Brief Summary of Minutes of Annual Meeting

Meeting was called to order August 5, 2015 at 8:00 a.m. MST. Welcome and introductions: Participants were welcomed by the host and Meeting Chair, Dr. David Sands, Montana State University (MSU), Plant Science and Plant Pathology; Dr. Charles Boyer, Dean of MSU College of Agriculture; Dr. Allison Harmon, Dean of MSU College of Health and Human Services; and Dr. Tammy Bray, Dean, College of Public Health and Human Sciences, Oregon State University (Administrative Advisor). Dr. Deirdra Chester, NIFA Program Leader, joined the meeting via Skype and provided an update on the NIFA budget and current and future funding opportunities. Dr. Juan Andrade was elected by the members present to be the chair of the next annual meeting. He will coordinate next year’s W3002 meeting in Urbana, Illinois, targeted for late May, 2016. Dr. Brian Lindshield, Kansas State University, was selected to be secretary. Campus Tour of the Montana State University Plant Growth Center, Ag BioScience Building and BioChemistry Building (Dr. David Sands, Dr. Chaofu Lu, Dr. Edward Dratz). Each W3002 Investigator attending the meeting provided an oral progress report in the following order: 1) ‘Diet, Gut Biome, and Bone,’ Connie Weaver, Purdue University 2) ‘Vitamin E Pharmacokinetics in Metabolic Syndrome Adults,’ Rich Bruno, Ohio State University 3) ‘Dietary Factors that Mitigate Inflammation and Cancer,’ Emily Ho, Oregon State University 4) ‘Role of Astaxanthin in the Prevention of Liver Fibrosis,’ Ji-Young Lee, University of Connecticut 5) ‘Contribution of Conjugated Linoleic Acid in Adipocyte, Muscle and Bone Metabolisms,’ Yeonhwa Park, University of Massachusetts 6) ‘Sleep Deprivation Reduces Energy Expenditure,’ Jennifer Teske, University of Arizona 7) ‘Protein Quality and Micronutrient Bioavailability of Extruded Corn, Soy, Sorghum and Cowpea Fortified-blended Foods,’ Brian Lindshield, Kansas State University 8) ‘Technologies to Assess Nutrient Status In and Deliver Micronutrients to Low-income Populations,’ Juan Andrade, University of Illinois 9) ‘Micronutrient Studies in Ethiopia,’ Barbara Stoecker, Oklahoma State University 10) ‘The Four Horseman and The Breeder’s Dilemma,’ David Sands, Montana State University Discussion Overall - Discussion regarding more connections between trace element intake and diseases. Dr. Sands - The soil source of these trace elements is important to consider. All - Ideas on methods on how to use mice models. Regarding fortified food blends and international nutrition work, there was discussion on standards and regulations that place constraints on nutritional advancement. Cultural models – for international work, domestic development and Native American nutrition Dr. Dingbo Daniel Lin, Department of Nutritional Sciences, Oklahoma State University (New-W3002 participant), gave a presentation on ‘Overnutrition and BCO2 in the Development of Type 2 Diabetes.’ Interspersed within the W3002 presentations, the following invited speakers from Montana State University gave brief reports on related research to W3002: 1) ‘Microbiome’: Dr. Seth Walk, Dr. Carl Yeoman, Pilar Manrique 2) ‘Plasmid Curing’: undergraduate students Amanda Leckband and Andrew Helming 3) ‘Nutrition Research on US Reservations’: Dr. Holly Hunts, Dr. Edward Dratz 4) ‘Low Glycemic Potatoes’: Dr. Alice Pilgeram The meeting adjourned on August 6, 2015, 3:00 p.m.

