shen M-C, Winzerling, JJ. The unique regulation of Aedes aegypti larval cell ferritin by iron. Insect Biochemistry and Molecular Biology, 37(5):418-29, 2007.<br /> <br /> Gibson RS, Abebe Y, Stabler S, Allen RH, Westcott JE, Stoecker BJ, Krebs NF, Hambidge KM. Zinc, gravida, infection, and iron, but not vitamin B-12 or folate status predict hemoglobin during pregnancy in southern Ethiopia. J Nutrition 138:581-586, 2008.<br /> <br /> Hajdusek O, Sojka D, Kopacek P, Buresova V, Franta Z, Sauman I, Winzerling, JJ, Grubhoffer L. Knockdown of proteins involved in iron metabolism limits tick reproduction and development. Proceedings National Academy Sciences, USA. 2009 Jan 27;106(4):1033-8. Epub 2009 Jan 26.<br /> <br /> Heck CI, de Mejia EG. Yerba mate tea (Ilex paraguariensis): a comprehensive review on chemistry, health implications and technological considerations. J. Food Sci., 72 (9), 138-151, 2007. <br /> <br /> Heck CI, Schmalko M, Gonzalez de Mejia E. Effect of Growing and Drying Conditions on Phenolic Composition of Mate teas (Ilex paraguariensis). J. Agric. Food Chem., 56 (18): 8394-8403, 2008.<br /> <br /> Herrejon K, Hartke JL, Scherer J, Chapman-Novakofski K. The creation and impact evaluation of Your Guide to Diet and Diabetes, an interactive web-based diabetes tutorial. Accepted to Diabetes Technology and Therapeutics, August, 2008.<br /> <br /> Hill K, Braun MM, Kern M, Martin BR, Navalta J, Sedlock D, McCabe LD, McCabe GP, Peacock M, Weaver CM. Predictors of calcium retention in adolescent boys. J. Clin. Endocrin. Metab. 93(12):4743-4748, 2008. <br /> <br /> Ho CC, de Moura F, Kim SH, Clifford AJ. Excentral cleavage of b-carotene in vivo in a healthy man. Am J Clin Nutr, 85:770-7, 2007. <br /> <br /> Ho CC, de Moura F, Kim SH, Burri BJ, Clifford AJ. b-Carotene absorption and conversion to retinoids in healthy humans assessed with a 14C-b-carotene tracer. J Nutr. (Submitted).<br /> <br /> Hord NG. Eukaryotic-microbiota cross-talk: potential mechanisms for health benefits of prebiotics and probiotic bacteria. 28:215-31, 2008.<br /> <br /> Hord NG, Fenton JI. Context is everything: mining the normal and preneoplastic microenvironment for insights into the diet and cancer risk conundrum. Molecular Food and Nutrition Research, 51(1):100-108, 2007.<br /> <br /> Hubbs-Tait L, Mulugeta A, Bogale A, Kennedy TS, Stoecker BJ. Main and interaction effects of iron, zinc, lead and parenting on children's cognitive outcomes. Developmental Neuropsychology, In Press, 2009. <br /> <br /> Johnson CD, Lucas EA, Hooshmand S, Campbell S, Akhter MP, Arjmandi BH. Addition of fructooligosaccharides and dried pum to soy-based diets reverses bone loss in the ovariectomized rat. Evid Based Complement Alternat Med. 2008 Jul 30. [Epub ahead of print].<br /> <br /> Kennedy TS, Thomas DG, Wogene T, Abebe Y, Hubbs-Tait L, Stoecker BJ, Hambidge KM. Growth and visual information processing in infants in southern Ethiopia. J Applied Develop Psych 29:129-140, 2008. <br /> <br /> Keylock KT, Lowder T, Leifheit KA, Cook M, Mariani RA, Ross K, Kim K, Chapman-Novakofski K, McAuley E, Woods JA. Higher antibody, but not cell-mediated, responses to vaccination in higher physically fit elderly. J Appl Physiol 102(3): 1090-1098, 2007. <br /> <br /> Khan N, Nast C, Evans EM, Chapman-Novakofski K. Development of a training program for undergraduate student-assisted teaching. J Nutr Educ Behav, 41(1):xxx 2009.<br /> <br /> Kim SH, Kelly PB, Clifford AJ. Biological/biomedical accelerator mass spectrometry targets. 1. Optimizing the CO2 reduction step using zinc dust. Anal Chem, 80:7651-60, 2008. <br /> <br /> Kim SH, Kelly PB, Clifford AJ. Biological/biomedical accelerator mass spectrometry targets. Physical, morphological, and structural characteristics. Anal Chem, 80:7661-9, 2008.<br /> <br /> MacFarlane AJ, Perry CA, Girnary HH, Gao D, Allen RH, Stabler SS, Shane B, Stover PJ. Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism. J. Biol. Chem. 284:1533-1539, 2009.<br /> <br /> Martinez-Villaluenga C, Bringe NA, Berhow MA, Gonzalez de Mejia E. ²-Conglycinin embeds active peptides that inhibit lipid accumulation in 3T3-L1 adipocytes in vitro. J. Agric. Food Chem., 56 (22), 1053310543, 2008.<br /> <br /> Martinez-Villaluenga C, Dia PV, Berhow M, Bringe NA, Gonzalez de Mejia E. Protein hydrolysates from ²-conglycinin enrich soybean genotypes inhibit lipid accumulation and inflammation in vitro. Molecular Nutrition and Food Research, In Press, 2008. MNF-0473-2008.<br /> <br /> Martino HSD, Martin BR, Weaver CM, Bressan J, Moreira MA, Costa NMB. Antinutrient factors and bioavailability of calcium of genetically modified soybeans. J. Food Sci. 72:S698-695, 2007. <br /> <br /> Mederios DM, Jiang Y, Klaahsen D, Lin D. Mitochondrial and sarcoplasmic protein changes in hearts from copper-deficient rats: up-regulation of PGC-1± transcript and protein as a cause for mitochondrial biogenesis in copper deficiency. J. Nutr. Biochem. In press.<br /> <br /> Medeiros DM. Assessing mitochondria biogenesis. Methods 46: 288-294, 2008.<br /> <br /> Miller JA, Hakim IA, Thomson CA, et al. Determination of d-Limonene in Adipose Tissue by Gas Chromatography-Mass Spectrometry J Chrom B. 870: 68-73, 2008.<br /> <br /> Morrow R, Deyhim F, Patil BS, Stoecker BJ. Feeding orange pulp improved bone quality in a rat model of male osteoporosis. Journal of Medicinal Food, In Press, 2009.<br /> <br /> Mulugeta A, Hagos F, Stoecker B, Kruseman G, Linderhof V, Abraha Z, Yohannes M, Samuel GG. Nutritional status of adolescent girls from rural communities of Tigray, Northern Ethiopia. Ethiopian Journal of Health and Development. In Press, 2009.<br /> <br /> Mulugeta A, Hagos F, Kruseman G, Linderhof V, Stoecker BJ, Abraha Z, Yohannes M, Samuel GG. Factors contributing to child malnutrition in Tigray, Northern Ethiopia. East African Medical Journal, In Press, 2008.<br /> <br /> Mustachich DJ, Gohil K, Bruno RS, Yan M, Leonard SW, Ho E, Cross CE, Traber MG. Alpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice. J Nutr Biochem, E-pub Sept 10, 2008.<br /> <br /> Nesaretnam K, Koon TH, Selvaduray KR, Bruno RS, Ho E. Modulation of cell growth and apoptosis response in human prostate cancer cells supplemented with tocotrienols. Eur J Lipid Sci Technol. 110:23-31, 2008. <br /> <br /> Olvera-Garcia V, Castano-Tostado E, Resendiz-Lopez I, Reynoso-Camacho R, Gonzalez de Mejia E, Elizondo-Azuela G, Loarca-Pina G. Hibiscus sabdariffa L. extracts inhibit the mutagenicity in microsuspension assay and the proliferation of HeLa cells. J. Food Sci. 73 (5): T75T81, 2008.<br /> <br /> Patade A, Devareddy L, Lucas EA, Korlagunta K, Daggy BP, Arjmandi, BH. Flaxseed reduces total- and LDL-cholesterol concentrations in Native American postmenopausal women. J Womens Health, 7(3):1-12, 2008.<br /> <br /> Reppert A, Steiner B, Chapman-Novakofski K. Prevalence of metabolic syndrome and associated risk factors in Illinois. Am J Health Promotion 23(2):130-138, 2008.<br /> <br /> Sprengelmeyer K, Banks D, Camp S, Farner B, Chapman-Novakofski K. From theories of behavior back to knowledge: results of a knowledge-focused diabetes education program. International J Food Science, Technology, & Nutrition 1(2):155-166, 2007.<br /> <br /> Serrano E, Anderson J, Chapman-Novakofski K. Not lost in translation: Nutrition education as translational science. J Nutrition Educ Behav 39(3): 164-170, 2007.<br /> <br /> Shane B. Folate and vitamin B12 metabolism: Overview and interaction with riboflavin, vitamin B6, and polymorphisms. In Folate and Vitamin B12 Deficiencies: Proceedings of a WHO Technical Consultation. Food Nutr. Bull. 29:S5-16, 2008.<br /> <br /> Shen C-L, Yeh JK, Stoecker BJ, Chyu M-C, Wang J-S. Green tea polyphenols mitigate deterioration of bone microarchitecture in middle-aged female rats. Bone Dec 11 (E-pub ahead of print] 2008. <br /> <br /> Silva-Sánchez C, Barba de la Rosa AP, León-Galván MF, de Lumen BO, de León-Rodríguez A, González de Mejía E. Bioactive peptides in Amaranth (Amaranthus hypochondriacus) Seed. J. Agric. Food Chem. 56 (4): 1233-1240, 2008.<br /> <br /> Song Y-S, Martinez-Villaluenga C, González de Mejia E. Quantification of human IgE immunoreactive soybean proteins in commercial soy ingredients and products. Submitted, J. Food Sci. 73 (6), T90-T99, 2008.<br /> <br /> Song Y-S, Frias J, Martinez-Villaluenga C, Vidal-Valdeverde C, Gonzalez de Mejia E. Immunoreactivity reduction of soybean meal by fermentation, effect on amino acid composition and antigenicity of commercial soy products. Food Chem., 108 (2): 571-581, 2008.<br /> <br /> Stoecker BJ, Abebe Y, Hubbs-Tait L, Kennedy TS, Gibson RS, Arbide I, Teshome A, Krebs NF, Hambidge MK. Zinc status and cognitive function of pregnant women in southern Ethiopia. European Journal of Clinical Nutrition, In Press, 2009.<br /> <br /> Stoecker BJ. Basis for dietary recommendations for chromium. In: Vincent JB, ed. The Nutritional Biochemistry of Chromium (III). Amsterdam: Elsevier B.V., pp. 43-55, 2007. <br /> <br /> Taylor AW, Bruno RS, Traber MG. Women and Smokers Have Elevated Urinary F2-Isoprostane Metabolites; Determinations using a Novel Extraction and LC-MS Methodology. Lipids; In Press, 2008.<br /> <br /> Thomson CA, Stendell-Hollis NR, Rock CL et al. Plasma and Dietary Carotenoids are Associated with Reduced Oxidative Stress in Women Previously Treated for Breast Cancer. CEBP. 16(10): 2008-2015, 2007.<br /> <br /> Thomson CA, Neuhouser ML, Shikany JM, et al. The Role of Antioxidants and Vitamin A in Ovarian Cancer: Results from the Womens Health Initiative Prospective Cohort. Nutr & Cancer. 60:(6): 710-719, 2008. <br /> <br /> Thomson CA, Stendell-Hollis NR, West JL, et al. High-Lycopene Tomato Intake Increases Serum Carotenoid Levels but not Biomarker Oxidative Stress and Inflammation in Healthy Adults. The Open Bioactive Compounds Journal. 1: 7-12, 2008. <br /> <br /> Ulrich CM, Neuhouser M, Liu AY, Boynton A, Gregory JF III, Shane B, James SJ, Reed MC, Nijhout HF. Mathematical modeling of folate metabolism: predicted effects of genetic polymorphisms on mechanisms and biomarkers relevant to carcinogenesis. Can. Epidemiol. Biomark. Prev. 17:1822-1831, 2008.<br /> <br /> Vaughn N, Rizzo A, Doane D, Beverly JL, Gonzalez de Mejia E. Intracerebroventricular administration of soy protein hydrolysates reduces body weight without affecting food intake in rats. Plant Foods Hum. Nutr., 63(1):41-46, 2008.<br /> <br /> Villarreal A, Stoecker BJ, Garcia C, Garcia K, Rios R, Gonzales C, Mandadi K, Faraji B, Patil BS, Deyhim F. Cranberry juice improved antioxidant status without affecting bone quality in orchidectomized male rats. Phytomedicine 14:815-20, 2007. <br /> <br /> Wang W, Dia VP, Vasconez M, Nelson R, Gonzalez de Mejia E. Analysis of soybean protein-derived peptides and the effect of cultivar, environmental conditions, and processing on lunasin concentration in soybean and soy products. In: Special edition of Journal of the Association of Official Analytical Chemists International on Accurate methodology for amino acids and bioactive peptides in functional foods and dietary supplements for assessing protein adequacy and health effects. JAOAC Int. 91 (4): 936-946, 2008.<br /> <br /> Wang W, Bringe N, Berhow M, Gonzalez de Mejia E. ß-conglycinins among sources of bioactives in hydrolysates of different soybean varieties that inhibit leukemia cells in vitro. J. Agric. Food Chem. 56 (11): 4012-4020, 2008.<br /> <br /> Wang W, Rupasinghe SG, Schuler MA, Gonzalez de Mejia E. Identification and characterization of topoisomerase II inhibitory peptides from soy protein hydrolysates. J. Agric. Food Chem. 56 (15): 6267-6277, 2008.<br /> <br /> Wardwell L, Chapman-Novakofski K, Herrel S, Woods J. Nutrient intake and immune function of elderly subjects. J Amer Diet Assoc 108:2005-2012, 2008.<br /> <br /> Wardwell L, Brewer M, Chapman-Novakofski K. Effects of age, gender and chronic obstructive pulmonary disease on taste acuity. Accepted to the International J Food Sciences and Nutrition, December, 2008.<br /> <br /> Weaver CM, McCabe LD, McCabe GP, Braun M, Martin BR, DiMeglio LA, Peacock M. Vitamin D status and calcium metabolism in adolescent black and white girls on a range of controlled calcium intakes. J. Clin. Endocrin. Metab. 93:3907-3914, 2008.<br /> <br /> Wilson S, Martinez-Villaluenga C, Gonzalez de Mejia E. Purification, thermal stability and antigenicity of the immunodominant soybean allergen P34 in soy cultivars, ingredients and products. J. Food Sci. 73 (6), T106-T114, 2008.<br /> <br /> Zhou G, Kohlhepp P, Geiser DL, Frasquillo C, Vazquez-Moreno L, Winzerling, JJ Fate of blood meal iron in mosquitoes. Journal of Insect Physiology, 53(11):1169-78, 2007.<br /> <br /> Zhou G, Geiser DL, Velasquez LS, Mayo JJ, Winzerling, JJ. Differential regulation of transferrin 1 and 2 in Aedes aegypti. Insect Biochemistry and Molecular Biology. 2008 Dec. 30. [Epub ahead of print], 2009.<br /> <br /> <br />

Impact Statements

1. 1. Advancing our understanding of the role of bioactive food compounds in optimizing health is a central impetus for the development of collaborative research of the W2002. Specifically efforts to identify the appropriate dose and intake of whole foods and isolated bioactive compounds will advance our ability to test the efficacy in clinical trials including assessment of impact on fatty liver disease oxidative stress, and inflammation all biological responses associated with obesity.
2. 2. Collaborative research will foster sharing of research techniques that validate requirements for nutrients and bioactive food compounds. Examining bone microstructure response to nutrient or bioactive compound exposure using sophisticated labeling techniques in controlled human feeding studies is critical as we establish optimal requirements for health. Nutrient balance studies will support the establishment of revised DRIs for nutrients and tea polyphenols, anthocyaninis, carotenoids and isothiocyanates for cancer risk reduction.
3. 3. Our efforts to develop and disseminate the research methods as well as technology and expertise beyond the W2002 group will culminate with our proposed symposia to be presented at FASEB in 2010. This proposal has been submitted for consideration by the planning committee. This is a viable approach to translating science to others of mutual interest and to assure a broader and more efficient spread of research approaches in relation to BAFC and health.
4. 4. Federal Grant funding (PI or Co-I and peer-reviewed) secured for the 2008 year include 12 USDA funded grants among 9 of the W2002 investigators as well as several NIH , CDC and industry funded grants that will continue to foster bioactive compound research

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Report Information

Participants

Edralin Lucas and Barbara Stoecker (Oklahoma State), Administrative Advisor -Tammy Bray (Oregon State), Richard Bruno (U Connecticut-Storrs), Karen Chapman-Novakofski (U Illinois), Andy Clifford (U California-Davis), Emily Ho (Oregon State), Norman Hord (Michigan State), Barry Shane (U California-Berkeley), Cynthia Thomson (U Arizona), Jairam Vanamala (Colorado State), Janos Zempleni (U Nebraska-Lincoln)

Absent: Eric Decker (U Massachusetts), Mark Failla (Ohio State), Elvira Gonzalez de Mejia (U Illinois), Sung Koo (U Connecticut-Storrs), Dennis Medeiros (Kansas State), Etta Saltos (AFRI), Connie Weaver (Purdue), Joy Winzerling (U Arizona)