The strength of this group can be indicated by their expressed interest in forming collaborative units based on common interests. We have numerous examples of suggestions for collaborations. Nutritional research, especially when combined with plant breeding can have a great impact on overall health and wellness of a population. The process of improving diets involves defining nutritional components, developing assays, creating public awareness of the resulting nutritionally improved food products, and finally incorporation into available products for consumers. Many of these collaborations were centered on eventual production of medically driven niche market foods for diabetics, celiac disease sufferers and similar groups. W3002 Objectives 1. Determine the bioavailability (absorption, distribution, metabolism, elimination) of nutrients and other food components. 2.Evaluate the bioactivity of nutrients and other food components in order to elucidate their underlying protective mechanisms. University of Arizona (Jennifer Teske). Short-term Outcomes: i) adopted technology to quantify components of total energy expenditure; ii) Presentation skills training for oral and posters for 1 doctoral student, 2 Master’s degree students, 4 undergraduates, and 2 high school students; iii) Students received 4 awards based on research. Outputs: i) One oral presentation on research presented by undergraduate student at an International Scientific conference; ii) Six poster presentations on research presented by doctoral (2 posters), high school (3 posters), Master’s degree (1 poster) students; iii) Research opportunities provided for 1 doctoral student, 2 Master’s degree students, 4 undergraduates, and 2 high school students. Most activities were associated with the use of the integrated equipment high-resolution indirect calorimetry, EEG/EMG recordings and infrared beam-break activity sensors to determine metabolic rate during rest, rapid eye movement sleep, non-rapid eye movement sleep, and high and low intensity physical activity. Milestones associated with project: to quantify energy expenditure due to low and high intensity physical activity. 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 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. University of Connecticut (Ji-Young Lee). I) Obesity is closely tied to hyperlipidemia, chronic inflammation, and insulin resistance. To gain insight into the effect of polyphenol-rich blackcurrant extract (BCE) on obesity-associated abnormalities, C57BL/6J mice a high fat/high cholesterol diet supplemented with 0.1% BCE for 12 wk. Plasma total cholesterol and glucose, liver steatosis, macrophage infiltration in adipose tissue were all significantly lower with BCE supplementation compared with control. Ex vivo analysis of splenocytes isolated from control and BCE-fed mice showed that upon lipopolysaccharide stimulation, the expression of tumor necrosis factor ? and interleukin 1 ? were significantly reduced in the BCE group. OUTCOME: BCE supplementation may be beneficial to prevent metabolic disturbance and chronic inflammation in obesity. II) We explored if the post-transcriptional regulation of LDL receptor (LDLR) by BCE involves proprotein convertase subtilisin/kexin type 9 (PCSK9) compared with chockberry extract (CBE). PCSK9 mRNA and protein were drastically increased, while LDLR was markedly induced, by BCE and CBE. However, when Caco-2 cells were treated with rapamycin, a mechanistic target of rapamycin C1 inhibitor, together with BCE or CBE, rapamycin partly abolished the induction of LDLR protein by BCE, but with no effect on CBE-induced LDLR protein. Importantly, BCE significantly increased transintestinal cholesterol efflux of LDL-derived cholesterol compared to control. OUTCOME: BCE induces TICE via the post-transcriptional induction of LDLR expression partly by mTORC1-dependent, but PCSK9-independent, pathway in the intestine. III) Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease, the most common chronic liver disease in the U.S. Fibrosis, a feature of NASH, results from the dysregulation of fibrogenesis in hepatic stellate cells (HSCs). We investigated whether astaxanthin (ASTX), a xanthophyll carotenoid, can inhibit HSC activation. In LX-2 cells, accumulation of ROS induced by tert-butyl hydrogen peroxide and TGF?1, a key fibrogenic cytokine, was abolished by ASTX. ASTX significantly decreased TGF?1-induced ?-smooth muscle actin (?-SMA) and procollagen type 1, alpha 1 (Col1A1) mRNA as well as ?-SMA protein levels. Knockdown of Smad3 revealed Smad3 is required for ASTX to block TGF?1-induced fibrogenic gene expression. ASTX attenuated TGF?1-induced Smad3 phosphorylation and nuclear translocation with a concomitant inhibition of Smad3, Smad7, TGF? receptor I (T?RI), and T?RII expression. The inhibitory effect of ASTX on HSC activation was confirmed in primary HSCs as evidenced by decreased mRNA and protein levels of ?-SMA during HSC activation. Taken together, ASTX exerted anti-fibrogenic effects by blocking TGF?1-signaling and resulting activation of Smad3 in HSCs. University of Illinois, Urbana-Champaign (Juan Andrade). Our research focuses on using low-cost technologies or approaches to improve nutrition in developing countries. The following research themes have been pursued and built upon: 1) development of an immunological base photonic crystal biosensor for the assessment of iron deficiency anemia; 2) development of lipid based dietary supplements to treat acute malnutrition. OUTPUTS: I) Biosensor: a proof-of-concept platform using photonic crystal technology for detection and quantification of soluble transferrin receptor was developed. The biosensor combines extraction using magnetic properties of iron oxide nanoparticles with detection on a photonic crystal platform. Bias of quantification of control serum in biosensor is similar to that from commercial ELISAs. II) Lipid based supplements: a lipid nutrition supplement (LNS) for the prevention and treatment of acute malnutrition without edema was formulated. The product was evaluated in terms of stability and sensory acceptability with subjects in India. The Mansinhbhai Institute of Dairy & Food Technology and Dudhsagar Dairy are major partners for implementation. OUTCOMES: I) Biosensor (knowledge): the isolation of biomarkers of interest was improved using the magnetic properties of iron oxide nanoparticles. Non-specific binding was reduced due to isolation of antigens before detection. II) Lipid based supplement (knowledge): the formulation of LNS for India can lead to cost savings as production can be accomplished in India using local staples. Kansas State University (Brian Lindshield). We have focused on the potential of sorghum and cowpeas instead of corn and soybeans to produce micronutrient fortified-blended foods (FBFs) that are commonly used for food aid. Two white and one red blend of sorghum-cowpea with SPI or WPC, white sorghum-soy, extruded corn-soy blend, CSB+ (current USAID FBF), and AIN-93G were fed ad libitum to 21-23 day old male weanling Sprague-Dawley rats (n=10) for 4 weeks, while measuring food intake and weights. Blend nutritional contents, anthropometric, and micronutrient data were analyzed post hoc. The CSB+ had significantly lower weight gain, caloric efficiency, protein efficiency, length, and food intake. Compared with AIN-93G and white sorghum-cowpea with WPC, the SPI FBF group had significantly lower caloric efficiency. There were no significant differences between WPC FBFs groups. University of Maine (Dorothy Klimis-Zacas). The Metabolic syndrome (MetS) is a major public health problem in the United States. The MetS is characterized by the concurrent presence of obesity, dyslipidemia, insulin resistance, glucose intolerance and hypertension, and other associated metabolic abnormalities. Finding economic and effective ways to prevent and reverse the MetS is extremely important for public health and the health care system, especially considering that its prevalence is dramatically increasing among the US population. Wild blueberries are among the commercially available fruits and vegetables that contain the highest levels of antioxidant polyphenols, mostly anthocyanins (ACNs). Past research in our laboratory has documented that wild blueberries beneficially affect the cardiovascular system and regulate vasomotor tone and arterial metabolism in animal models of normal endothelial function but also dysfunction, correct/normalize the dyslipidemia associated with the MetS and attenuate the inflammatory state. Preliminary results on the effects of wild blueberry consumption on plasma markers and gene expression related to glucose metabolism in the obese Zucker rat (OZR), an experimental model of metabolic syndrome and their lean littermate (LZR), documented that consumption of an 8% enriched wild blueberry diet (WB) for 8 weeks resulted in significant reduction of plasma glycated hemoglobin HbA1c, RBP4, and resistin concentrations in OZR. Additionally, following WB consumption, resistin expression was significantly down regulated in the liver of both OZR and LZR while RBP4 expression was significantly down regulated in the adipose tissue of both OZR and LZR. Thus, wild blueberry consumption normalizes some markers related to glucose metabolism and gene expression in the OZR, but has no effect on fasting blood glucose or insulin concentration. OUTPUTS: Results from the period covered in this report were disseminated at the Experimental Biology Meetings, April 2015, through published articles, presented at invited lectures and through