Brief Summary of Minutes

Accomplishments

This group has been very productive this year as illustrated by the publications and by developing collaborations among project members. Objectives of our project and activities addressing these objectives are reported below:<br /> <br /> Objective 1) Determine the bioavailability (absorption, distribution, metabolism, elimination) of nutrients and other food components and their environmental and genetic determinants.<br /> <br /> The University of California-Davis (Clifford) has conducted detailed investigations of bioavailability of beta-carotene in humans. Bioavailability estimates for absorption and metabolism in humans range from 2 to 90%. The retinol activity equivalent of ingested beta-carotene has an equally broad range. The wide ranges highlighted a major gap in our quantitative understanding of the in vivo human beta-carotene metabolism and its retinol activity equivalent. So that gap was filled by quantifying and interpreting the dynamic and kinetic behavior of metabolism of beta-carotene and its metabolites (retinyl ester and retinol) as it occurs in vivo in humans: using 14C-accelerator mass spectrometry (14C-AMS), genotyping, and modeling. A wide range in the inter-individual bioavailability of b-carotene was confirmed. This wide range had a genetic component as evidenced by single nucleotide polymorphism (SNPs) in lipoprotein lipase (S447S), beta-carotene mono-oxygenase I and/or mono-oxygenase II. Development and optimizing of high throughput 14C-AMS (the ultimate tool for 14C tracer studies in vivo in humans) for biological, biomedical, and environmental applications was key to the success of the project and is rapidly becoming of considerable interest for microdosing of nutrients, phytonutrients, and the development of new drugs and pharmaceuticals. <br /> <br /> The University of California-Berkley (Shane) has continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models have been evaluated to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. A mouse model has been developed that mimics the clinical effects of human B12 and folate deficiency, and which will allow investigation of potential adverse effects of high folate intake. Evaluation of genetic risk factors for neural tube defects and identification of putative modifier genes which influence folate status, homocysteine levels, and methylation potential continues. <br /> <br /> 2. Evaluate the bioactivity of nutrients and other food components in order to elucidate their underlying protective mechanisms.<br /> The University of Arizona (Thomson) has tested efficacy of vegetables to reduce oxidant stress and inflammation in at-risk overweight women. A significant dose-specific rise in plasma carotenoids in response to escalating dose/intake of the study provided vegetables (doses of 2, 5 and 10 servings daily), suggested excellent dietary adherence and was consistent with self-reported measures of adherence. Results of biomarker analyses suggested that change scores pre-post each feeding dose were not significantly different overall. However, the post-treatment high sensitivity C-reactive protein (hsCRP) was significantly lower, controlling for plasma carotenoid*dose intercept, in women presenting with BMI below 30 kg.m2 (p=0.01). No significant associations were shown for 8-epiprostaglandinF2±. Changes in blood pressure, particularly systolic measures, were also found. Future analyses will include additional inflammatory and oxidative stress indicators in collaboration with Dr. Bruno at UConn as well as collaboration with Dr. Hord to evaluate measures of vegetable and human nitrate levels in association with change in BP. Other trials with whole foods relevant to this multistate project include on-going trials with high anthocyanin carrots, Mediterranean diet with walnuts and lactation and a Ruby Red <br /> Oregon State University (Ho) has focused on the examination of the interaction of bioactive nutrients with both genetic and epigenetic mechanisms related to cancer and chronic disease development. The classic view of cancer etiology is that genetic alterations damage DNA structure and induce mutations resulting in non-functional proteins that lead to disease progression. More recently, the role of EPIGENETIC alterations during cancer has gained increasing attention. <br /> In both animal models and humans, dietary zinc deficiency increased DNA damage in peripheral blood cells. Importantly, these functional changes preceded any changes in plasma zinc levels. In animals zinc deficiency caused a selective loss of zinc in the dorsolateral lobe of the prostate; the area that is prone to developing cancer. Together these data suggest that maintaining adequate zinc status could be an important factor for maintain DNA integrity and preventing prostate cancer. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables such as broccoli, is a histone deacetylase (HDAC) inhibitor. It increases acetylated histone levels and has anti-cancer properties in the prostate. A mechanism of chemoprotection by SFN in human colon cancer cells and prostate epithelial cells was identified as inhibition of histone deacetylase (HDAC). SFN specifically targeted HDAC3 and HDAC6 in prostate cancer cells not normal cells . Administration of SFN also selectively induced cell death in cancer cells, but not normal prostate epithelial cells. This work suggests that this phytochemical may have the ability to alter epigenetic events that lead to disease prevention.<br /> <br /> Michigan State University (Hord) has quantified nitrate and nitrite concentrations by HPLC in a convenience sample of foods. Nitrites are produced endogenously through the oxidation of nitric oxide and through a reduction of nitrate by commensal bacteria in the mouth and gastrointestinal tract. As such, the dietary provision of nitrates and nitrites from vegetables and fruit may contribute to the blood pressure-lowering effects of the Dietary Approaches to Stop Hypertension (DASH) diet. Incorporating analyzed values into 2 hypothetical dietary patterns that emphasize high-nitrate or low-nitrate vegetable and fruit choices based on the DASH diet, yielded nitrate concentrations that varied from 174 to 1222 mg. Exposure concentrations of nitrate and nitrite from breast and formula milk as well as vegetables and fruits can approach or exceed the World Health Organization acceptable daily intake (ADIs) recommendation of 3.7 mg/kg body wt for nitrate. Regulatory limits for consumption of nitrates and nitrites are set due to concern over gastrointestinal cancer risk from processed meats and methemoglobinemia in infants from contaminated well water. Despite demonstrated physiologic roles for nitrate and nitrite in vascular and immune function, consideration of food sources of nitrates and nitrites from plant foods as healthful dietary components has received little attention. Current research projects have estimated potential human exposure concentrations across the life course and seek to understand the role of nitrite in the etiology of colorectal carcinogenesis in animal models.<br /> <br /> University of Nebraska at Lincoln (Zempleni) is investigating roles of holocarboxylase synthetase (HCS) in histone biotinylation. Biotinylation of histones is mediated by HCS and is an important mechanism to repress retrotransposons. De-repression of retrotransposons impairs genome stability and increases cancer risk. Both biotin and HCS deficiency decrease the enrichment of biotinylated histones at retrotransposons, leading to increased transcription of transposons, increased frequency of retrotranspositions, and increased incidence of chromosomal abnormalities. HCS is a chromatin protein but lacks a DNA-binding motif. HCS was found to interact physically with histone H3 to mediate chromatin binding of HCS. Binding of HCS to histone H3 caused biotinylation of lysine residues K9 and K18 in H3. Finally, a HCS knockdown Drosophila melanogaster was generated and showed that HCS deficiency decreases life span and heat stress resistance. Collectively, these studies provided evidence for the biological importance of histone biotinylation and generated insights into the mechanisms mediating the binding of HCS to chromatin.<br /> <br /> The University of Connecticut station (Bruno, Koo) has been actively involved in identifying the bioactivities of green tea in experimental models of obesity-triggered nonalcoholic fatty liver disease (NAFLD). Of the major tea products, green tea is uniquely processed such that its rich polyphenolic content, consisting mainly of catechins, is preserved. Presumably, the in vitro reactive oxygen and nitrogen scavenging abilities of green tea catechins contribute to their bioactivity in human health, but their relatively low bioavailability and high biotransformation raises debate over their ability to optimize human health. Green tea extract (GTE) attenuated hepatic steatosis and hepatic injury in genetically obese (ob/ob) mice. Furthermore, GTE-mediated attenuation in hepatic steatosis was accompanied by decreased mRNA expression of adipose sterol regulatory element-binding protein-1c, fatty acid synthase, stearoyl CoA desaturase-1, and hormone sensitive lipase as well as decreased serum nonesterified fatty acid concentrations. Thus, GTE decreased the efflux of lipid from adipose to the liver where it would otherwise be esterified and stored as triglyceride. Parallel studies demonstrated that GTE decreased hepatic TNF-± protein and inhibited adipose TNF-± mRNA expression. Hepatic total glutathione, malondialdehyde and Mn- and Cu/Zn-superoxide dismutase activities in obese mice fed GTE were also normalized to the levels of lean littermates. Also, GTE increased hepatic catalase and glutathione peroxidase activities and these activities were inversely correlated with alanine aminotransferase (ALT) and liver lipids. Thus, GTE mitigated hepatic steatosis, injury, and oxidative stress by decreasing adipose TNF-±, lipogenic, and lipolytic gene expression, decreasing hepatic lipid peroxidation and TNF-± concentration, and enhancing hepatic antioxidant defenses. These findings suggest that GTE may be an effective dietary strategy to mitigate obesity-triggered NAFLD. Studies to identify the mechanisms by which GTE protects against liver injury, associated with inflammation, in a dietary-induced obese rodent model of NAFLD are currently underway. Wistar rats were fed a high fat diet containing 0, 1, or 2% GTE or a low-fat control diet containing no GTE for 8-wk. High-fat controls had greater (P<0.05) body and adipose mass. GTE lowered these to that of low-fat controls without affecting food intake. Also, GTE prevented obesity-mediated increases in insulin-resistance and serum leptin. Serum ALT and aspartate (AST) aminotransferase activities were 81-98% greater in rats fed a high-fat diet. GTE decreased their activities by 32-39%. GTE restored hepatic glutathione levels and prevented obesity-triggered increases in hepatic malondialdehyde. Livers from high-fat controls had greater mRNA and protein expression of MCP-1 and TNF-±. GTE decreased the mRNA expression of MCP-1 and TNF-± and their protein levels in liver. Hepatic MCP-1 protein was positively correlated with ALT, AST, and MDA and inversely correlated with hepatic glutathione, suggesting that GTE-mediated improvements in liver inflammation decrease hepatic injury and oxidative stress associated with NAFLD. These findings indicate that GTE protects against obesity-triggered NAFLD by decreasing hepatic inflammation and oxidative stress that otherwise lead to hepatic lipid peroxidation and hepatic injury. <br /> <br /> The incorporation of the tropical fruit, mango, into the diet is being investigated at Oklahoma State University (Lucas) to test effects of blood glucose and body fat accumulation. Although pharmacological options are available for the treatment of these risk factors for coronary vascular disease, alternative approaches that take advantage of the bioactive components in foods are highly desirable. A study compared the effect of mango to that of a hypocholesterolemic drug (fenofibrate) and a hypoglycemic drug (rosiglitazone) in reducing body fat and improving clinical parameters (i.e., blood glucose and lipid profile) of mice fed a high fat diet (HF). Male C57BL/6J mice were randomly divided into six treatment groups: control, HF, HF + 1% (w/w) mango or 10% mango (w/w), HF + fenofibrate (500 mg/kg diet), and HF + rosiglitazone (50 mg/kg diet). After eight weeks of treatment, both doses of mango prevented increases in visceral fat mass and % body fat due to high fat diet in a manner similar to fenofibrate and rosiglitazone. Supplementation with 1% mango was more effective than 10% mango, rosiglitazone, or fenofibrate in improving glucose tolerance. Additionally, mango reduced plasma glucose, total cholesterol and non-esterified fatty acids. Findings suggested that incorporation of mango in the diet lowered risk factors for CVD in this rodent model of high-fat diet-induced obesity. <br /> <br /> Evaluation of effects of food and beverage components on bone quality have continued at Oklahoma State University (Stoecker). Components evaluated include orange and ruby red grapefruit pulp as well as components of green tea. Studies of effects on rat bone of feeding carrots high in anthocyanins are continuing. These bones from small animal models of male and female osteoporosis are being analyzed for mass and density by dual energy X-ray absorptiometry (DEXA) and for bone microarchitecture by micro-computed tomography (µCT). Data generated by µCT are being incorporated into finite element analysis models to estimate effects of food components on breaking strength of bone. <br /> <br /> Purdue University (Weaver) has compared the effect of receiving dietary calcium from nonfat dry milk solids and calcium carbonate on bone health during growth and subsequent bone maintenance. Milk consumption is declining and calcium from fortified foods and supplements is more prominent, although after early puberty most females consume inadequate calcium. To address this problem female rats were fed a nutrient adequate diet, but the source of calcium was varied during growth (10 weeks). Some rats were maintained for an additional 10 weeks in a calcium inadequate diet. Bones of rats fed non fat dry milk solids during growth were longer, wider, more dense, and had greater peak breaking force than rats fed calcium carbonate. Furthermore, rats fed milk during growth were better protected from subsequent inadequate calcium diets.<br /> <br /> Purdue University (Weaver) also compared several botanical supplements containing isoflavones and traditional therapies for treating osteoporosis for their ability to suppress bone resorption. Several sources of botanical supplements have been marked as estrogen replacements for preventing menopausal bone loss. A novel Ca-41 method was used to compare supplements from two types of soy, red clover, and kudzu, estradiol, and a bisphosphohate in postmenopausal women. Only the soy supplements significantly suppressed bone turnover. The effect was modest compared to traditional therapies.<br /> <br /> Translation of science to the public remains a challenge and University of Illinois (Chapman-Novakofski) is investigating various mediating variables that influence behavior. Knowledge alone is not effective in changing behavior; thus, grounding in a behavioral theory is required for effective interventions targeting diet and lifestyle change. Online interactive education is being investigated as an effective alternative or augmentation to group education settings. <br /> <br /> Scientists in the W2002 group have collaborated on a number of research projects which range from genetic and epigenetic mechanisms by which nutrients and bioactive food components affect health and disease to translation of in vitro and animal studies on nutrients and bioactives to human populations. Strengths and limitations of available biomeasures are evaluated and methods for measurement of oxidative stress and/or inflammation as intermediate indicators of chronic disease risk are shared.<br />

Publications

Impact Statements

1. 1) Concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification.
2. By quantifying the dynamic and kinetic behavior of the metabolism of beta-carotene and its metabolites as it occurs in vivo in humans, a dietary requirement of beta-carotene or its metabolites to meet a health promoting function can be specified.
3. Incidence of non-alcoholic fatty liver disease (NAFLD) has paralleled the ongoing obesity epidemic and no well established therapeutic options exist for patients with NAFLD beyond weight loss exist and such lifestyle modifications have a poor long-term success rate. Dietary strategies, such as green tea, may help in the prevention of NAFLD.
4. Calcium consumption from milk is declining and calcium from fortified foods and supplements is more prominent. However, in rat studies, bones of rats fed non fat dry milk solids during growth were longer, wider, more dense, and had greater peak breaking force than rats fed calcium carbonate.

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Report Information

Participants

Meeting Host - Bruno, Richard (richard.bruno@uconn.edu) - University of Connecticut; Administrative Advisor -Tammy Bray (tammy.bray@oregonstate.edu) - Oregon State University; Barbara Stoecker (barbara.stoecker@okstate.edu) - Oklahoma State University; Barry Shane (bandie@berkeley.edu) - University of California-Berkeley; Norm Hord (hord@msu.edu) - University of Michigan; Etta Saltos (ESALTOS@nifa.usda.gov) - USDA; Edralin Lucas (edralin.a.lucas@okstate.edu) - Oklahoma State University; Mark Failla (MFailla@ehe.osu.edu) - The Ohio State University; Elvira de Mejia (edemejia@illinois.edu) - University of Illinois; Jairam Vanamala (Jairam.Vanamala@colostate.edu) - Colorado State University; David Sands (davidsands41@yahoo.com) - Montana State University; Emily Ho (emily.ho@oregonstate.edu) - Oregon State University

Brief Summary of Minutes

Accomplishments

The participants of this multi-state project have been highly productive during the past reporting period as evidenced by >50 peer-reviewed publications among attending participants and enhancement of collaborations between project members. Project objectives are listed below along with scholarly activities of the lead station.<br /> <br /> Objective 1): Determine the bioavailability (absorption, distribution, metabolism, elimination) of nutrients and other food components and their environmental and genetic determinants.<br /> <br /> Objective 2): Evaluate the bioactivity of nutrients and other food components in order to elucidate their underlying protective mechanisms.<br /> <br /> Colorado State University (Jairam Vanamala). We developed a systematic approach to screen storage and processing effects on bioactivity of plant products (colored potatoes) by focusing on (i) analysis of both storage and processing (baking and chipping) on phenolic content (TP), composition, sensory attributes and biological properties (anti-proliferation and pro-apoptosis); and (ii) investigation of consumer and producer preferences for specialty potato products. We have also collected extensive samples from pigs (n = 40) consuming a high-fat diet for 12 wk followed by supplementation with white vs. purple potatoes at two different doses (10% vs. 20% of diet) with an aim to determine the appropriate dose needed to suppress an inflammatory cascade. We demonstrated that post-harvest storage of colored potatoes elevated TP and anti-oxidant activity (AA), but suppressed anti-proliferative and pro-apoptotic properties against human colon cancer cell lines. Storage also altered the LC-MS metabolite profile of all potato varieties tested. These results suggest that it is critical to use both analytical and biological assays in conjunction to determine the post-harvest storage and processing effects on bioactivity of plant products. Chipping, but not baking, altered the metabolite profile. Chips had approximately 5-10 times less bioactivity compared to the baked or fresh potatoes. To study the effect of storage and inter-varietal differences on chipped and baked potato sensory attributes, 114 untrained panelists rated the 7 potato cultivars using a 9-point hedonic scale at 30 and 90 days of storage. In general, phenolic content was inversely related to sensory attributes. These results suggest that it is critical to consider sensory attributes along with bioactive compound profile in developing health food products. Consumers were also more willing to pay higher premium for colored potato products if they are educated on health benefits.<br /> <br /> <br /> Kansas State University (Denis Medeiros). We have ongoing work examining the impact of copper-deficiency on cardiac chaperone proteins. We have for years studied the mechanisms as to why copper deficiency leads to cardiac hypertrophy and cardiomyopathy. We have described pathology of mitochondria including the gene program responsible for mitochondrial biogenesis. During the past reporting period, we detailed the impact copper deficiency on cardiac chaperone proteins, which are integral for ferrying copper between cell compartments in which copper is used, such as the synthesis of copper containing enzymes. The copper chaperone proteins we evaluated as a result of copper deficiency include CCS, Sco1, Cox 17, and Ctr-1. Rats were fed diets either adequate or deficient in copper from weanling for 5 wk thereafter. Copper deficiency did not change Ctr-1 or Cox 17 expression. Ctr-1 is thought to regulate the amount of copper entering the myocyte or heart cell. We had expected that this protein would increase, but it did not. Cox 17 is involved in brining copper to the mitochondria. Sco1 and CCS were two chaperone proteins that increased in the heart as a result of copper deficiency. Sco1 delivers the copper to cytochrome C oxidase and CCS to the site of Cu, Zn superoxide dismutase synthesis. We also studied the impact of copper deficiency on cytochrome C oxidase subunits I and IV. We show that nuclear encoded subunits of cytochrome c oxidase were down regulated. In our earlier studies, we used a polyclonal antibody to formulate to this conclusion. We re-performed our study using mono-clonal antibodies, as other have used to determine if the source of antibodies could explain this discrepancy. Using mono-clonal antibodies we found that mitochondria encoded subunit I (Cox I) and the nuclear encoded subunit IV (Cox IV) were both significantly reduced, in contrast to what we previously reported. This suggests that copper deficiency may be causing a change in the mitochondrial encoded subunits of cytochrome c oxidase whereby the monoclonal antibodies are perhaps able to bind to the mature form of the protein and the polyclonal form may be binding to the precursor or immature form of the protein. During the past reporting period, our laboratory has also successfully completed an exhaustive review regarding the role of iron in bone metabolism. The information is now being utilized to develop a strategy on how to better translate the findings of animal models on a high risk human population and to determine if iron status is a predictor of lower bone mineral density, and stress fractures in particular, in humans. <br /> <br /> <br /> Michigan State University (Norm Hord). Dietary exposure to nitrates and nitrites is associated with cardiovascular health benefits and, in the context of processed meats consumption, gastrointestinal cancer risk. Our work describes the scientific basis for these risk assessments by examining the effect of nitrite on phenotypes associated with colorectal cancer (CRC) risk in human carcinoma cells. Nitrite and nitrate used exogenously in processed meats to enhance taste and microbial food safety is associated with increased cancer risk, but these compounds are also found in vegetables, and associated with lower cancer risk. To clarify this controversy, we determined whether nitrite promotes or blocks phenotypes associated with the promotion of cancer in colon epithelial cells. The effect of nitrite on proliferation and invasion of 4 different stages of colorectal epithelial cancer was examined. Nitrite has no effect on stage 1 SW1116 colon cancer cell at any concentrations; nitrite inhibits stage 2 SW480 proliferation at 10nm-100µM and inhibits stage 3 HCT15 at 100nm and 1µM, but promotes proliferation in stage 4 cells at 100µM. Nitrite also inhibits stage 3 SW480 cells invasion in a dose-dependent manner. However, it significantly promotes the invasion of stage 4 cells at the highest concentration. FACS data indicates that nitrite dose-dependently decreased cell cycle progression in SW480 and HCT15 with changed G2/M transition and delayed G1 phase entry. However, 100µM nitrite promoted cell cycle progression in COLO205 cells with increased S-phase entry. Taken together, nitrite can inhibit cancer cell progression at low doses and early stage but may promote cancer cell progression at higher doses in stage 4 colon cancer indicating a dose and stage dependent effect. Subsequent studies were performed to estimate exposure to nitrates and nitrites from human, bovine and formula milks relative to regulatory intake limits. The World Health Organization and American Academy of Pediatrics recommends exclusive consumption of human milk for the first 6 mo of life because of the nutritional and immunological benefits for the infant. Consumption of formula, bovine, and soy milk may be used as alternatives to human milk for infants. Human milk concentrations of colostrum (expressed d 13 postpartum; n1/412), transition milk (expressed d 37 postpartum; n1/417), and mature milk (expressed >7 d postpartum; n1/450) were 0.08 mg/100mL nitrite and 0.19 mg/100mL nitrate, 0.001mg/100mL nitrite and 0.52mg/100mL nitrate, and 0.001mg/100mL nitrite and 0.3 mg/100mL nitrate, respectively, revealing that the concentrations of these anions change as the composition of milk changes. When expressed as a percentage of the World Health Organizations Acceptable Daily Intake limits, Silk® Soy Vanilla (WhiteWave Foods, Broomfield, CO) intake could result in high nitrate intakes (104% of this standard), while intake of Bright Beginnings Soy Pediatric® formula (PBM Nutritionals, Georgia, VT) could result in the highest nitrite intakes (383% of this standard). The temporal relationship between the provision of nitrite in human milk and the development of commensal microbiota capable of reducing dietary nitrate to nitrite supports a hypothesis that humans are adapted to provide nitrite to the gastrointestinal tract from birth. These data also support the hypothesis that the high concentrations of breast milk nitrite and nitrate are evidence for a physiologic requirement to support gastrointestinal and immune homeostasis in the neonate. <br /> <br /> <br /> Montana State University (David Sands). High intake of starchy (high glycemic) grains, legumes and potatoes is one of the leading causes of obesity and heart disease. In response, MSU has recently released a new variety of pea that has very low branched starch and can be used for production of low glycemic index flour and food products. Additional low glycemic varieties of legumes can be developed. We are actively expanding our selection of low glycemic varieties to include spring, winter and durum wheats, legumes, and potatoes. Such low glycemic index crops could demand a premium in price at the farm gate. Similarly, we will continue to develop high omega-3 and high vitamin E camelina for both food and animal feed, because of its benefits to humans and animals. MSU biochemists and geneticists will follow nutritionally important genes through crosses, using recently developed and sophisticated molecular (but not transgenic) techniques, greatly reducing the time to improve crops. The resultant varieties will be tested for growth and productivity statewide at the MSU Agriculture Research Centers and the nutritional composition of the new varieties will be assessed. New research collaborations have also been identified with group members (Bruno/UConn; Vanamala/Colorado) to examine the potential bioactivity of specialty crops in physiologically relevant model systems.<br /> <br /> <br /> Ohio State University (Mark Failla) has been studying the impact of type of dietary fat on transport of carotenoids and vitamin E across the Caco-2 human intestinal cell line. B-carotene, lutein and ±-tocopherol transport into the basolateral compartment was increased to a greater extent when cells were exposed to micelles containing free fatty acids mimicking the fatty acyl composition of olive, canola and soybean oils compared to micelles with fatty acyl profile mimicking butter. The amounts of ²-carotene, lutein and ±-tocopherol transported into the basolateral compartment was highly correlated with the amounts of triacylglycerides and apoB secreted. The carotenoids were primarily present in chylomicrons and vitamin E was distributed in both chylomicron and VLDL fractions. These data suggest that dietary triacylglycerides rich in unsaturated fatty acids and particularly oleate promote the absorption of carotenoids and vitamin E by stimulating the assembly and secretion of chylomicrons. The bioaccessibility and absorption of the 24-carbon carotenoid norbixin was also investigated using the coupled in vitro digestion/Caco-2 cell model. Norbixin, an abundant carotenoid in annatto, is extensively used as a natural coloring agent by the food industry. Norbixin added to milk was highly stable during simulated digestion and bile salts enhanced partitioning into the bioaccessible fraction, suggesting delivery to the apical membrane of absorptive cells in micelles. Uptake of norbixin was proportional to apical content and both all trans and cis isomers were transported across the monolayer. <br /> <br /> <br /> Oklahoma State University. Work from Dr. Lucas demonstrates that mango exerts important bioactivities that may mitigate the risk of obesity. Mango (Mangifera indica L.) provides a number of bioactive compounds that may play a role in the attenuation of excess body fat. The effects of freeze-dried mango fruit on body composition were examined in two separate studies involving mice fed high fat diet and ovariectomized (ovx) mice. In the first study, male C57BL/6J mice were randomly divided into four treatment groups (n=8/group): control, high fat diet (HF), HF + 1% or 10% mango (w/w). After 8 wk of treatment, mice receiving the HF diet had significantly higher epididymal fat mass and % body fat. Both doses of mango prevented the increase in epididymal fat mass and % body fat due to HF diet. In the second study, female C57BL/6 mice sham-operated and ovx and were randomly assigned to receive control diet, 5% or 25% (w/w) mango diet (n=8/group). After 8 wk of treatment, ovx mice had higher % body fat in comparison to the sham group. Both doses of mango had lower % body fat in comparison to the ovx group but not quite to the level of the sham group. The mechanism by which mango exerts this positive effects on body composition is being actively investigated.<br /> <br /> <br /> Oregon State (Emily Ho) has been actively examining the role of epigenetic alterations in the risk for cancer and the extent to which bioactive nutrients such as sulforaphane, catechins and zinc regulate the mechanisms related to cancer and chronic disease development. In both animal models and humans, dietary zinc deficiency increases DNA damage in peripheral blood cells. Importantly, these functional changes precede any changes in plasma zinc levels. Zinc status is also compromised with age with ongoing studies demonstrating that zinc supplementation in older animals reverses age-related zinc deficiency and inhibits age-related immune defects and inflammatory processes. Preliminary evidence further suggests that zinc alters DNA methylation patterns and may be a novel mechanism by which zinc affects gene expression. Separate studies examining plant-derived phytochemicals from tea and cruciferous vegetables have provide evidence of the chemoprotective effects of diet. Indeed, studies show that sulforaphane, a chemical found cruciferous vegetables is an HDAC inhibitor, increases acetylated histone levels and has anti-cancer properties in the prostate. Sulforaphane is an isothiocyanate found in cruciferous vegetables such as broccoli. This anticarcinogen was first identified as a potent inducer of Phase 2 enzymes, but evidence is mounting that SFN acts through other cancer chemopreventive mechanisms. We recently reported on a novel mechanism of chemoprotection by sulforaphane in human colon cancer cells and prostate epithelial cells, namely the inhibition of histone deacetylase (HDAC). We have also found that sulforaphane specifically targets HDAC3 and HDAC6 in prostate cancer cells, but not normal cells. This work suggests that this phytochemical may have the ability to alter epigenetic events that otherwise lead to disease prevention. In human trials, we have directly compared the effects of the whole food (broccoli sprouts) to commercially available supplements. We have found a significant decrease in bioavailability and impact on HDACs with supplements compared to the whole food. We believe the decreases in activity are due to lack of myrosinase release of sulforaphane from its glucosinolate precursors in the supplement. We have also performed new studies examining the effects of tea catechins on autoimmune responses, which were completed in collaboration with Bruno (UConn). Regulatory T cells (Treg) are critical in maintaining immune tolerance and suppressing autoimmunity. The transcription factor Foxp3 serves as a master switch that controls the development and function of Treg. We have found that EGCG both in vitro and in vivo can induce Foxp3 and increase Treg frequencies to cause immunosuppression. The mechanisms may be related to demethylation of the Foxp3 promoter.<br /> <br /> <br /> Purdue University (Connie Weaver). During the past reporting period, we have conducted several studies in animal models and humans to investigate the effect of dietary constituents thought to be beneficial for bone health by either enhancing calcium absorption or suppressing bone resorption. In both growing rats and humans we tested the effect of fibers including GOS and FOS on calcium absorption. We continued our studies of the effects of phytoestrogens on preventing bone loss in an OVX rat model and the effect of equol producing status on bone resorption in response to soy in postmenopausal women.<br /> <br /> <br /> University of California-Berkeley (Barry Shane). We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylenetetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin.<br /> <br /> <br /> University of Connecticut (Richard Bruno and Sung Koo). We have been actively investigating the hepatoprotective actions of green tea on liver injury associated with obesity-induced nonalcoholic steatohepatitis. We conducted a green tea extract (GTE) intervention study in obese rodents during the past reporting period. Wistar rats (16-wk old, n=63) were fed a low-fat (LF; 10% kcal) diet containing no GTE or a high-fat (HF; 60% kcal) diet containing 0, 1, or 2% GTE for 8 wks. We then examined whether GTE reduces inflammation associated with NASH by regulating COX-2. Rats fed HF diets developed liver steatosis and had greater (P<0.05) hepatic malondialdehyde (MDA) and serum alanine aminotransferase (ALT). GTE normalized the levels of hepatic lipid, MDA, and ALT to those of LF controls. The activity and protein expression of hepatic COX-2 were greater in HF fed controls. GTE normalized COX-2 activity and decreased its expression below the levels of LF controls. Arachidonic acid (AA) was elevated in the total lipid, phospholipid (PL), and free fatty acid (FFA) fractions of hepatic lipid extract. Although GTE reduced total AA by 6-8% (P<0.05), the concentrations of AA in the PL and FFA fractions remained unaffected as was cytosolic phospholipase A2 activity. HF increased cytochrome P450 2E1 mRNA expression, whereas GTE did not affect its expression. Thus, data suggest that GTE reduces dietary fat-induced hepatic inflammation and oxidative stress by decreasing the activity and expression of COX-2, without altering the flux of AA between membrane PL and FFA pools. Additional studies are warranted to define whether GTE suppresses COX-2 mediated prostaglandin generation. In separate studies, studies led by Dr. Bruno have examined the bioavailability and pharmacokinetics of quercetin in humans. We enrolled otherwise healthy obese men and postmenopausal women (n = 4M/5F; 55.9 ± 6.4 y; 30.8 ± 4.1 kg/m2) to complete a randomized, cross-over study. Participants ingested quercetin (1095 mg) on 3 occasions with a fat-free (<0.5 g), low-fat (4 g), or high-fat (15 g) meal. Plasma was obtained prior to (0 h) and after quercetin ingestion (1, 2, 3, 4, 6, 8, 10, 12, and 24 h) to measure quercetin and its methylated metabolites isorhamnetin and tamarixetin using HPLC-Coularray. Compared to the fat-free trial, quercetin bioavailability increased by 32% (AUC0-24 h; P<0.05) during the high-fat trial only. The high-fat meal also increased maximum quercetin concentrations (Cmax; 1.60 ± 0.88 ¼M) by 45%, but time to maximum concentration (Tmax; 353 ± 105 min) and half-life (t1/2; 515 ± 144 min) were unaffected. Isorhamnetin AUC0-24 h increased by 19% and Cmax increased by 40% (0.24 ± 0.11 vs. 0.17 ± 0.06 ¼M) without affecting Tmax (486 ± 113 min) or t1/2 (1154 ± 633 min). Tamarixetin AUC0-24 h increased by 43% and Cmax by 46% (0.52 ± 0.29 vs. 0.36 ± 0.11 ¼M) without affecting Tmax (399 ± 110 min) or t1/2 (299 ± 287 min). Thus, dietary fat improves quercetin bioavailability, and subsequent biotransformation, by increasing its absorption. Further work is warranted to define the optimal amount and type of fat to improve quercetin bioavailability and the extent to which the bioactivity of quercetin is exerted through its methylated metabolites.<br /> <br /> <br /> University of Nebraska (Janos Zempleni) has been examining the biotinylation of histones mediated by holocarboxylase synthetase (HCS), which is an important mechanism to repress retrotransposons. De-repression of retrotransposons impairs genome stability and increases cancer risk. In previous studies we showed that both biotin and HCS deficiency decreases the enrichment of biotinylated histones at retrotransposons, leading to increased transcription of transposons, increased frequency of retrotranspositions, and increased incidence of chromosomal abnormalities. In these previous studies we also demonstrated that histone biotinylation marks co-localize with methylated cytosines and lysine-9-dimethylated histone H3 (H3K9me2), suggesting epigenomic synergies among these chromatin marks. We tested the hypothesis that the epigenomic synergies are mediated by physical interactions among HCS, the DNA methyl transferase DNMT1, the methyl-CpG-binding protein 2 (MeCP2), and the histone H3 methyltransferase EHMT-1. Analysis by yeast-two-hybrid assays, co-immunoprecipitation, and limited proteolysis assays are consistent with the theory that HCS interacts with DNMT1, MeCP2, and EHMT-1, and that these interactions might be responsible for the roles of biotin and methyl donors such as folate in genome stability and gene regulation. The common interests in epigenetic modification by dietary constituents is an area that continues to be examined in collaboration with Ho (Oregon State).<br />