the media (newspaper articles, blogs and interviews). University of Massachusetts (Yeonhwa Park). We have studied various bioactive food components for their bioavailability and metabolism. Consumption of lipophilic bioactive agents (such as fucoxanthin, nobiletin, oil-soluble vitamins, conjugated linoleic acid) may reduce the incidences of certain chronic diseases. However, their utilization in foods is currently limited because of their poor water-solubility, high melting point, low bioavailability, and chemical instability. We have examined the impact of a number of different factors on the encapsulation, protection, and release of lipophilic bioactive agents, including carrier oil type, particle size, and emulsifier type. In addition, we also investigated the role of nobiletin and its colonic metabolites in a colitis-associated colon carcinogenesis model. This information has enabled us to identify mechanisms of lipophilic bioactives as well as to develop optimized delivery systems that can be used to incorporate lipophilic bioactive agents into foods and increase their oral bioavailability. Montana State Univeristy (David Sands). The research at Montana State University has involved coordination between four laboratories, and has emphasized development of high omega-3 animal feeds, and microgreens made with Camelina sativa, and low glycemic lines of potatoes. Camelina sativa is a new omega-3 oil and protein crop that in many ways rivals soy. It is fed to chickens for production of high omega-3 eggs and it is now being fed on an experimental basis to Tilapia for the same goal. Camelina microgreens are high in omega-3 fatty acids and can be grown at home for a year-round source of fresh greens. Steps are being made to introduce them into the restaurant industry through a kitchen growth chamber company. Aiming to develop a more diabetic-friendly potato, seven lines of potatoes that are lower in glycemic index are being analyzed for human consumption. A Sentinel Seed Strip is under development for use as an in-garden and on-farm assay of soil nutrient deficiencies. A natural plasmid curing agent(s) is being explored for food security use in reducing the impact of plasmid-mediated diseases. PrOatina, a high-protein, low glycemic hull-less oat is being pearled to remove bitter saponins and increase similarity to rice. OUTPUTS: I) Advanced testing of low glycemic potatoes for introduction into the retail market. II) Development of microgreens of Camelina sativa for the home and restaurant market. III) Development of tests for plasmid curing agents in crop plants. IV) Development of Sentinel Seed Strips to improve the detection of soil minerals deficiencies that lead to foods that are likewise deficient in essential mineral nutrients. V) Development of a less-bitter high protein oat through a saponin-removal pearling process. OUTCOMES: I) Identify low glycemic potato lines for possible value in obesity mitigation. II) Establish Camelina microgreens as a source of omega-3 fatty acids. Lower glucosinolate lines are now available. III) Establish a Sentinel Seed System to enable gardeners and subsistence farmers to know what elements are deficient in their soil. University of Nebraska, Lincoln (Janos Zempleni). We have continued our research of bioactive food compounds and their effects on human health along the following lines. (1) We have discovered synthetic and natural inhibitors of holocarboxylase synthetase (HLCS). The studies of natural HLCS inhibitors focused on resveratrol metabolites in grape products. Using these inhibitors we demonstrated that resveratrol metabolites cause a decrease in body fat mass in Drosophila melanogaster mutants that are genetically predisposed to high body fat mass, but by inhibition of insulin receptor signaling. (2) We have developed a high throughput screening assay for assessing the mitochondrial localization of proteins. Using this assay, we are in the process of screening large libraries (collections) of natural and synthetic molecules that prevent the anchoring of acetyl-CoA carboxylase 2 (ACC2) in the mitochondrial membrane. Theoretically, ACC2 inhibitors increase fatty acid oxidation and contribute toward a lean phenotype and metabolic health. (3) We have continued to shift the focus of our research program away from biotin metabolism and HLCS catalysis to a novel class of bioactive food compounds that we have discovered, i.e., microRNAs packaged in extracellular vesicles (EVs) in cow’s milk and chicken eggs. Briefly we have demonstrated that 1) human intestinal and vascular endothelial cells transport EVs and their microRNA cargo by endocytosis, 2) humans absorb biologically effective amounts of milk and egg microRNAs, 3) dietary microRNAs are delivered to peripheral tissues where they affect human gene expression, 4) endogenous synthesis of microRNAs does not compensate for dietary microRNA depletion, and 5) dietary microRNA depletion elicits phenotypes such as low fecundity, increased purine metabolism, and low body fat mass in mice. These studies of the phenotypes of dietary microRNA status are an important milestone guiding our ongoing studies of the mechanisms that elicit these phenotypes. OUTCOMES: We have discovered a novel class of bioactive compounds in foods, i.e., microRNAs. This research has major implications for the U.S. dairy and egg industry, and the way we assess the nutritional value of foods. Ohio State University (Richard Bruno). ?