Publications

Peer-Reviewed Publications<br /> <br /> <br /> 1. Bao B, Rodriguez-Melendez R, Wijeratne SSK, Zempleni J. Biotin regulates the expression of holocarboxylase synthetase in a miR-539 pathway in HEK-293 human embryonic kidney cells. J Nutr 140:1546-1551, 2010<br /> <br /> 2. Bao B, Pestinger V, Hassan YI, Borgstahl GEO, Kolar C, Zempleni J. Holocarboxylase synthetase is a chromatin protein and interacts directly with histone H3 to mediate biotinylation of K9 and K18. J Nutr Biochem (in press)<br /> <br /> 3. Bao B, Rodriguez-Melendez R, Zempleni J. Cytosine methylation in miR-153 gene promoters increases the expression of holocarboxylase synthetase, thereby increasing the abundance of histone H4 biotinylation marks in HEK-293 human kidney cells. J Nutr Biochem (in press)<br /> <br /> 4. Bowman GL, Shannon J, Ho E, Traber MG, Frei B, Oken BS, Kaye JA, Quinn JF (2010). Reliability and Validity of Food Frequency Questionnaire and Nutrient Biomarkers in Elders With and Without Mild Cognitive Impairment. Alzheimer Dis Assoc Disord. 25(1):49-57.<br /> <br /> 5. Carter TC, Pangilinan F, Troendle JF, et al. Evaluation of 64 candidate single nucleotide polymorphisms as risk factors for neural tube defects in a large Irish study population. Am J Med Genet A 2011;155A(1):14-21. doi: 10.1002/ajmg.a.33755 [doi].<br /> <br /> 6. Chandra Christopher L, Lucas EA, Clarke SL, Smith BJ, Kuvibidila S. White button and shiitake mushrooms reduce the incidence and severity of collagen-induced arthritis in dilute brown non-agouti mice. J Nutr 2011;141(1):131-136.<br /> <br /> 7. Cheong J, Gunaratna N, McCabe G, Jackson G, Kempa-Steczko A, Weaver C. Bone seeking labels as markers for bone turnover: Validation of urinary excretion in rats. Osteoporosis Intl. 2010 DOI: 10.1007/s00198-010-1281-7.<br /> <br /> 8. Chitchumroonchokchai C., Ferruzzi M., Campbell W., Failla M. Dietary fats with increased ratio of unsaturated to saturated fatty acids enhance absorption of carotenoids and vitamin E by increasing both efficiency of micellarization and lipoprotein secretion. FASEB J. 2010; 24:539.<br /> <br /> 9. Chung M-Y, Yeung SF, Park HJ, Volek JS, Bruno RS. (2010). Dietary ±- and ³-Tocopherol Protect Against LPS-triggered hepatic injury in spontaneously obese mice. J Nutr Biochem, e-Pub Feb 4, 2010.<br /> <br /> 10. Clarke, JD, Hsu, A., Yu, Z, Dashwood, RH and Ho, E. (2011) Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells. Mol Nutr Food Res, 2011 Mar 4. doi: 10.1002/mnfr.201000547. [Epub ahead of print]<br /> <br /> 11. Ferruzzi MG, Lobo JK, Janle E, Cooper B, Simon JE, Wu Q-L, Welch C, Ho L, Weaver C, Pasinetti GM. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment of Alzheimer's Disease. J Alzheimers Dis 18:113-24, 2009. <br /> <br /> 12. Filenko NA, Kolar C, West JT, Hassan YI, Borgstahl GEO, Zempleni J, Lyubchenko YL. The role of histone H4 biotinylation in the structure and dynamics of nucleosomes. PLoS ONE 6:e16299, 2011<br /> <br /> 13. Flögel A, Kim D-O, Chung S-J, Song WO, Fernandez M-L, Bruno RS, Koo SI, Chun OK. (2010). Development and validation of an algorithm to establish a total antioxidant capacity database of U.S. diet. Int J Food Sci Nutr, 61(6):600-23.<br /> <br /> 14. Getz J, Lin D, Medeiros DM. 2011. The cardiac copper chaperone proteins Sco1 and CCS are up-regulated, but Cox1 and Cox4 are down-regulated, by copper deficiency. Biol. Trace El. Res. In press. <br /> <br /> 15. Guo Y, Bruno RS. (2011). Vasoprotective activities of quercetin. AgroFood Industry Hi-Tech, In Press.<br /> <br /> 16. Hassan YI, Moriyama H, Zempleni J. The polypeptide Syn67 interacts physically with human holocarboxylase synthetase, but is not a target for biotinylation. Arch Biochem Biophys 495:35-41, 2010 (an image from this article was used for the journals cover page)<br /> <br /> 17. Ho, E and Dashwood, RH. (2010) Dietary manipulation of histone structure and function. World Rev Nutr Diet. 2010;101:95-102.<br /> <br /> 18. Hord, NG, Ghannam, J, Garg, JK, Pamela D. Berens, PB and Bryan NS. (2010) Nitrate and nitrite content of human, formula, bovine, and soy milks: implications for dietary nitrite and nitrate recommendations. Breastfeeding Medicine Oct 19. [Epub ahead of print].<br /> <br /> 19. Hsu, A., Bray, TM and Ho, E. (2010) Anti-inflammatory effects of soy and tea in prostate cancer prevention. Exp. Biol. Med; 235(6):659-67.<br /> <br /> 20. Hsu, A., Bray, TM, Helferich, WG, Doerge, D. and Ho, E. (2010) Differential effects of whole soy extract and soy isoflavones on apoptosis in prostate cancer cells Exp. Biol. Med. 235(1): 9097.<br /> <br /> 21. Hsu, A., Bruno, R.S., Lohr, C.V., Dashwood, R.H., Bray, T.M., and Ho, E. (2010) Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFkB pathway in the Noble rat model, in J. Nutr. Biochem 2010 Aug 27. [Epub ahead of print]<br /> <br /> 22. Song Y, Elias V, Loban A, Scrimgeour AG, Ho E. (2010) Marginal zinc deficiency increases oxidative DNA damage in the prostate after chronic exercise. Free Radic Biol Med. 48:82-88.<br /> <br /> 23. Janle E, Lila MA, Grannon, MD, Wood L, Higgins A, Yousef GG, Rogers RB, Kim H, Jackson GS, and Weaver C. Method for evaluating the potential of 14C labeled plant polyphenols to cross the blood-brain barrier using accelerator mass spectrometry. Nuclear Instruments and Methods in Physics Research B, 268:1313-1316, 2010.<br /> <br /> 24. Janle EM, Lila MA, Grannan M, Wood L, Higgins A, Yousef GG, Rogers RB, Kim H, Jackson GS, Ho L, Weaver CM. Pharmacokinetics and tissues distribution of 14C labeled grape polyphenols in the periphery and the central nervous system following oral administration. J Med Food 13(4)926-33, 2010.<br /> <br /> 25. Kaur Mall G, Chew YC, Zempleni J. The mechanisms of biotin homeostasis are qualitatively similar but quantitatively different in human Jurkat lymphoid and HepG2 liver cells. J Nutr 140:1086-1092, 2010<br /> <br /> 26. Klein MA, Nahin RL, Messina MJ, Rader JI, Thompson LU, Badger TM, Dwyer JT, Kim YS, Pontzer CH, Starke-Reed PE, and Weaver C. Guidance from an NIH Workshop on Designing, Implementing, and Reporting Clinical Studies of Soy Interventions. J Nutr 140:1192S-1204S, 2010. doi:10.3945/jn.110.121830.<br /> <br /> 27. Kuiper HC, Bruno RS, Traber MG, Stevens JF. (2011). Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. Free Rad Biol Med, 50(7):848-53.<br /> <br /> 28. Lawrance CC, Lucas EA, Clarke SL, Smith BJ, Kuvibidila S. Differential effects of isoflurane and CO2 inhalation on plasma levels of inflammatory markers associated with collagen-induced arthritis in DBA mice. Int Immunopharmacol. 2009;9(7-8):807-9.<br /> <br /> 29. Lucas EA, Li W, Peterson SK, Brown A, Kuvibidila S, Perkins-Veazie P, Clarke SL, Smith BJ. Mango modulates body fat and plasma glucose and lipids in mice fed high fat diet. British Journal of Nutrition in press <br /> <br /> 30. Lucas EA, Mahajan SS, Soung DY, Lightfoot SA, Smith BJ, Arjmandi BH. Flaxseed but not flaxseed oil prevented the rise in serum cholesterol due to ovariectomy in the golden Syrian hamsters. J Med Food, 2011;14(3):261-7.<br /> <br /> 31. Montrose DC, Horelik NA, Madigan JP, Stoner GD, Wang L-S, Bruno RS, Park HJ, Giardina C, Rosenberg DW. (2010). Anti-inflammatory effects of lyophilized black raspberry powder in ulcerative colitis. Carcinogenesis, <br /> 32(3):343-50.<br /> <br /> 32. Mun JG, Grannan MD, Lachcik PJ, Rogers RB, Yousef GG, Grace MH, Janle EM, Wu QL, Simon JE, Weaver CM, Lila MA. Tracking deposition of a 14C-radiolabeled kudzu hairy root-derived isoflavone-rich fraction into bone. Exp. Biol. Med 235:1224-1235, 2010.<br /> <br /> 33. Mun JG, Grannan M, Lachcik P, Reppert A, Yousef GG, Rogers RB, Janle EM, Weaver CM, Lila MA. Metabolic tracking of 14C-labeled isoflavones. Br J Nutr 9:1-8, 2009.<br /> <br /> 34. Ortiz, D., Pico, S., Pachon, H., Chitchumroonchokchai, C., Failla. M. Evaluation of bioaccessibility of health promoting compounds from beans, cassava, sweet potato and alfalfa foliar extracts. XXIX Latinoamerican Congress of Chemistry. Cartagena, Columbia. September 27-October 1, 2010.<br /> <br /> 35. Park HJ, Bruno RS. (2010). Hepatoprotective Activities Of Green Tea In Nonalcoholic Fatty Liver Disease. AgroFOOD Industry High-tech. (Invited Review), 21(1): 37-40.<br /> <br /> 36. Park HJ, Davis SR, Liang H-Y, Rosenberg DW, Bruno RS. (2010). Chlorogenic acid differentially alters hepatic and small intestinal thiol redox status without protecting against azoxymethane-induced colon carcinogenesis in mice. Nutr Cancer, 62(3):362-370.<br /> <br /> 37. Park HJ, DiNatale DD, Chung M-Y, Lee J-Y, Koo SI, Bruno RS. (2011). Green Tea Extract Attenuates Hepatic Steatosis by Decreasing Adipose Lipogenesis and Enhancing Hepatic Antioxidant Defenses in ob/ob Mice. J Nutr Biochem, 22(4):393-400.<br /> <br /> 38. Park HJ, Mah E, Bruno RS. (2010). Validation of HPLC-Boron Doped Diamond Detection for Assessing Hepatic Glutathione Redox Status. Anal Biochem, 407(2):151-9.<br /> <br /> 39. Park J, Marjani SL, Lai L, Samuel M, Wax D, Davis SR, Bruno RS, Prather RS, Yang X, Tian XC. (2010). Altered Gene Expression Profiles in the Brain, Kidney, and Lung of Deceased Neonatal Cloned Pigs. Cell Reprogram, 12(5):589-97. <br /> <br /> 40. Pestinger V, Wijeratne SSK, Rodriguez-Melendez R, Zempleni J. The histone biotinylation marks H3K9bio, H3K18bio, and H4K8bio are enriched in repeat regions and participate in the repression of transcriptionally competent genes in human primary fibroblasts and Jurkat lymphoblastoma cells. J Nutr Biochem (in press)<br /> <br /> 41. Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2010;49(8):535-48. doi: 10.2165/11532990-000000000-00000 [doi]<br /> <br /> 42. Polara-Cabrera K, Huo T., Schwartz S.J., Failla, M.L. Digestive stability and transport of norbixin, a 24-carbon carotenoid, across monolayers of Caco-2 cells. J. Agr. Food Chem., 2010; 58:5789-5794.<br /> <br /> 43. Rajendran, P, Williams, DE, Ho, E and Dashwood, RH. (201x) Role of metabolism in generating HDAC inhibitors. Crit Rev Biochem Mol Bio, in press<br /> <br /> 44. Reinwald, S., Mayer, L.P., Hoyer, P.B., Turner, C.H., Barnes, S., Weaver, C.M. A longitudinal study of the effect of genistein on bone in two different murine models of diminished estrogen-poducing capacity. J. Osteoporosis. 2010 <br /> <br /> 45. Rendina E, Lim YF, Marlow D, Wang Y, Clarke SL, Kuvibidila S, Lucas EA, Smith BJ. Dietary supplementation with dried plum prevents ovariectomy-induced bone loss in C57BL/6 mice and modulates the immune response. J Nut Biochem, 2011 Mar 15. [Epub ahead of print]<br /> <br /> 46. Rios-Avila L, Prince SA, Wijeratne SSK, Zempleni J. A 96-well plate assay for high-throughput analysis of holocarboxylase synthetase activity. Clin Chim Acta 412:735-739, 2011<br /> <br /> 47. Rios-Avila L, Pestinger V, Wijeratne SSK, Zempleni J. K16-biotinylated histone H4 is overrepresented in repeat regions and participates in the repression of transcriptionally competent genes in human Jurkat lymphoid cells. (submitted)<br /> <br /> 48. Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I--Folate, Vitamin B12, Vitamin B6. J Matern Fetal Neonatal Med 2010;23(12):1323-43. doi: 10.3109/14767051003678234 [doi].<br /> <br /> 49. Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part II--vitamin D, vitamin A, iron, zinc, iodine, essential fatty acids. J Matern Fetal Neonatal Med 2011;24(1):1-24. doi: 10.3109/14767051003678226 [doi].<br /> <br /> 50. Singh D, Pannier AK,* Zempleni J.* Identification of holocarboxylase synthetase chromatin binding sites using the DamID technology. *Contributed equally to this paper. Anal Biochem (in press)<br /> <br /> 51. Song Y, Elias V, Wong CP, Scrimgeour AG and Ho E. (2010) Zinc transporter expression profiles in the rat prostate following alterations in dietary zinc. Biometals 23:51-58.<br /> <br /> 52. Wijeratne SSK, Camporeale G, Zempleni J. K12-biotinylated histone H4 is enriched in telomeric repeats from human lung IMR-90 fibroblasts. J Nutr Biochem 21:310-316, 2010<br /> <br /> 53. Wong, CP, Magnusson, KR and Ho, E. (2010) Aging is associated with altered dendritic cell subset distribution and impaired proinflammatory cytokine response. Exp Gerontol 45:163-169.<br /> <br /> 54. Zempleni J, Li Y, Xue, J, Cordonier E. The role of holocarboxylase synthetase in genome stability is mediated partly by epigenomic synergies between methylation and biotinylation events. Epigenetics (in press)<br /> <br /> 55. Zhou J, Wang D, Schlegel V, and Zempleni J. Development of an internet based system for modeling biotin metabolism using Bayesian networks. Comp Methods Progr Biomed (in press)<br /> <br /> <br /> <br /> Books and Book Chapters<br /> <br /> 1. Zempleni J, Wijeratne SSK, Kuroishi T. Biotin. In: Present Knowledge in Nutrition. Erdman J, Macdonald I, Zeisel S (eds.), 10th edition. International Life Sciences Institute, Washington, DC, 2012 (in press)<br /> <br /> 2. Zempleni, J, Liu D, Xue J. Nutrition, histone epigenetic marks, and disease. In: Epigenomics in Health and Disease. Jirtle, RL, Tyson F (eds.), Springer, Heidelberg, Germany (submitted)<br /> <br /> 3. Bagley P, Shane B. (2010). Folate. In Encyclopedia of Dietary Supplements, Coates P, Betz JM, Blackman MR, Cragg GM, Levine M, Moss J, White JD, eds., 2nd ed., pp. 288-77, Informa Healthcare, New York.<br /> <br /> 4. Hord, NG (2011) Regulation of dietary nitrate and nitrite: balancing essential physiological roles with potential health risks, In: Nitrates and Nitrites in Human Health and Disease, Editors: Joseph Loscalzo, M.D., Ph.D. (Harvard University) and Nathan S. Bryan, PhD (Texas), New York, NY, Springer/Humana Press, In Press.<br /> <br /> 5. Medeiros DM, Bono E. The Iron factor in bone development. IN: J. Anderson, Calcium and Phosphorus in Health and Disease, CRC Press, Boca Raton, In press.<br /> <br /> 6. Lucas EA, Dumancas GG, Smith BJ, Clarke SL, Arjmandi BH. Health benefits of bitter melon (Momordica charantia). In Bioactive Foods in Promoting Health: Fruits and Vegetables. Edited by Ronald Ross Watson and Victor R. Preedy (in press).<br /> <br /> <br /> Dissertations <br /> <br /> 1. Chung, Min-Yu. Hepatoprotection of Vitamin E and Green Tea on Oxidative Stress and Inflammatory Responses In Animal Models of Obesity-Triggered Nonalcoholic Fatty Liver Disease. PhD Thesis 2011.<br /> <br /> 2. Hill, Katherine. Predictors of skeletal calcium accretion in adolescents from pooled metabolic balance studies. PhD. Thesis, 2010.<br /> <br /> 3. Legette, LeeCole. Effect of soy isoflavones and Prebiotics on bone metabolism in a postmenopausal rodent model. PhD. Thesis, 2010. <br /> <br /> <br /> Abstracts<br /> <br /> 1. KD Ballard, BR Kupchak, BM Volk, DJ Friedenreich, JC Aristizabal, E Mah, Y Guo, C Masterjohn, RS Bruno, WJ Kraemer, JS Volek. (2010). A 9-month progressive resistance training program attenuates acute exercise-induced lipid peroxidation in healthy men and women. American College of Sports Medicine (Abstract).<br /> <br /> 2. M-Y Chung, HJ Park, JE Manautou, SI Koo, RS Bruno. (2010). Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by pro-inflammatory enzymes. Northeast Chapter of the Society of Toxicology; Storrs, CT. Abstract.<br /> <br /> 3. Clarke, JD, Yu, Z, and Ho, E (2010). Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal and prostate cancer cells FASEB J. 2010 24:107.5<br /> <br /> 4. Ho, E, Hardin, K., Wong, CP,Hobson, B, Traber, MG and Tanguay, RL (2010) Using zebrafish as a model organism to understand the impact of maternal zinc status on embryonic zinc homeostasis during development FASEB J. 2010 24:718.10<br /> <br /> 5. Kuroishi T, Cerny RL, Zempleni J. Mass spectrometric analysis of biotinylated peptides and histones. Abstract 3809 (107.2) Experimental Biology Meeting<br /> <br /> 6. A Larson, Y Guo, KS Black, MA Hayman, RS Richardson, RS Bruno, T Jalili, JD Symons. (2010). A single dose of quercetin lowers blood pressure in hypertensive but not prehypertensive males. Experimental Biology, Anaheim, CA. Abstract.<br /> <br /> 7. E Mah, K Ballard,D Kawieki, JS Volek, RS Bruno. (2010). ³-Tocopherol supplementation improves postprandial vascular endothelial function in lean and obese men by decreasing oxidative and nitrative stress. Experimental Biology, Anaheim, CA. Abstract.<br /> <br /> 8. HJ Park, M-Y Chung, SI Koo, RS Bruno. (2010) Green tea extract (GTE) attenuates hepatic and adipose inflammation by altering glutathione redox status in nonalcoholic fatty liver disease (NAFLD). Experimental Biology, Anaheim, CA. Abstract.<br /> <br /> 9. HJ Park, M-Y Chung, SI Koo, Y-K Park, J-Y Lee, RS Bruno. (2010) Green tea extract protects against nonalcoholic fatty liver disease in diet-induced obese rats by decreasing hepatic inflammatory and oxidative stress responses. Institute of Food Technologists; Chicago, IL. Abstract.<br /> <br /> 10. Rodriguez-Melendez R, Bui DC, Ellis M, Johnson RM, Zempleni J. (2010) Identification of a potential role of K9-biotinylated histone H3 in honeybee (Apis mellifera) development. Abstract 3220 (550.2) Experimental Biology Meeting<br /> <br /> 11. Rios-Avila L, Wijeratne SSK, Pestinger V, Zempleni J. (2010) Characterization of the H4K16bio mark in human lymphoid cells. Abstract 2273 (550.1) Experimental Biology Meeting<br /> <br /> 12. Rios-Avila L, Pestinger V, Wijeratne SSK, Rodriguez-Melendez R, Zempleni J. Characterization of the H4K16bio mark in human cells. UNL Research Fair, April 7, 2010, Lincoln, NE<br /> <br /> 13. Sands, D.C., 2011. The quest for gluten-free grains more nutritious than wheat. International Celiac Disease Symposium. (Abstract). Oslo, Norway, 2011.<br /> <br /> 14. K Sankavaram, L Chong, RS Bruno, HC Freake. (2010). Zinc deficiency induces apoptosis but zinc induces necrosis in rat hepatoma cells. Experimental Biology, Anaheim, CA. Abstract.<br /> <br /> 15. Singh D, Zempleni J, Pannier A. Development of an Antibody Independent Technology to Monitor Chromatin Proteins in Cell Lines. University of Nebraska Medical Center, Regenerative Medicine Symposium, May 24, 2010, Omaha, NE<br /> <br /> 16. Tian XC, Park J, Bruno R, French RA, Prather RS. 2010. Functional genomics and epigenetics in pig cloning research. 43rd Annual Meeting of the Society for the Study of Reproduction; July 30-Aug 3, 2010; Milwaukee, WI. Biol Reprod 83 (S1):22 (Abstract 104).<br /> <br /> 17. Wijeratne SSK, Kuroishi T, Pestinger V, Rios-Avila L, Zempleni J. (2010) Histone biotinylation is a naturally occurring phenomenon. Abstract 2316 (107.1) Experimental Biology Meeting<br /> <br /> <br /> Other<br /> <br /> 1. Lucas EA, Peterson SK, Clarke SL, and Smith BJ. Cardiovascular health benefits of grape juice. Handbook of Oklahoma Vineyard Establishment and Management ed. Stafne ET (Oklahoma Cooperative Extension Service Circular E-1015, 2010).<br />