-Tocopherol (?-T) protects against nonalcoholic steatohepatitis (NASH), but its dietary intakes are poor with >22% of Americans having suboptimal ?-T status. We therefore tested the hypothesis that MetS adults, a population at high risk for NASH, would have lower ?-T bioavailability that could be improved by fat-containing dairy milk. A randomized, crossover, double-blind study was conducted in healthy and MetS adults (n = 10/group) who ingested encapsulated deuterium-labeled (d6)-RRR-?-T (15 mg) with 240 mL of non-fat (0.2 g fat), reduced-fat (4.8 g fat), or whole (7.9 g fat) milk prior to blood collection at regular intervals for 72 h. Compared to healthy participants, those with MetS had lower (P<0.05) baseline plasma ?-T (?mol/mmol lipid) and greater oxidized LDL (oxLDL), IL-6, IL-10, and C-reactive protein (CRP). Regardless of health status, d6-?-T bioavailability was unaffected by increasing amounts of dairy fat provided by milk beverages, but MetS participants had lower estimated d6-?-T absorption compared with healthy participants. They also had lower plasma d6-?-T AUC0-72 h and maximal concentrations (Cmax), and slower rates of plasma disappearance, but similar times to Cmax. MetS participants had lower d6-?-T AUC0-t final in lipoprotein fractions (chylomicron, VLDL, LDL, HDL), and %d6-?-T AUC0-t final in both the chylomicron and VLDL fractions were inversely correlated with oxLDL, IL-10, IL-6, and CRP. At dietary intakes equivalent to the Recommended Daily Allowance, ?-T bioavailability is unaffected by dairy fat quantity, but is lower in MetS adults, likely due to greater inflammation and oxidative stress that limits small intestinal ?-T absorption and/or impairs hepatic ?-T trafficking. These findings support higher dietary ?-T requirements for MetS adults. Oklahoma State University (Barbara Stoecker). Our laboratory focuses on the effects of micronutrient deficiencies on human health. We have investigated the effects of zinc supplementation in women in the context of the high prevalence of dietary zinc deficiency in Ethiopia. Data obtained from one trial included information on increased DNA breaks in women not supplemented with Zn compared to women who received the supplement. In another trial, zinc supplementation decreased abundance of mRNA for ZIP4 and ZIP8 in peripheral blood mononuclear cells of adult women. We have provided serum samples from women with very limited zinc intakes to colleagues in the W3002 multistate project to support metabolomics studies related to the roles of zinc in human health. We also are conducting a randomized control trial of vitamin D supplementation of lactating women in rural Ethiopia. Skin color is being measured as well as UVB light exposure. Both breast milk and blood samples have been collected. Dietary analysis indicates a very low intake of vitamin D. The vitamin D status biomarker in serum, 25(OH) vitamin D, and vitamin D in breast milk are being measured. Morbidity and motor milestones of infants are being measured from birth throughout their first year of life. Field work for this study will be completed in early 2016. Oklahoma State University (Edralin Lucas). The focus of our research group is examining the role of food and their bioactive components in alleviating chronic conditions such as diabetes, obesity, and osteoporosis. For this reporting period, we investigated the effects of 3-month dietary supplementation of freeze-dried mango on glucose parameters, and inflammatory markers of pre-diabetic individuals. Our findings indicate that chronic consumption of freeze-dried mango by pre-diabetic individuals does not negatively affect blood glucose and inflammatory markers. We also investigated the effects of freeze-dried mango on gut microbiome in mice fed high fat diet. Mango supplementation prevented the loss of Bifidobacteria and Akkermansia due to high fat feeding. Mango exerts this effect in a dose-dependent manner and is statistically similar to mice fed normal diet. Oregon State University (Emily Ho). Zinc and chronic disease: Recently we have found that zinc status is compromised with age. Zinc deficiency causes