Impact Statements

1. Wheats, potatoes, legumes and oil crops (such as Camelina) can all be selected for enhanced nutritional properties. This shift away from commodity and yield driven agriculture will lead to more profitability and sustainability of our agricultural sector. The health benefits to consumers will be considerable.
2. Using bioassays in conjunction with analytical assays is critically important to assess storage/processing effects on the health beneficial properties of plant products. These approaches demonstrate that purple potatoes have greater anti-cancer activity compared to white/yellow potatoes and that baking is a better processing method to retain the biological activity.
3. Our work has led to strategies that may lower cancer risk. We show that: i) biotin and folate synergize to maintain genome stability, thereby decreasing the risk of cancer and birth defects, ii) nutritional strategies that decrease oxidative stress, inflammation, DNA damage and/or target aberrant epigenetic alterations in prostate cancer may reduce the incidence of prostate cancer and associated health care costs, and iii) estimates of human exposure to dietary nitrates/nitrites will enable our understanding of these compounds in the etiology of colorectal carcinogenesis.
4. At the level of nutrient bioavailability, our works have the potential to impact the development of chronic diseases associated with aging. We show that i) the quantity and quality of dietary fat are important determinants of carotenoid bioavailability and potential mediators of the bioactivity of carotenoids, ii) select prebiotic enhances intestinal absorbtion of calcium, and iii) absorption of the polyphenol quercetin is enhanced by small amounts of dietary fat and its greater bioavailability leads to greater biotransformation to its methylated metabolites.
5. Our work examining the hepatoprotective actions of functional foods demonstrates that i) mango improves body composition in animal models of obesity, and could lead to an economical and safe option for reducing obesity in humans, and ii) green tea extract, in obese models, mitigates nonalcoholic steatohepatitis by decreasing hepatic inflammation, oxidative stress, and lipid accumulation. These works may help growers and food manufacturers identify novels uses of these plants in foodstuffs and the development of products that may reduce the growing trends of obesity.
6. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Our work strongly suggests that folate fortification has no adverse effects on vitamin B12 status, at least in a young human population, and our work in transgenic models have allowed a mechanistic study of the potential interactions between vitamin B12 and folate.

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Report Information

Participants

Vanamala, Jairam (jairam.vanamala@colostate.edu)- Colorado State University (Meeting Host);

Bray, Tammy (tammy.bray@oregonstate.edu) - Oregon State University (Administrative Advisor);

Weaver, Connie (weavercm@purdue.edu) - Purdue University;

Stoecker, Barbara (barbara.stoecker@okstate.edu) - Oklahoma State University;

Shane, Barry (bandie@berkeley.edu) - University of California-Berkeley;

Failla, Mark (MFailla@ehe.osu.edu) - The Ohio State University;

Zempleni, Janos (JZEMPLENI2@unl.edu) - University of Nebraska-Lincoln;

Ho, Emily (emily.ho@oregonstate.edu) - Oregon State University;

Lindshield, Brian (blindsh@k-state.edu) - Kansas State University;

Teske, Jennifer (teskeja@email.arizona.edu) - University of Arizona

Brief Summary of Minutes

Participants:
Meeting Host - Jairam Vanamala (jairam.vanamala@colostate.edu)- Colorado State University

Administrative Advisor - Tammy Bray (tammy.bray@oregonstate.edu) - Oregon State University

Connie Weaver (weavercm@purdue.edu) - Purdue University

Barbara Stoecker (barbara.stoecker@okstate.edu) - Oklahoma State University

Barry Shane (bandie@berkeley.edu) - University of California-Berkeley

Mark Failla (MFailla@ehe.osu.edu) - The Ohio State University

Janos Zempleni (JZEMPLENI2@unl.edu) - University of Nebraska-Lincoln

Emily Ho (emily.ho@oregonstate.edu) - Oregon State University

Brian Lindshield (blindsh@k-state.edu) - Kansas State University

Jennifer Teske (teskeja@email.arizona.edu) - University of Arizona

Absent: Richard Bruno (Univ. of Connecticut; Edralin A. Lucas (OK State); Elvira de Mejia (U IL)

Meeting was called to order at 8:30 AM.

Welcome and Introductions:

Participants were welcomed by the host and Colorado State University Administrators: Jairam Vanamala, Chris Melby, Department Head, Food Science and Human Nutrition; Dr. Jeff McCubbin - Dean, College of Applied Human Sciences; Craig Beyrouty, Dean, College of Agricultural Sciences.


Dr. Vanamala and the administrators shared insights on value of transdisciplinary approach in addressing complex food and nutrition problems. Investigators introduced themselves and their programs.

Tommy Bray spoke about brief history of W2002 and expectations for the multistate research meetings/participants. She answered questions from the audience regarding deadlines and processes for multistate renewal grant proposal.

Presentations, June 4
Station reports were shared from each investigator in the following order:

1) Connie Weaver - Discussed the effects of galactooligosaccharide (GOS) on colonic calcium absorption in pre-menarcheal girls and the rapid screening method accelerator mass spectrometry for tracer quantification; Indicated that the Diet Impact on Bone is Greatest During Periods of High Bone Turnover

2) Janos Zempleni - Discussed the importance of Holocarboxylase Synthetase in Biotinylation and how grape compounds inhibits the Holocarboxylase Synthetase

3) Emily Ho - Discussed the pharmacokinetics and bioavailability of sulforaphane and its chemoprotective role in modulating epigenetic events

4) Mark Failla - Discussed oral metabolism of anthocyanins

5) Barry Shane - Discussed B-vitamins, especially B12 and folate, in relation to 1-carbon metabolism

6) Brian Lindsheild - Discussed the importance of 5alpha-reductase inhibitors in development and progression of prostate cancer

7) Jennifer Teske - Discussed the role of sleep in chronic disease development


Presentations, June 5

Dr. Tammy Bray discussed the status of the W2002, its funding cycle, and indicated that the group should begin organizing for the renewal in the upcoming years.

Additional station reports were shared from each investigator in the following order

1) Barbara Stoecker - Discussed ongoing nutritional studies in international populations

2) Jairam Vanamala - Discussed the in vivo anti-oxidant and anti-inflammatory activity of processed (baked vs. chipped) purple-fleshed potatoes; Presented the importance of utilizing in vitro and in vivo models in conjunction with analytical techniques in assessing the farm to fork operation on health-benefiting properties of plant foods


Janos Zempleni was elected by group members to be administrative leader for the next annual cycle. Dr. Zempleni will coordinate next year's W2002 meeting in Nebraska. Objectives, timeline, and responsibilities for project renewal were discussed and decided that Dr. Zempleni, Ho and Vanamala will lead the efforts. Discussed the possibility of future collaborations among the participants and propsed to start a collaborative study on health-benefiting properties of color-fleshed potato anthocyanins.

Accomplishments

The participants of this multi-state project have been highly productive during the past reporting period as evidenced by >50 peer-reviewed publications among attending participants and enhancement of collaborations between project members. Project objectives are listed below along with scholarly activities of the lead station. <br /> <br /> Objective 1): Determine the bioavailability (absorption, distribution, metabolism, elimination) of nutrients and other food components and their environmental and genetic determinants. <br /> <br /> Objective 2): Evaluate the bioactivity of nutrients and other food components in order to elucidate their underlying protective mechanisms. <br /> <br /> Colorado State University (Jairam Vanamala). Potato (Solanum tubersom) is the third largest source of phenolic compounds in the human diet after oranges and apples. We have shown that locally-grown purple fleshed potatoes are a greater source of bioactive compounds, even after prolonged storage and processing (baking chipping), retains in vitro anti-cancer properties, compared to white-and yellow-fleshed cultivars. These results suggest that colored potatoes are a potential healthier alternative to common potato cultivars. This year we focused on assessing anti-oxidant and anti-inflammatory properties of colored potatoes in vivo using obese pigs, an agriculturally important animal with similar nutritional metabolism to humans, as a model. Samples from 40 pigs consuming a high-fat diet for 12 weeks followed by supplementation with white vs. purple potato chips (10% vs. 20% of diet;5 weeks) were utilized to determine the effect of dose on oxidative and/or inflammatory markers. The potato diets had no effect on the food intake, weight gain and back-fat thickness. However, serum oxidative stress markers, 8-isoprostane and malondialdehyde levels, were lower in pigs consuming purple potato diet (10 %) compared to control or white potato diet. Mesenteric fat free fatty acid analysis revealed that both purple and white potato diet (10 %, Purple > White) had lower saturated fatty acids (SFA) and greater poly unsaturated fatty acids (PUFA) levels compared to the pigs consuming high-fat control. Correspondingly, serum TNF-á, a pro-inflammatory cytokine, was also suppressed by the potato diets compared to high-fat control. These results suggest that purple potatoes, even after processing, might suppress both oxidative stress/inflammatory markers in vivo via alterations in the fatty acid composition. We also completed extensive sample collection from 64 pigs (3 weeks post weaning) consuming high fat diet supplemented with (10 %) purple and white potatoes (raw, baked and chipped) for 13 weeks. An additional control (fed with low fat diet) was included to establish baseline levels of oxidative stress/inflammatory markers. <br /> <br /> University of California, Berkeley (Barry Shane). We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin. Impact: Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification. Although it has been suggested that folate fortification exacerbates vitamin B12 deficiency symptoms, our recent studies on the Trinity Student cohort do not support any adverse effects of folate fortification on vitamin B12 status in a young population. Our genetic studies may suggest novel biomarkers for assessing vitamin status.<br /> <br /> Purdue University (Connie M. Weaver). Two novel fibers, GOS and Soluble Corn Fiber, increased calcium absorption in pubertal children associated with increases in proportion of gut bifido bacteria. Equol producing capability determined through pre-screening did not affect the bone resorption attenuation response to soy consumption in postmenopausal women. Several plant extracts were effective in reducing net bone turnover in an OVX rat model.<br /> <br /> Oregon State University (Emily Ho). The classic view of cancer etiology is that genetic alterations damage DNA structure and induce mutations resulting in non-functional proteins that lead to disease progression. More recently, the role of epigenetic alterations during cancer has gained increasing attention. The lab has focused on the examination of the interaction of bioactive nutrients such as sulforaphane, catechins and zinc on mechanisms related to cancer and chronic disease development.<br /> <br /> Zinc and chronic disease: In both animal models and humans, we have found that dietary zinc deficiency increases DNA damage in peripheral blood cells. Importantly, these functional changes precede any changes in plasma zinc levels. More recently we have found that zinc status is compromised with age. Zinc supplementation in older animals reverses age-related zinc deficiency and inhibits age-related immune defects and inflammatory processes. We have also have preliminary data that suggests that zinc alters DNA methylation patterns and may be a novel mechanism by which zinc affects gene expression and the inflammatory response.<br /> <br /> Plant-derived phytochemicals from tea and cruciferous vegetables: We have found that sulforaphane, a chemical found cruciferous vegetables is an inhibitor of histone deacetylases, increases acetylated histone levels and has anti-cancer properties in the prostate. We recently reported that SFN also causes decreases in DNA methyltransferase expression and causes hypomethylation of cyclinD2, a commonly repressed and hypermethylated gene in prostate cancer cells. Other phytochemicals derived from cruciferous vegetables, such as indole-3-carbinol may also have epigenetic targets and inhibit HDAC. This work suggests that phytochemical may have the ability to alter epigenetic events that lead to disease prevention. In human supplementation trials, we have directly compared the effects of the whole food(broccoli sprouts) to commercially available supplements. We have found a significant decrease in bioavailability and impact on HDACs with supplements compared to the whole food. Surprisingly, even when supplements are pre-treated with myrosinase, the release of sulforaphane from its glucosinolate precursors in the supplement is limited. <br /> <br /> Kansas State University (Brian L. Lindsheild). We're currently conducting a study to determine the effects of providing the 5alpha-reductase inhibitors finasteride and dutasteride starting at two different times on the development and progression of prostate cancer TRAMP mice. We're also using gas chromatography to quantify and characterize the fatty acids in saw palmetto supplements. Large clinical trials have found that both finasteride and dutasteride reduced the risk of prostate cancer; however they also increased the occurrence of more advanced prostate cancer among those who did develop it. Our research will provide evidence to help clarify finasteride and dutasteride are effective and provide information on whether these should potentially be recommended for men at high risk of prostate cancer. The saw palmetto project should provide information about what supplements contain and whether they're efficacious.<br /> <br /> The Ohio State University (Mark Failla). The amount of ²-carotene delivered to the plate after processing cassava according to traditional styles of cooking and ²-carotene bioaccessibility increased in proportion to provitamin A content in transgenic high ²-carotene cultivars. ²-carotene content during storage and its bioaccessibility were greater for transgenic potato containing the OR carotenoid storage protein than that for control potato. The bioavailability of carotenoids from a vegetable salad was increased in response to the amount of co-consumed fat with a trend towards increased carotenoid absorption when the relative amount of unsaturated fat was elevated. Xanthones from a mangosteen juice were identified as the free compounds and their phase 2 metabolites in serum and urine in healthy human participants. <br /> <br /> University of Nebraska at Lincoln (Janos Zempleni). Covalent binding of biotin to histones is catalyzed by holocarboxylase synthetase (HLCS) and has been linked with the repression of genes and repeat regions in human chromatin. However, less than 0.001% of histones H3 and H4 are biotinylated, thereby raising concerns that the abundance might be too low to elicit the strong phenotypes observed in HLCS- and biotin-deficient organisms in vivo. We are proposing an alternative model that integrates the findings from previous research by us and others. In this novel model, HLCS acts as an integral part of a multiprotein gene repression complex in human chromatin, and biotinylation of histones is a mere side effect of HLCS being in close physical proximity to histones. Specifically, we are proposing that HLCS interacts physically with the following chromatin proteins that are known to mediate gene repression by creating or interpreting epigenetic gene repression marks: euchromatic H3K9 methyltransferase EHMT-1, the maintenance DNA methyltransferase DNMT1, the methyl-CpG-binding domain protein MeCP2, histone deacetylases (HDACs) 1, 2, 3, and 8, the nuclear co-repressor N-CoR, and heterochromatin protein (HP) 1. Protein-protein interactions were predicted by using a new search algorithm and verified by using co-immunoprecipitation assays, limited proteolysis assays, and yeast-two-hybrid assays. As of today, we have confirmed physical interactions between HLCS and DNMT1, MeCP2, EHMT-1, and HDAC1. Studies with N-CoR and HP1 are in progress. Studies with synthetic inhibitors and transgenic models suggest that DNA methylation is a primary loading factor, followed by docking of HLCS, followed by docking of EHMT-1 and/or HDACs. Importantly, we discovered a novel biotinylation site in EHMT-1, namely K161, which might be essential for chromatin positioning of EHMT-1 and the subsequent methylation of K9 in histone H3. Impact. Biotin and folate synergize to maintain genome stability, thereby decreasing cancer risk and the risk for birth defects.<br /> <br /> Oklahoma State University (Barbara Stoecker). A study of 41 women (over 50 years of age) with and without metabolic syndrome (MetS) indicated that in addition to differences defining MetS, mean serum adiponectin was lower in the MetS group, and circulating insulin was higher (p<0.003). Insulin resistance was significantly elevated in the MetS group as was the android:gynoid fat ratio. Android fat was positively associated with serum glucose, triacylglycerols, and insulin and with insulin resistance, whereas gynoid fat showed no significant association with these variables. Total dietary antioxidant capacity was positively correlated with serum HDL-cholesterol, adiponectin and dietary fiber intakes which supports the idea that fruits and vegetables are good sources of antioxidants. <br /> <br /> Oklahoma State University (Edralin A. Lucas). Bitter melon (Momordica charantia, MC) has been shown to improve markers of insulin resistance including adiposity, glucose and lipid profile in mice fed high fat diet. Fatty acids can activate toll-like receptor (TLR) 4 signaling pathway resulting in the enhanced production and secretion of proinflammatory cytokines which may contribute to insulin resistance associated with diet induced obesity (DIO). We examined the effect of MC on glucose and lipid homeostasis in an animal model of DIO and the role of TLR4 in mediating these effects. Eight week old male TLR4 mutant (C3H/HeJ) and control (C57BL/6) mice were randomly assigned to four dietary treatment groups for eight weeks (n=12-13/group): control (10% calories from fat), high fat (HF, 60% calories from fat), HF+1% (w/w) MC, and HF+10% (w/w) MC. Our preliminary data suggests that the C3H/HeJ strain exhibited significantly higher body weight, body fat, plasma cholesterol, and triglycerides in response to a high fat diet when compared to the C57BL/6 strain regardless of dietary treatment. However, C3H/HeJ strain had significantly lower area under the curve after a glucose tolerance test, plasma fructosamine and free fatty acid in comparison to the C57BL/6 strain. Mice fed the 10% MC, but not the 1% MC, improved glucose tolerance in the C57BL/6 but not the C3H/HeJ strain, suggesting MC may act through TLR4 signaling to modulate glucose homeostasis. The effects of MC and TLR4 mutation on mRNA expression of genes involved in glucose and lipid metabolism are being assessed. <br /> <br /> University of Connecticut (Richard Bruno). Epidemiological observations suggest that the presence of nonalcoholic fatty liver disease (NAFLD) dramatically increases the risk for cardiovascular disease (CVD). Thus, we have conducted studies to examine the extent to which phytonutrients regulate oxidative stress and inflammatory responses in experimental and clinical models of NAFLD and CVD. In a high-fat feeding model of NAFLD, we examined the extent to which green tea extract (GTE) protects against liver injury by regulating hepatic and adipose inflammatory responses under the transcriptional control of nuclear factor kappa B (NFkB). Wistar rats (16-wk old, n=63) were fed a low-fat (LF; 10% kcal) diet containing no GTE or a high-fat (HF; 60% kcal) diet containing 0, 1, or 2% GTE for 8 wks. We then examined whether GTE reduced NFkB activation and expression levels of inflammatory mediators that are regulated in a NFkB-dependent manner. In a separate clinical study, a randomized cross-over trial was conducted in healthy men to examine the extent to which gamma-tocopherol (g-T) supplementation protects against vascular dysfunction otherwise induced by acute hyperglycemia by regulating lipid peroxidation and the ratio of asymmetric dimethylarginine relative to arginine (ADMA/Arg), an index of nitric oxide bioavailability. IMPACT: The findings of our NAFLD study in rats indicated that HF feeding increased serum alanine (ALT) and aspartate aminotransferases and hepatic lipids compared to the LF group. GTE at 1 and 2% decreased ALT and hepatic lipid relative to the HF group. In liver and epididymal adipose, the HF group had lower glutathione as well as greater mRNA and protein expression of TNF-alpha and monocyte chemoattractant protein-1 (MCP-1) and NFkB binding activity than the LF group. Compared to the HF group, GTE at 2% increased glutathione and lowered protein and mRNA levels of inflammatory cytokines in both tissues. NFkB binding activities at liver and adipose were also lower, likely by inhibiting the phosphorylation of inhibitor of NFkB. NFkB binding activities in liver and adipose were correlated with ALT, and hepatic NFkB binding activity was inversely related to liver glutathione. These results suggest that GTE-mediated improvements in glutathione status are associated with the inhibition of hepatic and adipose inflammatory responses mediated by NFkB, thereby protecting against NASH. In our clinical study, healthy men completed a randomized, crossover study where they followed their usual diet or were provided g-T (500 mg/d, 5 d) prior to a fasting 75 g oral glucose challenge. Brachial artery flow-mediated dilation (FMD), plasma glucose, insulin, antioxidants, malondialdehyde (MDA), inflammatory proteins, Arg, and ADMA were measured at regular intervals during a 3 h postprandial period. g-T supplementation increased plasma g-T by 3-fold and its physiological metabolite, g-carboxyethyl-hydroxychroman by >9-fold without affecting glucose, arginine or ADMA. Baseline FMD responses, MDA, Arg, and ADMA were unaffected by g-T supplementation. Postprandial FMD decreased 30-44% following glucose ingestion, but was maintained during the g-T trial. g-T supplementation also attenuated postprandial increases in MDA that occurred following glucose ingestion. Plasma Arg decreased in both trials to a similar extent regardless of g-T supplementation. However, the ratio of ADMA/Arg increased time-dependently in both trials, but to a lesser extent following g-T supplementation. Inflammatory cytokines and cellular adhesion molecules were unaffected by glucose ingestion or g-T supplementation. Collectively, these findings suggest that short-term g-T supplementation maintained vascular function during postprandial hyperglycemia by attenuating lipid peroxidation and disruptions in nitric oxide homeostasis, independent of inflammation.<br />

Publications

1. Regassa N, Stoecker BJ. (2012) Contextual risk factors for maternal malnutrition in a food-insecure zone in Southern Ethiopia. J Biosocial Sci: Available on CJO doi:10.1017/S002193201200017X. Published on line April 24.<br /> <br /> 2. *Girma M, Loha E, *Bogale A, Teyikie N, Abuye C, Stoecker BJ. (2012) Iodine deficiency in primary school children and knowledge of iodine deficiency and iodized salt among caretakers in Hawassa Town: Southern Ethiopia. Ethiop J Health Dev 26: (In Press).<br /> <br /> 3. Aubuchon-Endsley NL, Grant SL, Thomas DG, Kennedy TS, Berhanu G, Stoecker BJ, Hubbs-Tait L, Hambidge KM. (2012) Infant responsiveness, alertness, haemoglobin and growth in rural Sidama, Ethiopia. Matern Child Nutr Jan 10. doi: 10.1111/j. 1740-8709.2011.00391.x. [Epub ahead of print].<br /> <br /> 4. *Ersino G, Tadele H, *Bogale A, Abuye C, Stoecker BJ. Iodine status and knowledge of iodine deficiency disorders (IDD) among pregnant women in rural Sidama, southern Ethiopia. (Submitted to Ethiopian Medical Journal).<br /> <br /> <br /> 5. Abebe H, Abebe Y, Loha E, Stoecker BJ. Consumption of vitamin A rich foods and dark adaptation threshold of pregnant women at Damot Sore District, Wolayita, Southern Ethiopia. (Submitted to Ethiopian Journal of Health Sciences). <br /> <br /> 6. Regassa N, Stoecker BJ. (2011) Household food insecurity and hunger among households in Sidama district, southern Ethiopia. Public Health Nutrition 8:1-8 [Epub ahead of print].<br /> <br /> 7. *Bogale A, Stoecker BJ, Kennedy T, Hubbs-Tait L, Thomas D, Abebe Y, Hambidge KM. (2011) Nutritional status and cognitive performance of mother-child pairs in Sidama, Southern Ethiopia. Matern Child Nutr August 2 [E-pub ahead of print].<br /> <br /> 8. Shen CL, Yeh JK, Samathanam C, Cao JJ, Stoecker BJ, Dagda RY, Chyu MC, Wang JS. (2011) Protective actions of green tea polyphenols and alfacalcidol on bone microstructure in female rats with chronic inflammation. J Nutr Biochem 22:673-80.<br /> <br /> 9. Shen CL, Yeh JK, Samathanam C, Cao JJ, Stoecker BJ, Dagda RY, Chyu MC, Dunn DM, Wang JS. (2011) Green tea polyphenols attenuate deterioration of bone microarchitecture in female rats with systemic chronic inflammation. Osteoporosis Int 22:327-37. <br /> <br /> 10. Bowman GL, Shannon J, Ho E, Traber MG, Frei B, Oken BS, Kaye JA, Quinn JF (2011). Reliability and Validity of Food Frequency Questionnaire and Nutrient Biomarkers in Elders With and Without Mild Cognitive Impairment. Alzheimer Dis Assoc Disord. 25(1):49-57.<br /> <br /> 11. Hsu, A., Bruno, R.S., Lohr, C.V., Dashwood, R.H., Bray, T.M., and Ho, E. (2011) Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFkB pathway in the Noble rat model, in vivo J. Nutr. Biochem; 22(5):502-10.<br /> <br /> 12. Rajendran, P, Williams, DE, Ho, E and Dashwood, RH. (2011) Role of metabolism in generating HDAC inhibitors. Crit Rev Biochem Mol Bio, 46(3):181-99.<br /> <br /> 13. Clarke, JD, Hsu, A., Yu, Z, Dashwood, RH and Ho, E. (2011) Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells. Mol Nutr Food Res, 55(7):999-1009.<br /> <br /> 14. Ho E, Dukovcic S, Hobson B, Wong CP, Miller G, Hardin K, Traber MG, Tanguay RL (2011) Zinc transporter expression in zebrafish during development, Comp Biochem Physiol C Toxicol Pharmacol. 2011 May 11. [Epub ahead of print].<br /> <br /> 15. Rajendran, P, Delage, B, Dashwood, WM, Yu T, Wuth,, B, Williams, DE, Ho, E and Dashwood, RH. (2011) Histone deacetylase turnover and recovery in sulforaphane-treated colon cancer cells: competing actions of 14-3-3 and Pin1 in HDAC3/SMRT corepressor complex dissociation/reassembly. Mol Cancer. 2011 May 30;10:68.<br /> <br /> 16. Clarke, J.D., Riedl, K.,Bella, D., Schwartz, S., Hardin, K., and Ho, E. (2011) Comparison of isothiocyanate metabolite levels and histone deacetylase activity in human subjects consuming broccoli sprouts or broccoli supplement. Pharmacol Res, 64(5):456-63.<br /> <br /> <br /> 17. Wong, CP, Nguyen, LP, Noh, S, Bray, TM, Bruno, RS and Ho, E. (2011). Induction of T-regulatory cells by green tea polyphenol EGCG. Immunol Letters, 30;139(1-2):7-13.<br /> <br /> 18. Clarke, J.D., Hsu, A., Williams, D.E., Dashwood, R.H., and Ho, E. (2011) Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice. Pharm Res 28(12):3171-9.<br /> <br /> 19. Parasramka, M., Ho, E, Williams, DE and Dashwood, RH (2011) MicroRNAs, diet, and cancer chemoprevention: new mechanistic insights on the epigenetic actions of phytochemicals. Mol Carcinog. 2011 Jul 7. doi: 10.1002/mc.20822. [Epub ahead of print].<br /> <br /> 20. Clarke, J.D., Riedl, K.,Bella, D., Schwartz, S., Stevens, JF, and Ho, E. (2011) Comparison of Isothiocyanate Metabolite Levels and Histone Deacetylase Activity in Human Subjects Consuming Broccoli Sprouts or Broccoli Supplement. J. Agric. Food Chem. 59(20):10955-63. <br /> <br /> 21. Rajendran, P, Ho, E, Williams, DE and Dashwood, RH. (2011) Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells Clin Epigenetics. 2011;3(1):4. Epub 2011 Oct 26.<br /> <br /> 22. Hsu, A, Zhen, Yu, Wong, CP, Williams, DE, Dashwood, RH and Ho, E. Promoter De-methylation of Cyclin D2 by Sulforaphane in Prostate Cancer Cells. Clin Epigenetics. 2011;3(1):3. Epub 2011 Oct 26.<br /> <br /> 23. Ho, E., Beaver, LM, Williams, DE and Dashwood, RH. (2011) Dietary factors and epigenetic regulation for prostate cancer prevention. Adv in Nutr 2: 497-510.<br /> <br /> 24. Wong, CP and Ho, E (2012) Zinc and its role in age-related inflammation and immune dysfunction. (review) Mol Nutr Food Res. doi: 10.1002/mnfr.201100511. [Epub ahead of print]<br /> <br /> 25. Opoku-Acheampong A.B., Nelsen M.K., Unis D., Lindshield B.L. The Effect of Finasteride and Dutasteride on the Growth of WPE1-NA22 Prostate Cancer Xenografts in Nude Mice. PLoS ONE 7(1): e29068, 2012.<br /> <br /> 26. Lindshield, B.L., Adhikari, K. The Kansas State University Human Nutrition (HN 400) Flexbook. Educause Quarterly. 34(4), 2011.<br /> <br /> 27. Ford, N.A., Elsen, A.C., Zuniga, K., Lindshield, B.L., Erdman, J.W., Jr. Lycopene and apo-12'-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutrition and Cancer. 632: 256-263, 2011.<br /> <br /> 28. Adamec J, Kannasch A, Huang J, Hohman E, Fleet JC, Peacock M, Ferruzzi MG, Martin B, Weaver CM. Development and optimization of an LC-MS/MS based method for simultaneous quantification of vitamin D2, vitamin D3, 24-hydroxyvitamin D2 and 25-hydroxyvitamin D3. J Sep Sci. 34(1): 11-20, 2011.<br /> <br /> 29. Osborne DL, Weaver CM, McCabe LD, McCabe GM, Novotny R, Boushey C, Savaiano DA. Tanning predicts bone mass but not structure in adolescent females living in Hawaii. Am J Hum Biol. 23(4): 470-8, 2011.<br /> <br /> 30. Weaver CM, Martin BR, Nakatsu CH, Armstrong AP, Clavijo A, McCabe LD, McCabe GP, Duignan S, Schoterman MG, van den Heuvel EG. Galactooligosaccharides improve mineral absorption and bone properties in growing rats through gut fermentation. J Agric Food Chem. 59(12): 6501-10, 2011.<br /> <br /> 31. Legette LL, Lee WH, Martin BR, Story JA, Arabshahi A, Barnes S, Weaver CM. Genistein, a phytoestrogen, improves total cholesterol, and Synergy, a prebiotic, improves calcium utilization, but there were no synergistic effects. Menopause 18(8): 923-31, 2011.<br /> <br /> 32. Zhang Q, Wastney ME, Rosen CJ, Beamer WG, Weaver, CM. Insulin-like growth factor I increases bone calcium accumulation only during rapid growth in female rats. J Nutr. 141: 2010-6, 2011. Doi: 10.395/jn111.142679.<br /> <br /> 33. Weaver CM, Campbell WW, Teegarden D, Craig BA, Martin BR, Singh R, Braun MM, Apolzan J, Hannon TS, Schoeller DA, DiMeglio L, Hickey Y, Peacock M. Calcium, dairy products, and energy balance in overweight adolescents: A controlled trial. Am J Clin Nutr 94:1163-1170, 2011. DOI: 10.3945/ajcn.110.010264<br /> <br /> 34. Elble AE, Hill KM, Park CY, Martin BR, Peacock M, Weaver CM. Effect of calcium carbonate particle size on absorption and retention in adolescent girls. J Am Col Nutr 30:171-177, 2011.<br /> <br /> 35. Eicher-Miller HA, Mason AC, Weaver CM, McCabe GP, Boushey CJ. Food insecurity is associated with diet and bone mass disparities in early adolescent males but not females in the United States. J Nutr 111:1-8, 2011.<br /> <br /> <br /> 36. Hill KM, Braun MM, Egan KA, Martin BR, McCabe LD, Peacock M, McCabe GP, Weaver CM. Obesity augments calcium-induced increases in skeletal calcium retention in adolescents. J Clin Endocrinol Metab 96:2171-7, 2011. PMID21490075<br /> <br /> 37. Cheong J, Gunaratna N, McCabe G, Jackson G, Kempa-Steczko A, Weaver C. Bone seeking labels as markers for bone turnover: Validation of urinary excretion in rats. Osteoporosis Intl. 22:153-157, 2011.<br /> <br /> 38. O'Connell DN, Weinheimer EM, Martin BR, Weaver CM, Campbell WW. Water turnover assessment in overweight adolescents. Obesity 19:292-297, 2011.<br /> <br /> 39. Hohman EE, Martin BR, Lachcik PJ, Gordon DT, Fleet JC, Weaver CM. Bioavailability and Efficacy of Vitamin D2 from UV-irradiated yeast in growing, Vitamin D-deficient rats. Agri Food Chem 56:2341-2346, 2011.<br /> <br /> 40. Lee W-H, Wastney M E, Jackson GS, Martin BR, Weaver CM. Interpretation of 41Ca data using compartmental modeling in post-menopausal women. Anal Bioanal Chem. 399:1613-1622, 2011.<br /> <br /> 41. Lee W, McCabe GP, Martin BR, Weaver. Validation of a simple isotope method for estimating true calcium fraction absorption in adolescents. Osteoporos Int 22(1):159-166, 2011.<br /> <br /> 42. Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part II--vitamin D, vitamin A, iron, zinc, iodine, essential fatty acids. J Matern Fetal Neonatal Med 2011;24(1):1-24. doi: 10.3109/14767051003678226 [doi].<br /> <br /> 43. Carter TC, Pangilinan F, Troendle JF, et al. Evaluation of 64 candidate single nucleotide polymorphisms as risk factors for neural tube defects in a large Irish study population. Am J Med Genet A 2011;155A(1):14-21. doi: 10.1002/ajmg.a.33755 [doi].<br /> <br /> 44. Neuhouser ML, Nijhout HF, Gregory JF III, Reed MC, James SJ, Liu A, Shane B, Ulrich CM. (2011). Mathematical modeling predicts the effect of folate deficiency and excess on cancer related biomarkers. Cancer Epidemiol. Biomark. Prev. 20: 1912-1917.<br /> <br /> 45. Stone N, Pangilinan F, Molloy AM, Shane B, Scott JM, Ueland PM, Mills JL, Kirke PN, Sethupathy P, Brody LC. (2011). Bioinformatic and genetic association analysis of microRNA target sites in one-carbon metabolism genes. PLoS ONE 2011;6(7):e21851.<br /> <br /> <br /> 46. Mills JL, Carter TC, Scott JM, Troendle JF, Gibney ER, Shane B, Kirke PN, Ueland PM, Brody LC, Molloy AM. (2011). Do high blood folate concentrations exacerbate the metabolic abnormalities in people with low vitamin B12 status? Am. J. Clin. Nutr. 94: 495-500.<br /> <br /> 47. Shane B. (2011). Folate status assessment history: implications for measurement of biomarkers in the National Health and Nutrition Examination Survey. Am. J. Clin. Nutr. 94: 337-42S.<br /> <br /> 48. Yetley EA, Pfeiffer CM, Phinney KW, et al. (2011). Biomarkers of folate status in NHANES - a Roundtable summary. Am. J. Clin. Nutr. 94: 303-12S.<br /> <br /> 49. Yetley EA, Pfeiffer CM, Phinney KW, et al. (2011). Biomarkers of vitamin B-12 status in NHANES - a Roundtable summary. Am. J. Clin. Nutr. 94: 313-21S.<br /> <br /> 50. Davis MR, Rendina E, Peterson SK, Lucas EA, Smith BJ, Clarke SL. Enhanced expression of lipogenic genes may contribute to hyperglycemia and alterations in plasma lipids in response to dietary iron deficiency. Genes Nutr. 2012, Jan 7. [Epub ahead of print].<br /> <br /> 51. Rendina E, Lim YF, Marlow D, Wang Y, Clarke SL, Kuvibidila S, Lucas EA, Smith BJ. Dietary supplementation with dried plum prevents ovariectomy-induced bone loss while modulating the immune response in C57BL/6J mice. J Nut Biochem, 2012 Jan;23(1):60-8.<br /> <br /> <br /> 52. Peterson SK, Lucas EA, Traore D, Christopher LC, French C, Clarke SL, Lightfoot SA, Smith BJ, and Kuvibidila S. Effects of portabella mushrooms on collagen-induced arthritis, inflammatory cytokines, and body composition in dilute brown non-agouti (DBA1) mice. Functional Foods in Health and Disease (in press 2011).<br /> <br /> 53. Davis MR, Shawron KM, Rendina E, Lucas EA, Smith BJ, Clarke SL. Hypoxia inducible factor 2-alpha is translationally repressed in response to a dietary iron deficiency in Sprague-Dawley rats. J Nutr 2011 Sep;141(9):1590-6.<br /> <br /> 54. Lucas EA, Li W, Peterson SK, Brown A, Kuvibidila S, Perkins-Veazie P, Clarke SL, Smith BJ. Mango modulates body fat and plasma glucose and lipids in mice fed high fat diet. British J Nutr 2011; 28:1-11.<br /> <br /> <br /> 55. Lucas EA, Mahajan SS, Soung DY, Lightfoot SA, Smith BJ, Arjmandi BH. Flaxseed but not flaxseed oil prevented the rise in serum cholesterol due to ovariectomy in the Golden Syrian hamsters. J Medicinal Foods. 2011 Mar;14(3):261-7<br /> <br /> 56. Li, L.,Yang, Y., Xu, Y., Owsiany, K., Welsch, R., Chitchumroonchokchai, C.. Lu, S., Van Eck, J., Deng, X., Failla, M., Thannhauser,T.W. (2012) Expression of Or gene enhances carotenoid accumulation and stability during post-harvest storage of potato tubers. Molecular Plant 5: 339-352. <br /> <br /> 57. Failla, M.L., Chitchumroonchokchai, C., Siritunga, D., De Moura, F.F., Fregene,M., Sayre, R. (2012) Retention during processing and bioaccessibility of ²-carotene in transgenic cassava root. J. Agr. Food Chem. 60: 3861-3866.<br /> <br /> 58. Chitchumroonchokchai, C., Riedl, K.M., Suksumrarn, S., Clinton, S.K., Kinghorn, D.A., Failla, M.L. (2012) Bioavailability of xanthones from mangosteen juice in healthy adults. J. Nutrition, 142,675-680.<br /> <br /> 59. Goltz, S.R., Campbell, W.R., Chitchumroonchokchai, C., Failla, M.L., Ferruzzi, M.G. Meal triacylglycerol profile modulates carotenoid post-prandial absorption in humans. (2012) Mol. Nutr. Food Res., 56: 868-877.<br /> <br /> <br /> 60. Mah E, Noh SK, Ballard KD, Matos ME, Volek JS, Bruno RS. Postprandial hyperglycemia impairs vascular endothelial function in healthy men by inducing lipid peroxidation and increasing asymmetric dimethylarginine:arginine. J Nutr. 2011; 142:57-63.<br /> <br /> 61. Wong CP, Nguyen LP, Noh SK, Bray TM, Bruno RS, Ho E. Induction of regulatory T cells by green tea polyphenol EGCG. Immunol Lett. 2011; 139:7-13.<br /> <br /> 62. Chung MY, Park HJ, Manautou JE, Koo SI, Bruno RS. Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes. J Nutr Biochem. 2011; e-Pub May 2.<br /> <br /> 63. Masterjohn C, Mah E, Guo Y, Koo SI, Bruno RS. y-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men. J Nutr Biochem. 2011; e-Pub May 2.<br /> <br /> 64. Mah E, Matos MD, Kawiecki D, Ballard K, Guo Y, Volek JS, Bruno RS. Vitamin C status is related to proinflammatory responses and impaired vascular endothelial function in healthy, college-aged lean and obese men. J Am Diet Assoc. 2011; 111:737-43.<br /> <br /> 65. Hsu A, Bruno RS, Löhr CV, Taylor AW, Dashwood RH, Bray TM, Ho E. Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFkB pathway in the Noble rat model. J Nutr Biochem. 2011; 22:502-10.<br /> <br /> 66. Kuiper HC, Bruno RS, Traber MG, Stevens JF. Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. Free Radic Biol Med. 2011; 50:848-53.<br /> <br /> 67. Noh SK, Mah E, Ballard KD, Volek JS, Bruno RS. gamma-Tocopherol attenuates hyperglycemia-induced vascular endothelial dysfunction in men by decreasing asymmetric dimethylarginine accumulation. FASEB J. 2011; 25:218.7.<br /> <br /> 68. Guo Y, Davis CG, Mah E, Jalili T, Chun T, Bruno RS. Dietary fat increases quercetin bioavailability in obese men and postmenopausal women. FASEB J. 2011; 25:234.2.<br /> <br /> 69. Masterjohn C, Bruno RS. Normalization of dietary-fructose-induced liver injury in rats by green tea extract is accompanied by lower hepatic methylglyoxal accumulation. FASEB J. 2011; 25:95.3<br /> <br /> 70. Chung MY, Noh SK, Masterjohn C, Park HJ, Clark RM, Park YK, Lee JY, Koo SI, Bruno RS. Green tea extract protects against hepatic inflammation by reducing cyclooxygenase-2 in a rat model of dietary fat-induced nonalcoholic steatohepatitis. FASEB J. 2011; 25:106.2.<br /> <br /> 71. Singh D, Pannier AK,* Zempleni J.* Identification of holocarboxylase synthetase chromatin binding sites using the DamID technology. *Contributed equally to this paper. Anal Biochem 413:55-59, 2011.<br /> <br /> 72. Bao B, Wijeratne SSK, Rodriguez-Melendez R, Zempleni J. Human holocarboxylase synthetase with a start site at methionine-58 is the predominant nuclear variant of this protein and has catalytic activity. Biochem Biophys Res Commun 412:115-120, 2011.<br /> <br /> 73. Zhou J, Wang D, Schlegel V, and Zempleni J. Development of an internet based system for modeling biotin metabolism using Bayesian networks. Comp Methods Progr Biomed 104:254-259, 2011.<br /> <br /> 74. Kuroishi T, Rios-Avila L, Pestinger V, Wijeratne SSK, Zempleni J. Biotinylation is a natural, albeit rare, modification of human histones Mol Genet Metabol 104:537-545, 2011.<br /> <br /> 75. Esaki S, Malkaram SA, Zempleni J. Effects of single nucleotide polymorphisms in the human holocarboxylase synthetase gene on enzyme catalysis. Eur J Hum Genet 20:428-433, 2012.<br /> <br /> 76. Bao B, Rodriguez-Melendez R, Zempleni J. Cytosine methylation in miR-153 gene promoters increases the expression of holocarboxylase synthetase, thereby increasing the abundance of histone H4 biotinylation marks in HEK-293 human kidney cells. J Nutr Biochem 23:635-639.<br /> <br /> 77. Rios-Avila L, Pestinger V, Wijeratne SSK, Zempleni J. K16-biotinylated histone H4 is overrepresented in repeat regions and participates in the repression of transcriptionally competent genes in human Jurkat lymphoid cells. J Nutr Biochem (in press).<br /> <br /> 78. Vanamala, J., L. Reddivari, R. Sridhar and P. Andy. 2011. Functional proteomics of resveratrol-elevated human colon cancer cell apoptosis: identification of novel signaling pathways. Proteomics Science, 9:49. <br /> <br /> 79. Radhakrishnan, S., L. Reddivari, and J. Vanamala. 2011. Grape seed extract and resveratrol synergistically elevate human colon cancer cell apoptosis and suppress cell proliferation via activation of p53 and caspase-3 dependent signaling pathways. The Frontiers in Bioscience. (Elite Ed). 3:1509-1523.<br /> <br /> 80. Gaurav, M., L. Reddivari, D. Holm and J. Vanamala. 2011. Post-harvest storage of colored potatoes elevates phenolic content and anti-oxidant activity but suppresses anti-proliferative and pro-apoptotic properties against human colon cancer cell lines. Journal of Agriculture and Food Chemistry, 59(15):8155-66.<br /> <br /> 81. Allen G, Buchholz BA, Clifford AJ Kelly PB. Radio-Carbon and Laser Desorption Time-of-Flight Mass spectrometry Analysis of Size Fractionated Particulate Matter. Submitted<br /> <br /> 82. Novotny JA, Fadel JG, Holstege DM, Furr HC, Clifford AJ. This Kinetic, Bioavailability, and Metabolism Study of RRR-a-Tocopherol in Healthy Adults Suggests Lower Intake Requirements than Previous Estimates. J Nutr. Accepted.<br /> <br /> 83. Clifford AJ, Chen K, McWade L, Rincon G, Kim S, Holstege DM, Owens JE, Liu B, Muller H, Medrano JF, Fadel JG, Moshfegh AJ, Baer DJ, Novotny JA. Gender and Single Nucleotide Polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, CETP, and SCARB1 Are Significant Predictors of Plasma Homocysteine Normalized by RBC Folate in Healthy Adults. J Nutr. 2012 Sep;142(9):1764-71.<br /> <br /> 84. Kim SH, Cruz GD, Fadel JG, Clifford AJ. Food Authenticity using Natural Carbon Isotopes (12C, 13C, 14C) in Grass-fed and Grain-fed Beef. Food Science and Biotechnology. 2012;21(1):295-298.<br /> <br /> 85. Chuang JC, Matel HD, Nambiar KP, Kim S, Fadel JG, Holstege DM, Clifford AJ. Quantitation of [5-14CH3]-2R,4'R,8'R)-a-Tocopherol in Humans. J Nutr. 2011 Aug;141(8):1482-8. <br /> <br /> 86. Kim SH, Chuang JC, Kelly PB, Clifford AJ. Carbon Isotopes Profiles of Human Whole Blood, Plasma, Red Blood Cells, Urine and Feces for Biological/Biomedical 14C-Accelerator Mass Spectrometry Applications. Anal Chem. 2011:83(9):3312-3318. <br /> <br /> 87. Kim SH, Kelly PB, Clifford AJ. Calculating radiation exposures during use of 14C-labelled nutrients, food components, and biopharmaceuticals to quantify metabolic behavior in humans. J Agric Food Chem. 2010;58: 4632-37. <br /> <br />