immune cells to be sensitized to inflammation and also occurs in older animals and humans. Plant-derived phytochemicals and cancer: We have found that sulforaphane, a chemical found in cruciferous vegetables inhibits histone deacetylases, decreases DNA methyl transferase expression, alters histone methylation, lincRNA expression and has anti-cancer properties in the prostate. Bioavailability is decreased in supplemental forms of SFN compared to the whole food. Supplemental SFN did show benefits in decreasing cell proliferation markers and histone deacetylase 3 expression in breast tissue in women previously diagnosed with breast cancer. GOALS: I) Test the effects of zinc status on the gut microbiota, epigenetics, oxidative stress, inflammation, DNA damage and cancer susceptibility in rodent models and humans. II) Understand the determinants of bioavailability of phytochemicals derived from cruciferous vegetables. III) Test the ability of sulforaphane supplementation from various sources (supplement vs whole food) to reduce the incidence of prostate and breast cancer via epigenetic modifications. Oregon State University (Norman Hord). This report summarizes progress to address potential health benefits of plant food-derived dietary nitrate. Since nitrate and nitrite have been associated with risk of methemoglobinemia in newborns and gastrointestinal cancer risk in adults when consumed in processed meats, nitrate concentrations in drinking water are regulated by the U.S. EPA. With regard to dietary nitrate intake, vegetable and fruit intake constitute the source of 80% of nitrate in the diet and these food groups are positively associated in epidemiologic studies with decreased risk of cardiovascular disease and low bone mass. Our projects work across the spectrum from food-based analysis to zebrafish and rodent model systems to assess dietary exposures, potential toxicities and potential health benefits, respectively. Each represents preliminary data being prepared for publication. Project 1: We have assessed nitrate and nitrite concentrations using foods and mixed dishes representing one day of intakes from traditional food patterns, rather than using limited food database information available, from a variety of cultural patterns in order to estimate actual intake levels. Outcome 1: Our data indicate that these cultural patterns contained diverse nitrate concentrations (range ~350 to 100 mg/day nitrate), represented as a rank order in nitrate concentration from one day food intake patterns as follows: Mediterranean>Chinese>Japanese>American=Indian. This rank order is consistent with the hypothesis that nitrate intakes may form an inverse ecological association with cardiovascular disease rates in these countries; in clinical studies, the highest concentrations measured in these dietary patterns have been demonstrated to produce cardioprotective benefits. Project 2: We have interrogated the effect of dietary nitrate in pilot studies in rodents to determine whether it reduces ovariectomy-induced bone loss in female rats or improves glucose tolerance in male mice fed a Western-type dietary pattern. Outcome 2: In both of these rodent studies, we found that dietary nitrate does not reduce bone loss or improve glucose tolerance in the rodent models examined. Project 3: The objective of this project funded by the OSU Environmental Health Sciences Center, was to identify a potential role for dietary nitrate-derived NO in fetal cardiovascular development and to investigate whether supplementation with dietary nitrate (10, 50, 100, 250, 500, and 1000 µM/L) prevents or reduces occurrence of congenital cardiovascular defects (CCVD) in zebrafish embryos. These concentrations are selected on the basis of published literature on plasma nitrate levels in normal and pregnant conditions, as well as on the basis of estimates of per capita daily dietary nitrate intake for the average US population (75 mg, ? 1 mM). Outcome 3: Our data indicate that only dietary nitrate concentrations of 1000 µM/L were associated with occurrence of CCVD. These data indicate minimal risk of CCVD due to dietary nitrate concentrations typically consumed in U.S. populations. Purdue University (Connie Weaver). Prebiotics enhanced mineral absorption in animal models and humans and bone parameters in animal models. We extended our studies on the effect of soluble corn fiber (SCF) on enhancing calcium absorption in adolescents to study the effect on bone calcium retention in postmenopausal women. We used our novel approach of urinary excretion of the rare isotope, 41Ca, from pre-labeled bone to test the dose responsive effect of feeding 0, 10 and 20 g SCF/d. SCF increased (p<0.01) bone calcium retention in a dose responsive manner.

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