Impact Statements

1. In general, phenolic content was inversely related to sensory attributes. These results suggest that it is critical to consider sensory attributes along with bioactive compound profile in developing health food products. Consumers were also more willing to pay higher premium for colored potato products if they are educated on health benefits.
2. Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification. Although it has been suggested that folate fortification exacerbates vitamin B12 deficiency symptoms, our recent studies on the Trinity Student cohort do not support any adverse effects of folate fortification on vitamin B12 status in a young population. Our genetic studies may suggest novel biomarkers for assessing vitamin status.
3. Two novel fibers, GOS and Soluble Corn Fiber, increased calcium absorption in pubertal children associated with increases in proportion of gut bifido bacteria. Equol producing capability determined through pre-screening did not affect the bone resorption attenuation response to soy consumption in postmenopausal women. Several plant extracts were effective in reducing net bone turnover in an OVX rat model.
4. Our work examining the hepatoprotective actions of functional foods demonstrates that i) mango improves body composition in animal models of obesity, and could lead to an economical and safe option for reducing obesity in humans, and ii) green tea extract, in obese models, mitigates nonalcoholic steatohepatitis by decreasing hepatic inflammation, oxidative stress, and lipid accumulation. These works may help growers and food manufacturers identify novels uses of these plants in foodstuffs and the development of products that may reduce the growing trends of obesity.
5. Polymorphisms in genes encoding folate-dependent enzymes have been implicated as risk factors for cancer and vascular disease. Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Our work strongly suggests that folate fortification has no adverse effects on vitamin B12 status, at least in a young human population, and our work in transgenic models have allowed a mechanistic study of the potential interactions between vitamin B12 and folate.

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Report Information

Participants

W2002 Participants who attended the annual meeting held June 3-4, 2013;


Zempleni, Janos (Meeting Chair) (jzempleni2@unl.edu) - University of Nebraska - Lincoln;
Bruno, Richard (bruno.27@osu.edu) - Ohio State University;
Ho, Emily (via Skype) (emily.ho@oregonstate.edu) - Oregon State University;
Lee, Ji-Young (ji-young.lee@uconn.edu) - University of Connecticut;
Stoecker, Barbara (Barbara.Stoecker@okstate.edu) - Oklahoma State University;
Vanamala, Jairam (vanamala@cahs.colostate.edu) - Colorado State University;
Weaver, Connie (weavercm@purdue.edu) - Purdue University;
Yang, Bin (bin.yang@wsu.edu) - Washington State University;
Chester, Deidra - USDA Representative (via phone)

Brief Summary of Minutes

BRIEF SUMMARY OF THE ANNUAL MEETING

Meeting was called to order June 3, 2013, at 9:00 a.m. CDST.

Welcome and Introductions: Participants were welcomed by the Meeting Chair, Dr. Janos Zempleni, and University of Nebraska Administrators. Dr. Zempleni introduced Drs. David Jackson, Associate Dean and Associate Director, Agricultural Research Division, and Tim Carr, Department Chair, Nutrition and Health Sciences. Dr. Jackson provided a brief overview of multistate groups and the expectations in these groups. W2002 investigators introduced themselves and their programs. Dr. Carr provided an overview of current activities in the department, including recent and upcoming hires, and gave a tour of the department.

Dr. Zempleni presented a brief overview of the W2002 project. The two scientists, who reviewed our proposal for re-authorization, requested only minimal edits. The proposal has been revised to address those changes and was uploaded by the administrative staff at Oregon State, Deanne Hudson.

Following this, the election of the W3002 Chair was conducted. Dr. Connie Weaver was elected by the members present to be the chair for the next annual cycle. She will coordinate next year's W3002 meeting in Indiana. Objectives, timeline, and responsibilities were discussed. Dr. Weaver will consult with the group about an appropriate meeting date in the near future.

Dr. Deirdra Chester, NIFA Program Leader, joined the meeting by phone and provided an update on the NIFA budget and current and future funding opportunities.

Each W2002 investigator attending the meeting provided an oral progress report in the following order:

1) Emily Ho (via Skype): Benefits of Zinc and Dietary Factors in Cancer Prevention

2) Jairam Vanamala: Genetics of Carotenoid Bioavailability and Obesity in Children


3) Richard Bruno: Regulation of Vascular Endothelial Function by gamma-Tocopherol in Clinical Models of Oxidative Stress

4) Barbara Stoecker: Micronutrient Deficiencies in Ethiopia

5) Connie Weaver: Update on Work with Calcium Risk for CVD and Potassium in Bioavailability

6) Bin Yang: Enzymatic Enhancement of the Biological Activities of Flavonoids from Ganoderma

7) Janos Zempleni: Roles of Biotin and Holocarboxylase Synthetase in Disease Prevention.


June 4, 2013

Invited speaker, Dr. Samodha Fernando, Assistant Professor in the Department of Animal Science, University of Nebraska-Lincoln, gave a talk on microbiome research and gene sequencing and bioinformatics expertise in his laboratory.
Following this, additional discussion took place regarding building research collaboration.

The meeting was adjourned at 1 p.m. CDST.

Accomplishments

ACCOMPLISHMENTS<br /> <br /> The participants of this multi-state project have been highly productive during the past reporting period as evidenced by >100 peer-reviewed publications among participants and enhancement of collaborations between project members. Project objectives are listed below along with scholarly activities of the lead station. <br /> <br /> Objective 1): Determine the bioavailability (absorption, distribution, metabolism, elimination) of nutrients and other food components and their environmental and genetic determinants. <br /> <br /> Objective 2): Evaluate the bioactivity of nutrients and other food components in order to elucidate their underlying protective mechanisms. <br /> <br /> University of Arizona (Jennifer Teske): <br /> Establishing a rodent model to test the hypothesis that insufficient sleep increases risk for bacterial infection, obesity, and reduced quality of life. SUMMARY OF PROGRESS: Insufficient sleep may alter nutrient bioavailability through changes in the gut-brain bidirectional axis, which is integral to gastrointestinal functions such as motility, intestinal barrier function and mucosal immunity. We recently developed and validated a novel method of sleep interruption that is not confounded by increases in stress and thus developed a rodent model of insufficient sleep that mirrors the human condition whereby insufficient sleep with daily sleep opportunity results in hyperphagia, lower physical activity and body weight gain. Moreover, we showed that obese rodents were more sensitive to the deleterious effect of insufficient sleep relative to lean rats. These findings challenge the previous belief that sleep deprivation increases energy expenditure. We are currently testing the dose and duration of insufficient sleep that triggers hyperphagia and body weight gain and the relationship between feeding, physical activity and energy expenditure. To treat normalize abnormal sleep patterns in obese rats, we are testing compounds centrally to promote sleep during the resting phase, increase physical activity in the active phase and normalize eating patterns to prevent eating during the resting phase.<br /> <br /> University of California, Berkeley (Barry Shane): <br /> OUTPUT: We have continued studies on the metabolic and nutritional effects of common polymorphisms in human folate-related genes that have been shown to influence disease risk. We have continued to evaluate the B12-dependent methionine synthase (MS) and methylene-tetrahydrofolate reductase (MTHFR) genetic mouse models to mimic the effects of these polymorphisms and to evaluate their effects on metabolism and how this is modified by nutritional status. We have developed a mouse model that mimics the clinical effects of human B12 and folate deficiency, and which will allow us to investigate potential adverse effects of high folate intake. We continue to evaluate genetic risk factors for neural tube defects and to identify putative modifier genes which influence folate status, homocysteine levels, and methylation potential using a number of mouse strains and a cohort of students at Trinity College, Dublin.<br /> <br /> University of California, Davis (Andrew Clifford): <br /> ABSTRACT: In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body weight. We used a linear regression model. Selected genes corresponded to folate metabolism, vitamins B-12, A, and E, and cholesterol pathways or lipid metabolism. Extracted DNA from both the Sacramento and Beltsville populations was analyzed using an allele discrimination assay with a MALDI-TOF mass spectrometry platform. The adjusted phenotype, y, was HDL levels adjusted for gender and body weight only statistical analyses were performed using the genotype association and regression modules from the SNP Variation Suite v7. Statistically significant SNP (where P values were adjusted for false discovery rate) included: CETP (rs7499892 and rs5882); SLC46A1 (rs37514694; rs739439); SLC19A1 (rs3788199); CD36 (rs3211956); BCMO1 (rs6564851), APOA5 (rs662799), and ABCA1 (rs4149267). Many prior association trends of the SNP with HDL were replicated in our cross-validation study. Significantly, the association of SNP in folate transporters (SLC46A1 rs37514694 and rs739439; SLC19A1 rs3788199) with HDL was identified in our study. Given recent literature on the role of niacin in the biogenesis of HDL, focus on status and metabolism of B-vitamins and metabolites of eccentric cleavage of beta-carotene with lipid metabolism is exciting for future study. MID: 23656756 [PubMed - as supplied by publisher] CONCLUSIONS/IMPACTS: The strength of our study is the cross-validation between two independent populations (one on the West coast, from Sacramento, CA, and one from the East coast, from the Washington, D.C. area) with similar SNP associations identified in both populations. It would be of significant research interest to focus on the relation of B vitamins on HDL status. In this work, we have identified SNP in two folate transporters (SLC46A1 rs35714695 and rs739439; SLC19A1 rs3788199) having statistically significant ASE in relation to HDL status in both study populations. Cholesterol may be important for facilitating the import of folate across the cell membrane and higher serum folate concentrations have been associated with lower levels of LDL-C and higher levels of HDL-C [19]. Past work by Kitami et al. focused on the importance of the homeostatic role of cholesterol metabolism on folate retention in mouse strains, so there has been an established relationship between cholesterol and folate in the mouse [4]. Recent work by Zhang et al. identified the role of niacin (also known as vitamin B3) on early hepatic HDL formation through transcription of ABCA1. In that study, apoA1 lipidation Clifford et al. Lipids in Health and Disease 2013, 12:66 Page 5 of 10 http://www.lipidworld.com/content/12/1/66 and formation of nascent HDL was mediated and stabilized by niacin, which may prevent premature HDL catabolism [51]. Finally, the identification of the positive association of the BCMO1 SNP rs6564851 with HDL levels was of significance. This SNP has a high MAF in the two independent study populations of this work (Tables 1 and 2). Additionally, the presence of this SNP has been associated with a 48% reduction in activity of converting beta-carotene into vitamin A through central cleavage, resulting in higher circulating levels of plasma carotenoids [29]. These higher levels of carotenoids may be associated with higher levels of HDL and LDL [1]. The biological effects of the eccentric cleavage products of beta-carotene (the apo-beta-carotenoids), especially on lipid metabolism and oxidative stress, are an exciting area of future study.<br /> <br /> University of California, Davis (Andrew Clifford):<br /> ABSTRACT: Kinetic models enable nutrient needs and kinetic behaviors to be quantified and provide mechanistic insights into metabolism. Therefore, we modeled and quantified the kinetics, bioavailability, and metabolism of RRR-alpha-tocopherol in 12 healthy adults. Six men and 6 women, aged 27 ± 6 y, each ingested 1.81 nmol of [5(-14)CH(3)]-(2R, 4'R, 8'R)-alpha-tocopherol; each dose had 3.70 kBq of (14)C. Complete collections of urine and feces were made over the first 21 d from dosing. Serial blood samples were drawn over the first 70 d from dosing. All specimens were analyzed for RRR-alpha-tocopherol. Specimens were also analyzed for (14)C using accelerator MS. From these data, we modeled and quantified the kinetics of RRR-alpha-tocopherol in vivo in humans. The model had 11 compartments, 3 delay compartments, and reservoirs for urine and feces. Bioavailability of RRR-alpha-tocopherol was 81 ± 1%. The model estimated residence time and half-life of the slowest turning-over compartment of alpha-tocopherol (adipose tissue) at 499 ± 702 d and 184 ± 48 d, respectively. The total body store of RRR-alpha-tocopherol was 25,900 ± 6=220 µmol (11 ± 3 g) and we calculated the adipose tissue level to be 1.53 µmol/g (657 µg/g). We found that a daily intake of 9.2 µmol (4 mg) of RRR-alpha-tocopherol maintained plasma RRR-alpha-tocopherol concentrations at 23 µmol/L. These findings suggest that the dietary requirement for vitamin E may be less than that currently recommended and these results will be important for future updates of intake recommendations. PMID: 23077194 [PubMed - indexed for MEDLINE] PMCID: PMC3497961 [Available on 2013/12/1]<br /> <br /> University of California, Davis (Andrew Clifford):<br /> ABSTRACT: Using linear regression models, we studied the main and 2-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine (Hcy)/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma Hcy normalized by RBC folate measurements (nHcy) in 373 healthy Caucasian adults (50% women). Variable selection was conducted by stepwise Akaike information criterion or least angle regression and both methods led to the same final model. Significant predictors (where P values were adjusted for false discovery rate) included type of blood sample [whole blood (WB) vs. plasma-depleted WB; P < 0.001] used for folate analysis, gender (P < 0.001), and SNP in genes SPTLC1 (rs11790991; P = 0.040), CRBP2 (rs2118981; P < 0.001), BHMT (rs3733890; P = 0.019), and CETP (rs5882; P = 0.017). Significant 2-way interaction effects included gender × MTHFR (rs1801131; P = 0.012), gender × CRBP2 (rs2118981; P = 0.011), and gender × SCARB1 (rs83882; P = 0.003). The relation of nHcy concentrations with the significant SNP (SPTLC1, BHMT, CETP, CRBP2, MTHFR, and SCARB1) is of interest, especially because we surveyed the main and interaction effects in healthy adults, but it is an important area for future study. As discussed, understanding Hcy and genetic regulation is important, because Hcy may be related to inflammation, obesity, cardiovascular disease, and diabetes mellitus. We conclude that gender and SNP significantly affect nHcy. PMID: 22833659 [PubMed - indexed for MEDLINE] <br /> <br /> Colorado State University (Jairam Vanamala):<br /> Purple-fleshed potato prevents and reverses high-fat diet elevated oxidative/inflammatory markers in distal colon, mesenteric fat and systemic circulation. SUMMARY OF PROGRESS: Purple-fleshed potatoes (PP) are rich in anti-inflammatory bioactive compounds such as anthocyanins and carotenoids. However, potatoes are typically processed before consumption. This year we focused on anti-oxidant and anti-inflammatory properties of raw vs. processed PP in vivo compared to WP - white-fleshed potato. We hypothesized that processed PP will not only prevent HFD elevated oxidative stress/inflammation biomarkers (prevention) in young pigs, but also suppress these biomarkers in a pig with established obesity (reversal). To test our hypothesis, in the prevention study, we utilized 56 pigs, 3 weeks post-weaning, consuming one of the seven diets: HFD and HFD supplemented with WP or PP (raw/baked/chips; 10% w/w) for 13 weeks. We also had 8 animals consuming standard low-fat diet (LFD) to establish baseline levels of oxidative stress and inflammation. In the protection study, pigs initially consumed HFD for 12 weeks before being assigned for an additional 5 weeks to one of the 5 diets; HFD and HFD containing 10/20% processed PP or WP (chips, N=8). In both prevention and reversal studies there were no significant differences in feed intake or weight gain between treatment groups. In the prevention study, animals consuming HFD had greater levels of oxidative stress and inflammatory markers in the colon, mesenteric fat and systemic circulation compared to LFD. Both PP and WP diets (raw/baked/chips) numerically elevated colonic mucosal glutathione ratio (GSH: GSSG), however, only the values in raw PP consuming pigs were significantly higher compared to HFD control. In addition, potato diets suppressed expression of pro-inflammatory markers (TNF-alpha, NFkB and TLR-4) in the colonic mucosa and mesenteric fat compared to HFD control. All the potato diets suppressed urinary oxidative stress markers; 8-isoprostane (8IP) and DNA adduct 8-OHDG; and serum levels of pro-inflammatory cytokine TNF-alpha; compared to HFD control, to levels similar to LFD animals. However, in the reversal study only the consumption of processed PP but not WP elevated colon mucosal and mesenteric fat GSH: GSSG ratio compared to HFD control. Similarly, colon mucosal and mesenteric fat expression of TNF-alpha, NFkB and TLR-4, and systemic levels of 8IP and TNF-alpha; were suppressed by processed PP diets compared to HFD control. These findings indicate that PP, even after processing, prevents and protects against HFD elevated colonic, mesenteric and systemic oxidative stress/inflammation in HFD consuming pigs. Potato products are not only rich in bioactive phenolics but also contain toxic compounds such as glycoalkaloids (GA) and acrylamide (AL). However limited information is available on how storage and processing alter GA and AL. GA and AL content measured by UPLC- PDA differed among the cultivars and ranged from 33 to 114 microg/gfw and 330 to 1533 ppb, respectively. Depending on the cultivar storage either elevated or did not affect the GA content, however, processing (baking and chipping) reduced the GA levels. Though 3 months of storage and processing did not increase the GA content above the safety limit, chipping and frying resulted in AL formation. <br /> <br /> University of Connecticut (Sung Koo and Ji-Young Lee): <br /> Lowering plasma total and low-density lipoprotein (LDL) cholesterol concentrations by dietary factors has proven its effectiveness to reduce coronary heart disease (CHD) risk. Studies have almost exclusively focused on the liver but contribution of intestine to the hypocholesterolemic effect of dietary factors has been largely neglected. Recently, significance of transintestinal cholesterol efflux (TICE) in removing excess cholesterol from the body has emerged. We found that EGCG and blackcurrent polyphenol-rich extract altered the expression of genes involved in cholesterol absorption, chylomicron assembly, and apical as well as basolateral cholesterol efflux in Caco-2 cells. Our results suggest that the polyphenols may be able to increase apical efflux of LDL-derived cholesterol in the intestine, an event known as TICE. This raises the possibility that cholesterol-lowering effects of the polyphenols could be attributed partly to TICE stimulation. OUTPUTS: The results from this project were disseminated by oral or poster presentation at the Experimental Biology in April 2013. <br /> <br /> University of Massachusetts (Eric Decker and Yeonhwa Park): <br /> Delivery Systems for Bioactive Components. Nanotechnological principles are being used to design effective delivery systems for lipophilic bioactive food components (nutraceuticals). We have developed a variety of different structured delivery systems from food-grade ingredients, such as nanoemulsions, microemulsions, solid lipid nanoparticles and nanolaminated droplets. These delivery systems can be encapsulated within a wide range of different functional food and beverage products without adversely affecting their desirable properties. We have shown that the dimensions (particle size), composition (fatty acid chain length) and interfacial properties (composition, charge, interactions) influence the biological fate of these structured delivery systems, and the bioaccessibility of encapsulated components. For example, we have shown that the bioaccessibility of beta-carotene encapsulated within nanoemulsion-based delivery systems increases with decreasing particle size, and is higher when the hydrophobic core consists of long chain fatty acids than medium chain fatty acids or indigestible oils. Results with standardized in vitro digestion models have been correlated to animal feeding studies.<br /> <br /> University of Nebraska, Lincoln (Janos Zempleni):<br /> SUMMARY OF PROGRESS: My laboratory has expanded our research activities beyond epigenetic mechanisms through which biotin and chromatin proteins maintain genome stability and participate in gene regulation, and now include the roles of biotin-related enzymes and bioactive compounds in foods and their roles as checkpoints in adipocyte differentiation and fatty acid oxidation: 1) Epigenetics: Holocarboxylase synthetase (HLCS) is the sole protein biotin ligase in the human proteome. HLCS interacts physically with chromatin proteins known to mediate gene repression, including euchromatic H3K9 methyltransferase EHMT-1, the maintenance DNA methyltransferase DNMT1, the methyl-CpG-binding domain protein MeCP2, histone deacetylase (HDAC) 1, and the nuclear co-repressor N-CoR. Studies with synthetic inhibitors and transgenic models suggest that DNA methylation is a primary loading factor, followed by docking of HLCS, followed by docking of EHMT-1 and/or HDACs. Importantly, we discovered a novel biotinylation site in EHMT-1, namely K161, which might be essential for chromatin positioning of EHMT-1 and the subsequent methylation of K9 in histone H3. Biotin synergizes with folate in the repression of pro-inflammatory cytokines. 2) Adipocyte differentiation and fatty acid oxidation: We have generated preliminary evidence suggesting that the biotin-dependent acetyl-CoA carboxylase 2 (ACC2) is a checkpoint in adipocyte differentiation, and also plays a critical role in inhibiting the mitochondrial uptake of fatty acids. Inhibition of ACC2 by bioactive food compounds impairs adipocyte differentiation by >80% and causes a 50% body fat loss in Drosophila melanogaster mutants genetically predisposed to storing excess body fat. We have devised an innovative, high-throughput screen for identifying synthetic and natural compounds that increase mitochondrial uptake and oxidation of fatty acids.<br /> <br /> Ohio State University (Richard Bruno): <br /> Epidemiological observations suggest that the presence of nonalcoholic fatty liver disease (NAFLD) dramatically increases the risk for cardiovascular disease (CVD). Thus, we have conducted studies to examine the extent to which phytonutrients regulate oxidative stress and inflammatory responses in experimental and clinical models of NAFLD and CVD. In a high-fat feeding model of NAFLD, we examined the extent to which green tea extract (GTE) protects against liver injury by regulating hepatic and adipose inflammatory responses under the transcriptional control of nuclear factor kappa B (NFkB). Wistar rats were fed a low-fat (LF; 10% kcal) diet containing no GTE or a high-fat (HF; 60% kcal) diet containing 0, 1, or 2% GTE for 8 wks. We then examined whether GTE reduced NFkB activation and expression levels of inflammatory mediators that are regulated in a NFkB-dependent manner. In a separate clinical study, a randomized cross-over trial was conducted in healthy men to examine the extent to which gamma-tocopherol (g-T) supplementation protects against vascular dysfunction otherwise induced by acute hyperglycemia by regulating lipid peroxidation and the ratio of asymmetric dimethylarginine relative to arginine (ADMA/Arg), an index of nitric oxide bioavailability. SUMMARY: Validated dietary approaches are needed to prevent and treat obesity-related disorders, especially cardiovascular disease and nonalcoholic fatty liver disease (NAFLD) that continue to be problematic at the state, national, and global levels. SITUATION: Weight management is well-recognized to reduce the risk of obesity and related disorders, but weight loss has a poor long-term success rate as evidenced by the frequent occurrence of weight regain. This indicates a critical need to develop complementary dietary strategies that regulate body weight and/or its associated inflammatory responses leading to chronic disease. RESPONSE: OARDC/OSU scientists demonstrated that the regular consumption of green tea reduces obesity, fat infiltration to the liver, and inflammation in laboratory animals with NAFLD whereas dietary supplementation of gamma-tocopherol (a unique form of vitamin E) to humans reduces blood vessel dysfunction otherwise induced by elevations in blood sugar. These studies provide the foundational basis for larger scale clinical studies in effort to validate these novel health-promoting dietary approaches.<br /> <br /> Ohio State University (Mark Failla):<br /> Our program is focused on the absorption, metabolism and efficacy of health promoting dietary compounds. During the past year we have used Caco-2 human intestinal cells, mice and human subjects to address questions about carotenoids, isoflavonoids, xanthones, and anthocyanins. A summary of recent findings follows.<br /> <br /> Absorption, metabolism and bioactivity of mangosteen xanthones. There are numerous, largely unsubstantiated, health claims for commercially sold juices and products prepared from tropical fruits and botanicals. One such fruit juice product is prepared from mangosteen for which sales of beverages in the US exceeded $200 million in 2008. To date, the majority of the health claims for mangosteen have been based on cellular studies, limited studies with rodents and two reported human intervention studies with healthy individuals. Slight reductions in a plasma marker of inflammation were noted in the chronic human intervention trial. The primary bioactive component in mangosteen juice products is a family of polyphenolic compounds referred to as xanthones. In order for this compound to promote systemic health, they and/or their bioactive metabolites must be absorbed and delivered to target tissues. As no information is available in the literature on the absorption and metabolism of xanthones, we examined the tissues of mice fed diet with 0.1% alpha-mangostin, the most abundant xanthone in mangosteen pericarp. Chronic consumption of this diet reduced the growth of a HT-29 xenograft by 40%. We also examined plasma and urine from healthy human subjects fed two ounces of mangosteen juice as part of a typical fast food breakfast. We also have found that human cell lines of intestinal, hepatic and immunological origin take up alpha-mangostin and transform it to phase II metabolites and other xanthones. Pre-treatment of these cells with the xanthone decreased secretion of proinflammatory cytokines in response to inflammatory insults. <br /> <br /> Influence of type and amount of dietary fat on the bioaccessibility and bioavailability of bioactive compounds from foods. We have found that fats rich in unsaturated long-chain fatty acids promote the solubilization of carotenoids, isoflavonoids and xanthones in mixed micelles during digestion and in turn enhance uptake by Caco-2 cells. A single meal trial with human subjects examined the effect of 3 types of dietary fat at 3 levels of intake on carotenoid absorption. Both bioaccessibility and bioavailability of hydrocarbon carotenoids was enhanced by co-ingestion of fats rich in long chain, unsaturated fatty acids. The bioaccessibility of isoflavonoids in a soft soy pretzel was not increased by the adding either additional lard or canola oil to the standard formulation. Thus, the soy-based product can serve as a healthy snack food.<br /> <br /> <br /> Retention during cooking and bioaccessibility of provitamin A carotenoids in biofortified cassava. The amount of beta-carotene delivered to the plate after processing cassava according to cultural styles of cooking and ²beta-carotene bioaccessibility increased in proportion to provitamin A content in transgenic high beta-carotene cultivars, as we previously reported for accessions with high provitamin A that were generated by traditional breeding practices. The bioavailability of carotenoids from a vegetable salad was increased in response to the amount of co-consumed fat with a trend towards increased carotenoid absorption when the relative amount of unsaturated fat was elevated.<br /> <br /> <br /> <br /> Effect of structure on anthocyanin stability in the oral cavity. Anthocyanin-rich fruits have exhibited chemopreventive and therapeutic properties in the oral cavity of animal models and humans. Confectionaries and oral gels are being developed to increase retention of dried berries and extracts in the mouth as a means of increasing retention of the compounds in the oral cavity. Information regarding the stability of various anthocyanins from fruit sources in the oral cavity and the comparative bioactivity of the natural compounds vs. spontaneously and enzymatically generated metabolites is very limited. Such information is needed for the strategic development of health-promoting oral delivery devices. We have found that delphindin and petunidin anthocyanins are less stable in saliva and in the human oral cavity than other anthocyanidins. We have also found that mixtures of anthocyanins from different fruits have anti-inflammatory activity in cultures of activated human oral cell lines. This activity for some mixtures was not lost when the majority of the anthocyanins had spontaneously degraded in cell culture medium prior to its addition to the cell lines. This supports the possibility that the phenolics produced during the degradation of the anthocyanins possess anti-inflammatory activity. <br /> <br /> Oklahoma State University (Edralin Lucas):<br /> Effects of mango supplementation on body weight and composition and clinical parameters of obese individuals. Previously, mango fruit (Mangifera indica L.) has been shown to improve body composition and blood glucose in an animal model of diet-induced obesity. The objective of this pilot clinical study was to examine the effects of supplementation of freeze-dried mango fruit on body weight and composition and clinical parameters (i.e. glucose, lipid, liver function, and hematological parameters) in obese adults. Twenty adults (11 males and 9 females) with body mass index of 30-45 kg/m2 participated in the study and were given 10 g of freeze-dried mango daily for 12 weeks. Body composition, anthropometric and clinical parameters were measured at baseline and at the end of supplementation. There were no significant changes in body weight and composition, blood lipids, liver function, and hematological parameters after mango supplementation. However, similar to animal findings, mango significantly reduced blood glucose concentrations. Our findings indicate that regular consumption of mango does not increase body weight and blood glucose of obese individuals.<br /> <br /> Oklahoma State University (Barbara Stoecker):<br /> Relations between consumption of animal source foods and cognitive performance of primary school children in Ethiopia have been examined. Additionally, micronutrient status has been a major focus of completed work. Vitamin D status of rural women in southern Ethiopia was assessed by serum 25(OH)D concentrations, and biomarkers of iodine status in women not consuming iodized salt were measured. The work with iodine has been used to promote legislation in Ethiopia mandating iodization of salt for human consumption. <br /> <br /> To assess relations between consumption of animal source foods (ASF) and cognitive performance, primary school children were selected from five schools in Hawassa, Ethiopia, by two stage random sampling. The Raven's Colored Progressive Matrices (CPM board version) and selected tests from the Kaufman Assessment Battery for Children (KABC-II) were used to assess cognitive performance. Mean individual diet diversity scores were low 3.8 (1.1) and only 15% of children reported consumption of ASF, which included meat, poultry, fish or eggs. Stunted (height-for-age < -2 Z-score) children had lower cognitive test scores compared to children not stunted for several tests. Children who consumed meat, poultry, fish or eggs had higher scores for selected tests. Consumption of ASF and optimal anthropometric status support cognitive function in school children.<br /> <br /> Another study assessed vitamin D status of dark-skinned rural women living at 7 degree North latitude by measuring serum 25(OH)D concentrations. None of the women reported consuming vitamin D rich foods. Fewer than 16% of participants had 25(OH)D concentrations above 50 nmol/L despite extensive sunlight exposure. Furthermore, 15% of women had 25(OH)D < 30 nmol/L a marker for possible risk of deficiency. <br /> <br /> A cross-sectional survey in three rural communities of Sidama Zone, southern Ethiopia assessed urinary iodine concentration (UIC), goiter and dietary intake of iodine in a sample of 202 women. Median UIC was 37.2 µg/L which indicates a significant public health problem. None of the participants ever consumed iodized salt or had ever heard about use of iodized salt. Hence, there is a need to supply iodized salt and educational messages in order to achieve the goal of elimination of iodine deficiency disorders in the community. <br /> <br /> Oregon State University (Emily Ho):<br /> The lab has focused on the examination of the interaction of bioactive nutrients such as sulforaphane and zinc on mechanisms related to cancer and chronic disease development. ACCOMPLISHMENTS: Zinc and chronic disease: Recently we have found that zinc status is compromised with age. Zinc supplementation in older animals reverses age-related zinc deficiency and inhibits age-related immune defects and inflammatory processes. Age-related zinc deficiency may be related to methylation of the zinc transporter ZIP6. We also have preliminary data that suggests that zinc alters DNA methylation patterns and may be a novel mechanism by which zinc affects gene expression and the inflammatory response. We have also identified using untargeted metabolomics strategies that methyl-histidine may be a biomarker for human zinc deficiency. Plant-derived phytochemicals from tea and cruciferous vegetables: We have found that sulforaphane, a chemical found cruciferous vegetables is an inhibitor of histone deacetylases, increases acetylated histone levels and has anti-cancer properties in the prostate. We recently reported that SFN also causes decreases histone methylation, in particular H3K9me3. SFN does not affect H3K9 methyltransferase (SUVH3K9) expression, but alters cellular localization. Other phytochemicals derived from cruciferous vegetables, such as indole-3-carbinol may also have epigenetic targets and inhibit HDAC. This work suggests that phytochemical may have the ability to alter epigenetic events that lead to disease prevention. In human supplementation trials, we have directly compared the effects of the "whole food" (broccoli sprouts) to commercially available supplements. We have found a significant decrease in bioavailability and impact on HDACs with supplements compared to the whole food. Surprisingly, even when supplements are pre-treated with myrosinase, the release of sulforaphane from its glucosinolate precursors in the supplement is limited. Metabolomics in plasma samples from these studies also reveal that targets of SFN from supplements and food sources different significantly. OUTPUTS: 1) Test the effects of zinc status on epigenetics, oxidative stress, inflammation, DNA damage and cancer susceptibility in rodent models and humans. 2) Understand the determinants of bioavailability of phytochemicals derived from cruciferous vegetables. 3) Test the ability of sulforaphane supplementation from various sources (supplement vs. whole food) to reduce the incidence of prostate cancer via epigenetic modifications. OUTCOMES: 1) Identify new risk factors in prostate cancer and offer novel dietary modifications to reduce the incidence of prostate cancer. 2) Establish low dietary zinc as risk factor for inflammatory processes, DNA damage and cancer risk and identify new biomarkers for human zinc deficiency. 3) Establish low cruciferous vegetable intake as a risk factor for the development of prostate cancer by altering histone modifications and cell proliferation pathways. 4) Gain knowledge of the mechanisms behind the health benefits of micronutrients and phytochemicals such as zinc and compounds derived from cruciferous vegetables.<br /> <br /> Purdue University (Connie Weaver):<br /> The effect of high calcium intakes as dairy or calcium carbonate arterial calcification in the Ossabaw miniature pig model is being studied to address the controversy regarding the association of calcium supplementation and cardiovascular disease. Potassium is a shortfall nutrient. Our lab is studying the bioavailability and function of potassium from food and salts.<br /> <br /> Washington State University (Bin Yang):<br /> GOALS/OBJECTIVES/EXPECTED OUTPUTS: 1.Determine the bioavailability (absorption, distribution, metabolism, elimination) of nutrients and other food components and their environmental and genetic determinants. 2. Evaluate the bioactivity of nutrients and other food components in order to elucidate their underlying protective mechanisms. Flavonoids are widely distributed plant secondary metabolites, and they play important roles in preventing cardiovascular disease(Prahalathan, Saravanakumar et al. 2012) and cancer mainly due to its anti-oxidant activity(Spagnuolo, Russo et al. 2012), and even proved activity in promotion of bone health beyond calcium and vitamin D (Weaver, Alekel et al. 2012). Ginkgo leaves and its extracts have been well-known for its activity and used as capsule. Ganoderm lucid has been used to reduce the risk of numerous diseases and maintain good health in traditional Chinese medicine and nutrition since ancient times. Now there is considerable interest in altering the form of dietary flavones glycosides in order to positively affect their bioavailability and their biological activities in humans. GOALS AND OBJECTIVES: Objective 1. Bioavailability of flavonoids: Isolation and enzyme-catalyzed modification of flavonoids from G.lucid and Ginkgo. Objective 2. Evaluate the bioactivity of different flavones glycosides or aglycone in anti-oxidation. METHODS: Objective 1. Bioavailability of flavonoids: Isolation and enzyme-catalyzed alteration of flavonoids from G.lucid and Ginkgo. Flavonoids will be isolated and examined by chromatography and the particular structure will be elucidated by NMR and MS. The glycosides will be modified through glycosidase and glycosyltransferase catalyzed reactions. The absorption of modified glycosides and aglycone will be tested using a gastrointestinal tract simulating system. Objective 2. Evaluate the bioactivity of modified flavonoid glycosides or aglycone in anti-oxidation. Antioxidant activities of flavonoids and flavonoids with modified glycosides from G. lucid will be determined in vitro against different radical systems, such as DPPH (1, 1-diphenyl-2-picrylhydrazyl), ABTS [2,2'-azinobis (3-ethylenebenzothiazoline-6-sulphonic acid)] and hydroxyl radicals, in addition to ferric reducing antioxidant power assay. Anti-oxidant capacities of these flavonoids will be evaluated through cell-based anti-oxidant protection (CAP-e) assay and reactive oxygen species (ROS) formation in polymorphonuclear (PMN) cells (ROS PMN assay).<br />

Publications

Ahmed, K., Y. Li, D.J. McClements, and H. Xiao, Nanoemulsion- and emulsion-based delivery systems for curcumin: Encapsulation and release properties. Food Chemistry, 2012. 132(2): p. 799-807.<br /> <br /> Anderson, D. A., Woeller, C. F., Chiang, E.P., Shane, B. and Stover, P. J. (2012). SHMT anchors the de novo thymidylate synthesis pathway to the nuclear lamina for DNA synthesis. J Biol Chem. 287: 7051-7062.<br /> <br /> Ballard KD, BR Kupchak, BM Volk, A Shkreta, C Liptak, AS Ptolemy, E Mah, MS Kellogg, RS Bruno, RL Seip, CM Maresh, WJ Kraemer, JS Volek. (2012). Acute effects of ingestion of a novel whey-derived peptide on vascular endothelial function in overweight, middle-aged men and women. Br J Nutr, 13:1-12.<br /> <br /> Ballard KD, BR Kupchak, BM Volk, E Mah, A Shkreta, C Liptak, AS Ptolemy, MS Kellogg, RS Bruno, RL Seip, CM Maresh, WJ Kraemer, JS Volek. (2012). Acute effects of ingestion of a novel whey-derived extract on vascular endothelial function in middle-aged men and women. FASEB J, 26:1026.18.<br /> <br /> Beaver, LM, Yu, T, Sokolowoski, E, Williams, DE, Dashwood, RH and Ho, E. (2012) Chemopreventative phytochemical 3,3'-diindolylmethane inhibits histone deacetylases in prostate cancer cells. Tox Appl Pharm, 263:345-51.<br /> <br /> Bhattacharyya MH, Weaver CM. Calcium Isolation from Large-Volume Human Urine Samples for 41Ca Analysis by Accelerator Mass Spectrometry. Appl Rad Isotopes Accepted, 2013.<br /> <br /> Bogale A, Stoecker BJ, Kennedy T, Hubbs-Tait L, Thomas D, Abebe Y, Hambidge KM. (2013) Nutritional status and cognitive performance of mother-child pairs in Sidama, Southern Ethiopia. Matern Child Nutr 9:274-84. <br /> <br /> Bower AM, Park HJ, Chung M-Y, Lee J, Bruno RS. (2012). Green Tea Extract Protects Against Fibrogenesis Associated With Nonalcoholic Steatohepatitis In Diet-Induced Obese Rats. FASEB J, 26:363.6.<br /> <br /> Camara Teixeira D, Malkaram SA, Zempleni J. Enrichment of meiotic recombination hotspot sequences by avidin capture technology. Gene 516:101-106, 2013.<br /> <br /> Caudill, M. A., Miller, J. W., Gregory, J. F. III and Shane, B. Folate, choline, vitamin B12, and vitamin B6. (2012) In Biochemical, Physiological and Molecular Aspects of Human Nutrition, Stipanuk, M. H. and Caudill, M. A., eds., third edition, chapter 25, pp. 565-609, Elsevier, New York.<br /> <br /> Chitchumroonchokchai, C., Thomas-Ahner. J., Li, J., Riedl, K.M., Suksumrarn, S., Clinton, S.K., Kinghorn, A.D., Failla, M.L. (2013) Anti-tumorigenicity of dietary alpha-mangostin in a HT-29 colon cell xenograft model and the biodistribution of xanthone metabolites. Molecular Nutrition and Food Research, 57: 203-211. <br /> <br /> Chung MY, HJ Park, M OConner, J Manautou, RS Bruno. (2012). Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by pro-inflammatory enzymes. J Nutr Biochem, 23(4):361-7.<br /> <br /> <br /> Clifford AJ, Rincon G, Owens JE, Medrano JF, Moshfegh AJ, Baer DJ, Novotny JA. Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults. Lipids Health Dis. 2013 May 8;12(1):66. [Epub ahead of print]<br /> <br /> Davis MR, Hester KK, Shawron KM, Lucas EA, Smith BJ, Clarke SL. Comparisons of the iron deficient metabolic response in rats fed either an AIN-76 or AIN-93 based diet. Nutr Metab (Lond). 2012; 9(1): 95.<br /> <br /> Davis MR, Rendina E, Peterson SK, Lucas EA, Smith BJ, Clarke SL. Enhanced expression of lipogenic genes may contribute to hyperglycemia and alterations in plasma lipids in response to dietary iron deficiency. Genes Nutr. 2012,7(3):415-25.<br /> <br /> Eng WK, Giraud D, Schlegel VL, Wang D, Lee BH, Zempleni J. Identification and assessment of markers of biotin status in healthy adults. Br J Nutr. 2013 Jul:110(2)321-9.<br /> <br /> G/Egziabher T, Stoecker BJ. Vitamin D insufficiency in a sunshine sufficient area: Southern Ethiopia. Food Nutr Bull (In Press). <br /> <br /> G/Egziabher T, Teyikie N, Mulugeta A, Abebe Y, Hambidge KM, Stoecker BJ. Lack of dietary sources of iodine and prevalence of iodine deficiency in rural women from Sidama Zone, Southern Ethiopia. African Journal of Food, Agriculture, Nutrition and Development (In Press).<br /> <br /> Gaurav, M., L. Reddivari, D. Holm and J. Vanamala. 2012. Combined effects of storage and processing on the bioactive compounds and pro-apoptotic properties of color-fleshed potatoes in human colon cancer cells. Journal of Agriculture and Food Chemistry, 60(44):11088-96.<br /> <br /> Girma M, Stoecker BJ, Loha E, Bogale A, Abebe Y, Hambidge KM. Nutritional status and cognitive performance among primary school children in Hawassa Town, Southern Ethiopia (Submitted to Public Health Nutrition).<br /> <br /> Guo Y, E Mah, T Jalili, RS Bruno. (2012). Quercetin Bioavailability And Biotransformation Are Inversely Related To Vitamin C Status In College-Aged Adults. FASEB J, 26: 124.3. <br /> <br /> Gutierrez-Orozco, F., Chitchumroonchokchai, C., Lesinski G.B., Suksamrarn,S., Failla, M.L. (2013) Alpha-Mangostin: Anti-inflammatory activity and metabolism by human cells. J. Agr. Food Chem. 61: 3891-3891. <br /> <br /> Hill KM, Jonnalagadda SS, Albertson AM, Josh NA, Weaver CM. Top food sources contributing to vitamin D intake and the association of ready-to-eat cereal and breakfast consumption habits to vitamin D intake in Canadians and United States Americans. J Food Sci 77:H170-5, 2012.<br /> <br /> Hill KM, Laing EM, Hausman DB, Acton A, Martin BR, McCabe GP, Weaver CM, Lewis RD, Peacock M. Bone turnover is not influenced by serum 25-hydroxyvitamin D in pubertal healthy black and white children. Bone 51:795-799, 2012. <br /> <br /> Hill KM, Martin BR, Wastney ME, McCabe GP, Moe SM, Weaver CM, Peacock M. Oral calcium carbonate affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease. Kidney Intl 2012. doi: 10.1038/ki.2012.403<br /> <br /> Ho E, Dukovcic S, Hobson B, Wong CP, Miller G, Hardin K, Traber MG, Tanguay RL (2012) Zinc transporter expression in zebrafish during development, Comp Biochem Physiol C Toxicol Pharmacol. 155(1):26-32. <br /> <br /> Kim B, S. G. Lee, C. S. Ku, Y. Park, Y. Yang, T. X Pham, C. Wegner, S. I. Koo, O. K. Chun, J. Lee. Comparison of hypolipidemic effects of three berries in diet-induced obese C57BL/6J mice. FASEB J 2013; 27:1078.12.<br /> <br /> Kim JH, D. Gilliard, D. J. Good, and Y. Park, Preventive Effects of Conjugated Linoleic Acid on Obesity by Improved Physical Activity in Nescient Basic Helix-Loop-Helix 2 Knockout Mice During Growth Period, Food Function, 2012. 3:1280-1285.<br /> <br /> Kim JH, J. Kim, and Y. Park, trans-10,cis-12 Conjugated Linoleic Acid Enhances Endurance Capacity by Increasing Fatty Acid Oxidation and Reducing Glycogen Utilization in Mice, Lipids, 2012. 47: 855-863.<br /> <br /> Kim, B., A. Perkins, J. Lee. Regulation of genes involved intestinal cholesterol metabolism by polyphenol-rich black currant extract in Caco-2 cells. FASEB J 2013; 27:1078.8.<br /> <br /> Komanpatana, K., Giusti, M.M., Chitchumronchokchai, C., MorenoCruz, M., Riedl, K.M., Kumar, P., Failla, M.L. Susceptibility of anthocyanins to ex vivo degradation in human saliva. (2012) Food Chem. 135: 738-747.<br /> <br /> Larson A, MAH Witman, Y Guo, K Black, M Hayman, RS Richardson, RS Bruno, T Jalili, JD Symons. (2012). Acute, quercetin-induced reductions in blood pressure in hypertensives are not secondary to lower plasma angiotensin converting enzyme activity or endothelin-1:nitric oxide. Nutr Res, 32(8):557-64.<br /> <br /> Legette LL, Lee WH, Martin BR, Story JA, Campbell JK, Weaver CM. Enhanced magnesium absorption and inulin-based fibers exert chronic effects on calcium utilization in a postmenopausal rodent model. J Food Sci 77:89-94, 2012.<br /> <br /> Lesmes, U. and D.J. McClements, Controlling lipid digestibility: Response of lipid droplets coated by beta-lactoglobulin-dextran Maillard conjugates to simulated gastrointestinal conditions. Food Hydrocolloids, 2012. 26(1): p. 221-230.<br /> <br /> Li Y, Hassan YI, Moriyama H, Zempleni J. Holocarboxylase synthetase interacts physically with euchromatic histone-lysine N-methyltransferase, linking histone biotinylation with methylation events. J Nutr Biochem (in press).<br /> <br /> Li, L., Yang, Y., Xu, Y., Owsiany, K., Welch, R., Chitchumroonchokchai, C., Lu, S., Van Eck, J., Deng, X., Failla, M., Thannhauser, T.W. (2012) The Or gene enhances carotenoid accumulation and stability during post-harvest storage of potato tubers. Molecular Plant 5: 339-352.<br /> <br /> Li, Y., H. Xiao, and D.J. McClements, Encapsulation and Delivery of Crystalline Hydrophobic Nutraceuticals using Nanoemulsions: Factors Affecting Polymethoxyflavone Solubility. Food Biophysics, 2012. 7(4): p. 341-353.<br /> <br /> Li, Y., J. Kim, Y. Park, and D.J. McClements, Modulation of lipid digestibility using structured emulsion-based delivery systems: Comparison of in vivo and in vitro measurements. Food & Function, 2012. 3(5): p. 528-536.<br /> <br /> Lucas EA, Brown A, Li W, Peterson SK, Wang Y, Perkins-Veazie P, Clarke SL, Smith BJ. Mango modulates blood glucose similar to rosiglitazone without compromising bone parameters in mice fed high fat diet. J Pharm and Nutrition Sciences 2012; 2(2): 115-126. <br /> <br /> Mah E and RS Bruno. (2012). Postprandial hyperglycemia on vascular endothelial function: mechanisms and consequences. Nutr Res, 32(10): 727-40. <br /> <br /> Mao, Y.Y. and D.J. McClements, Influence of electrostatic heteroaggregation of lipid droplets on their stability and digestibility under simulated gastrointestinal conditions. Food & Function, 2012. 3(10): p. 1025-1034.<br /> <br /> Masterjohn C and RS Bruno. (2012). Therapeutic potential of green tea on nonalcoholic fatty liver disease. Nutr Rev, 70(1): 41-56. (Invited).<br /> <br /> Masterjohn C, E Mah, Y Guo, SI Koo, RS Bruno (2012). y-Tocopherol abolishes postprandial increases in plasma methyglyoxal following an oral dose of glucose in healthy, college-aged men. J Nutr Biochem, 23(3):292-8. <br /> <br /> Matalanis, A. and D.J. McClements, Impact of Encapsulation Within Hydrogel Microspheres on Lipid Digestion: An In Vitro Study. Food Biophysics, 2012. 7(2): p. 145-154.<br /> <br /> Mavanji V, Teske JA, Billington CJ, Kotz CM. Partial sleep deprivation by environmental noise increases food intake and body weight in obesity resistant rats. Obesity (Silver Spring). (in press).<br /> <br /> McClements, D.J. and H. Xiao, Potential biological fate of ingested nanoemulsions: influence of particle characteristics. Food & Function, 2012. 3(3): p. 202-220.<br /> <br /> McNay EC, Teske JA, Kotz CM, Dunn-Meynell A, Levin B, McCrimmon RJ and Sherwin RS. Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity in the absence of hyperphagia or insulin resistance: a model for weight gain associated with intensive insulin therapy. American Journal of Physiology Endocrinology and Metabolism. 304(2):131-8, 2012.<br /> <br /> Moseley K, Weaver C, Appel L, Sebastian A, Sellmeyer DE. Potassium citrate supplementation results in sustained improvement in calcium balance in older men and women. J Bone Miner Res 28:497-504, 2013.<br /> <br /> Novotny JA, Fadel JG, Holstege DM, Furr HC, Clifford AJ. This kinetic, bioavailability, and metabolism study of RRR-alpha-tocopherol in healthy adults suggests lower intake requirements than previous estimates. J Nutr. 2012 Dec;142(12):2105-11. doi: 10.3945/jn.112.166462. Epub 2012 Oct 17. Author Video <br /> <br /> Osborne DL, Weaver CM, McCabe LD, McCabe GP, Novotny R, Van Loan MD, Going S, Matkovic V, Boushey CJ, Savaiano DA. Body size and pubertal development explain ethnic differences in structural geometry at the femur in Asian, Hispanic, and white early adolescent girls living in the U.S. Bone 51:888-95, 2012.<br /> <br /> Palacios C, Wigertz, Braun M, Martin BR, McCabe GP, McCabe L, Pratt JH, Peacock M, Weaver CM. Magnesium retention from metabolic balance studies in female adolescents: impact of race, dietary salt and calcium. Am J Clin Nutr 97:1014-9, 2013.<br /> <br /> Pangilinan, F., Molloy, A. M., Mills, J. L., Troendle, J. F., Parle-McDermott, A., Signore, C. C., OLeary, V., Chines, P., Dolle, J., Geiler, K., Mitchell, A., VanderMeer, J., Krebs, K. M., Sanchez, A., Cornman-Homonoff, J., Stone, N., Conley, M., Kirke, P. N., Shane, B., Scott, J. M. and Brody, L. C. (2012). Evaluation of Common Genetic Variants in 82 Candidate Genes as Risk Factors for Neural Tube Defects. BMC Medical Genetics 13: 29. (http://www.biomedcentral.com/1471-2350/13/29).<br /> <br /> Parasramka, M, Wang, R., Saeed, H., Williams, DE, Ho, E, and Dashwood, RH. (2012) A role for low-abundance miRNAs in colon cancer: the miR-206/Krüppel-like factor 4 (KLF4) axis. Clin Epigenetics. 4(1):16.<br /> <br /> Parasramka, M., Dashwood, WM, Wang, R., Amir, A, Ho, E, Williams, DE and Dashwood, RH (2012) MicroRNA profiling of carcinogen-induced rat colon tumors and the influence of dietary spinach. Mol Nutr Food Res. 56:1259-69.<br /> <br /> Park HJ, J-Y Lee, M-Y Chung, Y-K Park, AM Bower, SI Koo, C Giardina, RS Bruno. (2012). Green tea extract suppresses NFkB activation and inflammatory responses in diet-induced obese rats with nonalcoholic steatohepatitis. J Nutr, 142(1):57-63.<br /> <br /> Park YH and Y. Park (2012) Chapter 22: Conjugated Fatty Acids as a Prevention Tool for Obesity and Osteoporosis, In: Emerging Trends in Dietary Components for Preventing and Combating Diseases, pp393-405, Editors: B. S. Patil, G. K. Jayaprakasha, K. N. C. Murthy, N. P. Seeram, ACS Book.<br /> <br /> Pei R, SW Leonard, MG Traber, RS Bruno. (2012). alpha-Tocopherol Supplementation Reduces y-Tocopherol- Dependent Scavenging Of Reactive Nitrogen Species By Decreasing y-Tocopherol. FASEB J, 26:365.6.<br /> <br /> Perez-Leighton CE, Boland, K, Teske JA, Billington CJ, Kotz CM. Behavioral responses to orexin, orexin receptor gene expression and intrinsic physical activity contribute to individual sensitivity to obesity. American Journal of Physiology Endocrinology and Metabolism. 303(7):E865-E874, 2012.<br /> <br /> Pool, H., S. Mendoza, H. Xiao, and D.J. McClements, Encapsulation and release of hydrophobic bioactive components in nanoemulsion-based delivery systems: impact of physical form on quercetin bioaccessibility. Food & Function, 2013. 4(1): p. 162-174.<br /> <br /> Pool, H., D. Quintanar, J.D. Figueroa, J.E.H. Bechara, D.J. McClements, and S. Mendoza, Polymeric Nanoparticles as Oral Delivery Systems for Encapsulation and Release of Polyphenolic Compounds: Impact on Quercetin Antioxidant Activity & Bioaccessibility. Food Biophysics, 2012. 7(3): p. 276-288.<br /> <br /> Qian, C., E.A. Decker, H. Xiao, and D.J. McClements, Nanoemulsion delivery systems: Influence of carrier oil on beta-carotene bioaccessibility. Food Chemistry, 2012. 135(3): p. 1440-1447.<br /> <br /> Regassa N, Stoecker BJ. (2012) Household food insecurity and hunger among households in Sidama district, southern Ethiopia. Public Health Nutrition 15:1276-83. <br /> <br /> Rios-Avila L, Pestinger V, Wijeratne SSK, Zempleni J. K16-biotinylated histone H4 is overrepresented in repeat regions and participates in the repression of transcriptionally competent genes in human Jurkat lymphoid cells. J Nutr Biochem 23:1559-1564, 2012. <br /> <br /> Schaevitz, L. S., Picker, J. D., Rana, J., Kolodny, N. H., Shane, B., Berger-Sweeney, J.E. and Coyle, J.T. (2012). Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders. Dev. Neurobiol. 72: 891-905. doi: 10.1002/dneu.21000.<br /> <br /> Shane, B. (2012). Folate-responsive birth defects: of mice and women. Am. J. Clin. Nutr. 2012; 95:1-2.<br /> <br /> Shorey LE, Ho E, Dashwood RH, Williams DE, Benninghoff AD (2012) 3,3'-Diindolylmethane induces G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia cells. PloS ONE 7(4):e34975. Epub 21012 Apr 13.<br /> <br /> Simmons, A.L., Chitchumroonchokchai, C. Vodovotz, Y., Failla, M.L. (2012) Isoflavone retention during processing, bioaccessibility, and transport by Caco-2 Cells: Effects of source and amount of fat in a soy soft pretzel. J. Agr. Food Chem. 60: 12196-12203.<br /> <br /> Simon RR, Borzellaeca JF, DeLuca HF, Weaver CM. Safety assessment of the post-harvest treatment of button mushrooms (Agaricus bisporus) using ultraviolet light. Food Chem Toxicol 56:278-289, 2013.<br /> <br /> Singh MP, Wijeratne SSK, Zempleni J. Biotinylation of lysine 16 in histone H4 contributes toward nucleosome condensation. Arch Biochem Biophys 529:105-111, 2013.<br /> <br /> Takedachi M, Oohara H, Smith BJ, Iyama M, Kobashi M, Maeda K, Long CL, Humphrey MB, Stoecker BJ, Toyosawa S, Thompson LF, Murakami S. (2012) CD73-generated adenosine promotes osteoblast differentiation. J Cell Phys 227: 2622-31.<br /> <br /> Teske JA, Billington CJ, Kuskowski M, Kotz CM. Spontaneous physical activity protects against fat mass gain. International Journal of Obesity 36(4): 603-613, 2012.<br /> <br /> Tokle, T., U. Lesmes, E.A. Decker, and D.J. McClements, Impact of dietary fiber coatings on behavior of protein-stabilized lipid droplets under simulated gastrointestinal conditions. Food & Function, 2012. 3(1): p. 58-66.<br /> <br /> Troncoso, E., J.M. Aguilera, and D.J. McClements, Fabrication, characterization and lipase digestibility of food-grade nanoemulsions. Food Hydrocolloids, 2012. 27(2): p. 355-363. <br /> <br /> Troncoso, E., J.M. Aguilera, and D.J. McClements, Influence of particle size on the in vitro digestibility of protein-coated lipid nanoparticles. Journal of Colloid and Interface Science, 2012. 382: p. 110-116.<br /> <br /> Vanamala, J, Radhakrishnan, S, Reddivari, L, Massey, A. 2012. Anthocyanins as apoptotic agents. Book chapter in Novel Apoptotic Regulators in Carcinogenesis, Ed. George Chen, The Springer Press. <br /> <br /> Victoria-Campos, C.I., Ornelas-Paz, J.J., Yahia, E.M., Failla, M.L. (2013) Effect of interaction of heat-processing and fat type on the micellarization of individual lipid soluble pigments from pungent peppers (Capsicum annuum). J. Agr. Food Chem. 61: 3642-3653.<br /> <br /> Warden ST, Hill KM, Ferira AJ, Laing EM, Martin BR, Hausman DB, Weaver CM, Peacock M, Lewis RD. Racial differences in cortical bone and their relationship to biochemical variables in black and white children in the early stages of puberty. Osteoporosis Intl. 2012. DOI 10.1007/s00198-012-2174-8<br /> <br /> Wastney M, Lee W, Jackson GS, Alloosh M, Sturek, Lachcik P, Peacock M, Martin B, Weaver CM. Soft tissue calcification in the Ossabaw miniature pig: experimental and kinetic modeling studies. Osteoporos Intl 2012. DOI 10.1007/s00198-012-2229-x<br /> <br /> Wegner C., B. Kim, Y. Yang, Y. Park, S. I. Koo, J. Lee. 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Impact Statements

1. Insufficient sleep promotes excessive energy intake and fatigue, which reduces energy expenditure and increases risk for bacterial infection, obesity, insomnia, personal injury and reduced quality of life. University of Arizona (Jennifer Teske)
2. Neural tube defects are the most common birth defects in humans and identification of genetic risk factors for this condition will allow screening to identify at risk individuals. Recently, concerns have been raised about increased cancer risk and exacerbation of B12 deficiency by folate fortification. The models we have developed may indicate whether chronic disease risk can be modified by dietary changes and may shed some insight into possible adverse effects of folate fortification. University of California, Berkeley (Barry Shane)
3. We provide new information on the importance of the homeostatic role of cholesterol metabolism on folate retention in mouse models. Recent work identified the role of niacin (also known as vitamin B3) on early hepatic HDL formation through transcription of ABCA1. We have also identified polymorphisms important in carotenoid metabolism. The biological effects of the eccentric cleavage products of beta-carotene especially on lipid metabolism and oxidative stress, are an exciting area of future study. University of California, Davis (Andrew Clifford)
4. In summary, a compartmental model has been developed that describes RRR-alpha-tocopherol kinetics in healthy adults by focusing on the absorption, storage, and elimination of RRR-alpha-tocopherol. Our compartmental model will be useful for the development of improved RDA values for vitamin E. Moreover, these results provide multiple indications that the current EAR and RDA for vitamin E may be set higher than necessary. University of California, Davis (Andrew Clifford)
5. For the first time we show in a pig model that potato diets even after processing (raw/baked/chips) suppressed colonic, mesenteric and systemic oxidative stress and inflammatory markers compared to the high-fat control to levels similar to that of normal, standard diet fed animals. Results of prevention study demonstrate that both WP and PP (raw/baked/chips) diets were about effective in suppressing high-fat diet elevated oxidative stress and inflammatory biomarkers. Colorado State University (Jairam Vanamala)
6. Polyphenols found in green tea and berries regulate cholesterol metabolism, which is likely to increase TICE. As TICE is known to play an important role in removing cholesterol from the body, the polyphenols can reduce CHD risk. University of Connecticut (Sung Koo and Ji-Young Lee)
7. Functional foods with improved health benefits can be designed by developing food-grade structured delivery systems for bioactive components. University of Massachusetts (Eric Decker and Yeonhwa Park)
8. Biotin and folate synergize at the epigenetic level to repress pro-inflammatory cytokines, decreasing the risk for inflammatory bowel disease. Natural and synthetic compounds interact with acetyl-CoA carboxylase 2, thereby causing a 50% body fat loss and decreasing the risk for obesity-related diseases. University of Nebraska, Lincoln (Janos Zempleni)
9. Our better understanding phytonutrients such as vitamin E and those present in green tea are expected to result in novel dietary practices that promote optimal health in humans and potentially lead to innovative agricultural practices that enhance phytonutrient enrichment in crops and/or complementary efforts that better our ability to isolate and characterize these important dietary agents. Ohio State University (Richard Bruno)
10. Our program is focused on the absorption, metabolism and efficacy of health promoting dietary compounds. During the past year we have used Caco-2 human intestinal cells, mice and human subjects to address identify mechanisms around absorption and bioactivity of carotenoids, isoflavonoids, xanthones, and anthocyanins. Ohio State University (Mark Failla)
11. Effects of mango supplementation on body weight and composition and clinical parameters of obese individuals: Mango significantly reduced blood glucose concentrations. Our findings indicate that regular consumption of mango does not increase body weight and blood glucose of obese individuals. Oklahoma State University (Edralin Lucas)
12. Relations between consumption of animal source foods and cognitive performance of primary school children in Ethiopia have been examined. Micronutrient status has also been a major focus. Vitamin D status of rural women in southern Ethiopia was assessed by serum 25(OH)D concentrations, and biomarkers of iodine status in women not consuming iodized salt were measured. The work with iodine has been used to promote legislation in Ethiopia mandating iodization of salt for human consumption. Oklahoma State University (Barbara Stoecker)
13. To assess relations between consumption of animal source foods (ASF) and cognitive performance, primary school children were selected from five schools in Hawassa, Ethiopia, by two stage random sampling. Consumption of ASF and optimal anthropometric status support cognitive function in school children. Oklahoma State University (Barbara Stoecker)
14. Another study assessed vitamin D status of dark-skinned rural women living at 7æ N latitude by measuring serum 25(OH)D concentrations. None of the women reported consuming vitamin D rich foods. Fewer than 16% of participants had 25(OH)D concentrations above 50 nmol/L despite extensive sunlight exposure. Furthermore, 15% of women had 25(OH)D < 30 nmol/L a marker for possible risk of deficiency. Oklahoma State University (Barbara Stoecker)
15. A cross-sectional survey in three rural communities of Sidama Zone, southern Ethiopia assessed urinary iodine concentration (UIC), goiter and dietary intake of iodine in a sample of 202 women. Median UIC was 37.2 µg/L which indicates a significant public health problem. None of the participants ever consumed iodized salt or had ever heard about use of iodized salt. Hence, there is a need to supply iodized salt and educational messages in order to achieve the goal of elimination of iodine deficiency disorders in the community. Oklahoma State University (Barbara Stoecker)
16. Diet plays an important role in mitigating the development and progression of several cancers, including prostate. This work will form the basis for future work and larger trials to identify effective dietary intervention strategies that are broadly applicable nutrition recommendations and will significantly reduce the burden of prostate cancer. Oregon State University (Emily Ho)
17. The effect of high calcium intakes as dairy or calcium carbonate arterial calcification in the Ossabaw miniature pig model is being studied to address the controversy regarding the association of calcium supplementation and cardiovascular disease. Potassium is a shortfall nutrient. Our lab is studying the bioavailability and function of potassium from food and salts. Purdue University (Connie Weaver)
18. Flavonoids are polyphenolic compounds found in many plant foods. Epidemiological studies have shown that flavonoids may play a dietary role on reducing the risk from chronic diseases, such as cardiovascular disease and cancer, by functioning as antioxidants. The relationship between structure and anti-oxidatic activity of flavonoids from Ginko and Ganoderma Lucid will be revealed. Washington State University (Bin Yang)

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